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1
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Guo Y, Wu H, Wiesmüller L, Chen M. Canonical and non-canonical functions of p53 isoforms: potentiating the complexity of tumor development and therapy resistance. Cell Death Dis 2024; 15:412. [PMID: 38866752 PMCID: PMC11169513 DOI: 10.1038/s41419-024-06783-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 05/26/2024] [Accepted: 05/28/2024] [Indexed: 06/14/2024]
Abstract
Full-length p53 (p53α) plays a pivotal role in maintaining genomic integrity and preventing tumor development. Over the years, p53 was found to exist in various isoforms, which are generated through alternative splicing, alternative initiation of translation, and internal ribosome entry site. p53 isoforms, either C-terminally altered or N-terminally truncated, exhibit distinct biological roles compared to p53α, and have significant implications for tumor development and therapy resistance. Due to a lack of part and/or complete C- or N-terminal domains, ectopic expression of some p53 isoforms failed to induce expression of canonical transcriptional targets of p53α like CDKN1A or MDM2, even though they may bind their promoters. Yet, p53 isoforms like Δ40p53α still activate subsets of targets including MDM2 and BAX. Furthermore, certain p53 isoforms transactivate even novel targets compared to p53α. More recently, non-canonical functions of p53α in DNA repair and of different isoforms in DNA replication unrelated to transcriptional activities were discovered, amplifying the potential of p53 as a master regulator of physiological and tumor suppressor functions in human cells. Both regarding canonical and non-canonical functions, alternative p53 isoforms frequently exert dominant negative effects on p53α and its partners, which is modified by the relative isoform levels. Underlying mechanisms include hetero-oligomerization, changes in subcellular localization, and aggregation. These processes ultimately influence the net activities of p53α and give rise to diverse cellular outcomes. Biological roles of p53 isoforms have implications for tumor development and cancer therapy resistance. Dysregulated expression of isoforms has been observed in various cancer types and is associated with different clinical outcomes. In conclusion, p53 isoforms have expanded our understanding of the complex regulatory network involving p53 in tumors. Unraveling the mechanisms underlying the biological roles of p53 isoforms provides new avenues for studies aiming at a better understanding of tumor development and developing therapeutic interventions to overcome resistance.
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Affiliation(s)
- Yitian Guo
- Department of Urology, Zhongda Hospital Southeast University, Nanjing, China.
| | - Hang Wu
- Department of Rehabilitation Medicine, Zhongda Hospital Southeast University, Nanjing, China
| | - Lisa Wiesmüller
- Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany
| | - Ming Chen
- Department of Urology, Zhongda Hospital Southeast University, Nanjing, China.
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2
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Ray Das S, Delahunt B, Lasham A, Li K, Wright D, Print C, Slatter T, Braithwaite A, Mehta S. Combining TP53 mutation and isoform has the potential to improve clinical practice. Pathology 2024; 56:473-483. [PMID: 38594116 DOI: 10.1016/j.pathol.2024.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 01/21/2024] [Accepted: 02/06/2024] [Indexed: 04/11/2024]
Abstract
The clinical importance of assessing and combining data on TP53 mutations and isoforms is discussed in this article. It gives a succinct overview of the structural makeup and key biological roles of the isoforms. It then provides a comprehensive summary of the roles that p53 isoforms play in cancer development, therapy response and resistance. The review provides a summary of studies demonstrating the role of p53 isoforms as potential prognostic indicators. It further provides evidence on how the presence of TP53 mutations may affect one or more of these activities and the association of p53 isoforms with clinicopathological data in various tumour types. The review gives insight into the present diagnostic hurdles for identifying TP53 isoforms and makes recommendations to improve their evaluation. In conclusion, this review offers suggestions for enhancing the identification and integration of TP53 isoforms in conjunction with mutation data within the clinical context.
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Affiliation(s)
- Sankalita Ray Das
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Brett Delahunt
- Pathology and Molecular Medicine, University of Otago, Wellington, New Zealand
| | - Annette Lasham
- Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre for Biodiscovery, University of Auckland, Auckland, New Zealand; Te Aka Mātauranga Matepukupuku (Centre for Cancer Research), University of Auckland, Auckland, New Zealand
| | - Kunyu Li
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Biodiscovery, University of Auckland, Auckland, New Zealand
| | - Deborah Wright
- Department of Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Cristin Print
- Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre for Biodiscovery, University of Auckland, Auckland, New Zealand; Te Aka Mātauranga Matepukupuku (Centre for Cancer Research), University of Auckland, Auckland, New Zealand
| | - Tania Slatter
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Biodiscovery, University of Auckland, Auckland, New Zealand
| | - Antony Braithwaite
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Biodiscovery, University of Auckland, Auckland, New Zealand
| | - Sunali Mehta
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Biodiscovery, University of Auckland, Auckland, New Zealand.
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3
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Czekay RP, Higgins CE, Aydin HB, Samarakoon R, Subasi NB, Higgins SP, Lee H, Higgins PJ. SERPINE1: Role in Cholangiocarcinoma Progression and a Therapeutic Target in the Desmoplastic Microenvironment. Cells 2024; 13:796. [PMID: 38786020 PMCID: PMC11119900 DOI: 10.3390/cells13100796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 05/03/2024] [Accepted: 05/03/2024] [Indexed: 05/25/2024] Open
Abstract
A heterogenous population of inflammatory elements, other immune and nonimmune cells and cancer-associated fibroblasts (CAFs) are evident in solid malignancies where they coexist with the growing tumor mass. In highly desmoplastic malignancies, CAFs are the prominent mesenchymal cell type in the tumor microenvironment (TME), where their presence and abundance signal a poor prognosis. CAFs play a major role in the progression of various cancers by remodeling the supporting stroma into a dense, fibrotic matrix while secreting factors that promote the maintenance of cancer stem-like characteristics, tumor cell survival, aggressive growth and metastasis and reduced sensitivity to chemotherapeutics. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Identifying the molecular underpinnings for such multidirectional crosstalk among the various normal and neoplastic cell types in the TME may provide new targets and novel opportunities for therapeutic intervention. This review highlights recent concepts regarding the complexity of CAF biology in cholangiocarcinoma, a highly desmoplastic cancer. The discussion focuses on CAF heterogeneity, functionality in drug resistance, contributions to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes.
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Affiliation(s)
- Ralf-Peter Czekay
- Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA; (R.-P.C.); (C.E.H.); (R.S.); (S.P.H.)
| | - Craig E. Higgins
- Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA; (R.-P.C.); (C.E.H.); (R.S.); (S.P.H.)
| | - Hasan Basri Aydin
- Department of Pathology & Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA; (H.B.A.); (N.B.S.); (H.L.)
| | - Rohan Samarakoon
- Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA; (R.-P.C.); (C.E.H.); (R.S.); (S.P.H.)
| | - Nusret Bekir Subasi
- Department of Pathology & Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA; (H.B.A.); (N.B.S.); (H.L.)
| | - Stephen P. Higgins
- Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA; (R.-P.C.); (C.E.H.); (R.S.); (S.P.H.)
| | - Hwajeong Lee
- Department of Pathology & Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA; (H.B.A.); (N.B.S.); (H.L.)
| | - Paul J. Higgins
- Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA; (R.-P.C.); (C.E.H.); (R.S.); (S.P.H.)
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4
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Steffens Reinhardt L, Groen K, Zhang X, Morten BC, Wawruszak A, Avery-Kiejda KA. p53 isoform expression promotes a stemness phenotype and inhibits doxorubicin sensitivity in breast cancer. Cell Death Dis 2023; 14:509. [PMID: 37553320 PMCID: PMC10409720 DOI: 10.1038/s41419-023-06031-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 07/19/2023] [Accepted: 07/31/2023] [Indexed: 08/10/2023]
Abstract
In breast cancer, dysregulated TP53 expression signatures are a better predictor of chemotherapy response and survival outcomes than TP53 mutations. Our previous studies have shown that high levels of Δ40p53 are associated with worse disease-free survival and disruption of p53-induced DNA damage response in breast cancers. Here, we further investigated the in vitro and in vivo implications of Δ40p53 expression in breast cancer. We have shown that genes associated with cell differentiation are downregulated while those associated with stem cell regulation are upregulated in invasive ductal carcinomas expressing high levels of Δ40p53. In contrast to p53, endogenous ∆40p53 co-localised with the stem cell markers Sox2, Oct4, and Nanog in MCF-7 and ZR75-1 cell lines. ∆40p53 and Sox2 co-localisation was also detected in breast cancer specimens. Further, in cells expressing a high ∆40p53:p53 ratio, increased expression of stem cell markers, greater mammosphere and colony formation capacities, and downregulation of miR-145 and miR-200 (p53-target microRNAs that repress stemness) were observed compared to the control subline. In vivo, a high ∆40p53:p53 ratio led to increased tumour growth, Ki67 and Sox2 expression, and blood microvessel areas in the vehicle-treated mice. High expression of ∆40p53 also reduced tumour sensitivity to doxorubicin compared to control tumours. Enhanced therapeutic efficacy of doxorubicin was observed when transiently targeting Δ40p53 or when treating cells with OTSSP167 with concomitant chemotherapy. Taken together, high Δ40p53 levels induce tumour growth and may promote chemoresistance by inducing a stemness phenotype in breast cancer; thus, targeting Δ40p53 in tumours that have a high Δ40p53:p53 ratio could enhance the efficacy of standard-of-care therapies such as doxorubicin.
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Affiliation(s)
- Luiza Steffens Reinhardt
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW, Australia
- Hunter Medical Research Institute, New Lambton, NSW, Australia
- Cancer Detection & Therapy Research Program, Hunter Medical Research Institute, New Lambton, NSW, Australia
| | - Kira Groen
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW, Australia
- Hunter Medical Research Institute, New Lambton, NSW, Australia
| | - Xiajie Zhang
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW, Australia
- Hunter Medical Research Institute, New Lambton, NSW, Australia
- Cancer Detection & Therapy Research Program, Hunter Medical Research Institute, New Lambton, NSW, Australia
| | - Brianna C Morten
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW, Australia
- Hunter Medical Research Institute, New Lambton, NSW, Australia
| | - Anna Wawruszak
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW, Australia
- Hunter Medical Research Institute, New Lambton, NSW, Australia
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland
| | - Kelly A Avery-Kiejda
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW, Australia.
- Hunter Medical Research Institute, New Lambton, NSW, Australia.
- Cancer Detection & Therapy Research Program, Hunter Medical Research Institute, New Lambton, NSW, Australia.
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5
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Steffens Reinhardt L, Groen K, Newton C, Avery-Kiejda KA. The role of truncated p53 isoforms in the DNA damage response. Biochim Biophys Acta Rev Cancer 2023; 1878:188882. [PMID: 36977456 DOI: 10.1016/j.bbcan.2023.188882] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 02/23/2023] [Accepted: 02/25/2023] [Indexed: 03/28/2023]
Abstract
The tumour suppressor p53 is activated following genotoxic stress and regulates the expression of target genes involved in the DNA damage response (DDR). The discovery that p53 isoforms alter the transcription of p53 target genes or p53 protein interactions unveiled an alternative DDR. This review will focus on the role p53 isoforms play in response to DNA damage. The expression of the C-terminally truncated p53 isoforms may be modulated via DNA damage-induced alternative splicing, whereas alternative translation plays an important role in modulating the expression of N-terminally truncated isoforms. The DDR induced by p53 isoforms may enhance the canonical p53 DDR or block cell death mechanisms in a DNA damage- and cell-specific manner, which could contribute to chemoresistance in a cancer context. Thus, a better understanding of the involvement of p53 isoforms in the cell fate decisions could uncover potential therapeutic targets in cancer and other diseases.
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Affiliation(s)
- Luiza Steffens Reinhardt
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia
| | - Kira Groen
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia
| | - Cheryl Newton
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia
| | - Kelly A Avery-Kiejda
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia.
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6
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Vlašić I, Horvat A, Tadijan A, Slade N. p53 Family in Resistance to Targeted Therapy of Melanoma. Int J Mol Sci 2022; 24:ijms24010065. [PMID: 36613518 PMCID: PMC9820688 DOI: 10.3390/ijms24010065] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
Metastatic melanoma is one of the most aggressive tumors, with frequent mutations affecting components of the MAPK pathway, mainly protein kinase BRAF. Despite promising initial response to BRAF inhibitors, melanoma progresses due to development of resistance. In addition to frequent reactivation of MAPK or activation of PI3K/AKT signaling pathways, recently, the p53 pathway has been shown to contribute to acquired resistance to targeted MAPK inhibitor therapy. Canonical tumor suppressor p53 is inactivated in melanoma by diverse mechanisms. The TP53 gene and two other family members, TP63 and TP73, encode numerous protein isoforms that exhibit diverse functions during tumorigenesis. The p53 family isoforms can be produced by usage of alternative promoters and/or splicing on the C- and N-terminus. Various p53 family isoforms are expressed in melanoma cell lines and tumor samples, and several of them have already shown to have specific functions in melanoma, affecting proliferation, survival, metastatic potential, invasion, migration, and response to therapy. Of special interest are p53 family isoforms with increased expression and direct involvement in acquired resistance to MAPK inhibitors in melanoma cells, implying that modulating their expression or targeting their functional pathways could be a potential therapeutic strategy to overcome resistance to MAPK inhibitors in melanoma.
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7
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p53 Isoforms as Cancer Biomarkers and Therapeutic Targets. Cancers (Basel) 2022; 14:cancers14133145. [PMID: 35804915 PMCID: PMC9264937 DOI: 10.3390/cancers14133145] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 06/22/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary The well-known tumor suppressor protein p53 plays important roles in tumor prevention through transcriptional regulation of its target genes. Reactivation of p53 activity has been a potent strategy for cancer treatment. Accumulating evidences indicate that p53 isoforms truncated/modified in the N- or C-terminus can modulate the p53 pathway in a p53-dependent or p53-independent manner. It is thus imperative to characterize the roles of the p53 isoforms in cancer development. This review illustrates how p53 isoforms participate in tumor development and/or suppression. It also summarizes the knowledge about the p53 isoforms as promising cancer biomarkers and therapeutic targets. Abstract This review aims to summarize the implications of the major isoforms of the tumor suppressor protein p53 in aggressive cancer development. The current knowledge of p53 isoforms, their involvement in cell-signaling pathways, and their interactions with other cellular proteins or factors suggests the existence of an intricate molecular network that regulates their oncogenic function. Moreover, existing literature about the involvement of the p53 isoforms in various cancers leads to the proposition of therapeutic solutions by altering the cellular levels of the p53 isoforms. This review thus summarizes how the major p53 isoforms Δ40p53α/β/γ, Δ133p53α/β/γ, and Δ160p53α/β/γ might have clinical relevance in the diagnosis and effective treatments of cancer.
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8
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Antonio-Véjar V, Ortiz-Sánchez E, Rosendo-Chalma P, Patiño-Morales CC, Guido-Jiménez MC, Alvarado-Ortiz E, Hernández G, García-Carrancá A. New insights into the interactions of HPV-16 E6*I and E6*II with p53 isoforms and induction of apoptosis in cancer-derived cell lines. Pathol Res Pract 2022; 234:153890. [PMID: 35487028 DOI: 10.1016/j.prp.2022.153890] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 04/04/2022] [Accepted: 04/06/2022] [Indexed: 02/07/2023]
Abstract
An important characteristic of cancers associated with high-risk human papillomaviruses (HR-HPV) is the inability of p53 to activate apoptosis due to the effect of the oncoprotein E6. However, the effect of HPV-16 E6 splice variant isoforms (namely E6*I and E6*II), their interaction with the existing p53 isoforms, and their influence on apoptosis is unclear. Here, we report the outcome of ectopic expression of HPV-16 E6, E6*I, and E6*II on the relative levels of p53 and p53 isoforms Δ40p53 and Δ133p53 and their interactions with these proteins. Additionally, we evaluated the effect of ectopic expression of p53, Δ40p53, and Δ133p53 on apoptosis in a p53 null pulmonary cell line (H1299) co-transfected with E6 isoforms and p53+/+ cell lines with HR-HPV (SiHa and HeLa), transfected with p53 isoforms and treated with cisplatin, a conventional drug used to treat cervical cancer. Our results show that E6 and E6*II induced a significant decrease in p53, but only E6 triggered a Δ40p53 decrease and that E6*II interacts with p53 but not with Δ40p53 and Δ133p53. On the other hand, E6*I did not show any effect or interaction with the p53 isoforms. We found that apoptosis was elevated in H1299 cells transfected with p53 (p = 0.0001) and Δ40p53 (p = 0.0001). A weak apoptotic effect was observed when Δ133p53 was ectopically expressed (p = 0.0195). We observed that both p53 (p = 0.0006) and Δ40p53 (p = 0.0014) induced apoptosis in cisplatin-treated SiHa cells; however in cisplatin-treated HeLa cells, only p53 induced apoptosis (p = 0.0029). No significant differences in apoptosis were observed upon ectopic expression of p53, Δ40p53, and Δ133p53 in SiHa and HeLa cells. Our findings suggest a possible therapeutic application for the combining of p53 or Δ40p53 with cisplatin to induce an increased apoptosis of cancer cells expressing E6 isoforms from HPV-16.
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Affiliation(s)
- Verónica Antonio-Véjar
- Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, 10450, Mexico; Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, 39090, Guerrero, Mexico; Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cancerología, Ciudad de México, 14080, Mexico.
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México, 14080, Mexico.
| | - Pedro Rosendo-Chalma
- Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, 10450, Mexico; Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cancerología, Ciudad de México, 14080, Mexico.
| | - Carlos C Patiño-Morales
- Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cancerología, Ciudad de México, 14080, Mexico.
| | - Miriam C Guido-Jiménez
- Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cancerología, Ciudad de México, 14080, Mexico.
| | - Eduardo Alvarado-Ortiz
- Programa de Posgrado en Ciencias Biológicas. Universidad Nacional Autónoma de México (UNAM), Ciudad de México, 04510, Mexico; Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cancerología, Ciudad de México, 14080, Mexico.
| | - Greco Hernández
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México, 14080, Mexico.
| | - Alejandro García-Carrancá
- Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cancerología, Ciudad de México, 14080, Mexico.
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9
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Rojas EA, Corchete LA, De Ramón C, Krzeminski P, Quwaider D, García‐Sanz R, Martínez‐López J, Oriol A, Rosiñol L, Bladé J, Lahuerta JJ, San Miguel JF, González M, Mateos MV, Bourdon J, Misiewicz‐Krzeminska I, Gutiérrez NC. Expression of p53 protein isoforms predicts survival in patients with multiple myeloma. Am J Hematol 2022; 97:700-710. [PMID: 35188691 PMCID: PMC9313569 DOI: 10.1002/ajh.26507] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 01/21/2022] [Accepted: 02/15/2022] [Indexed: 12/20/2022]
Abstract
Loss and/or mutation of the TP53 gene are associated with short survival in multiple myeloma, but the p53 landscape goes far beyond. At least 12 p53 protein isoforms have been identified as a result of a combination of alternative splicing, alternative promoters and/or alternative transcription site starts, which are grouped as α, β, γ, from transactivation domain (TA), long, and short isoforms. Nowadays, there are no studies evaluating the expression of p53 isoforms and its clinical relevance in multiple myeloma (MM). We used capillary nanoimmunoassay to quantify the expression of p53 protein isoforms in CD138-purified samples from 156 patients with newly diagnosed MM who were treated as part of the PETHEMA/GEM2012 clinical trial and investigated their prognostic impact. Quantitative real-time polymerase chain reaction was used to corroborate the results at RNA levels. Low and high levels of expression of short and TAp53β/γ isoforms, respectively, were associated with adverse prognosis in MM patients. Multivariate Cox models identified high levels of TAp53β/γ (hazard ratio [HR], 4.49; p < .001) and high-risk cytogenetics (HR, 2.69; p < .001) as independent prognostic factors associated with shorter time to progression. The current cytogenetic-risk classification was notably improved when expression levels of p53 protein isoforms were incorporated, whereby high-risk MM expressing high levels of short isoforms had significantly longer survival than high-risk patients with low levels of these isoforms. This is the first study that demonstrates the prognostic value of p53 isoforms in MM patients, providing new insights on the role of p53 protein dysregulation in MM biology.
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Affiliation(s)
- Elizabeta A. Rojas
- Hematology Department University Hospital of Salamanca, IBSAL Salamanca Spain
- Cancer Research Center‐IBMCC (USAL‐CSIC) Salamanca Spain
| | - Luis A. Corchete
- Hematology Department University Hospital of Salamanca, IBSAL Salamanca Spain
- Cancer Research Center‐IBMCC (USAL‐CSIC) Salamanca Spain
| | - Cristina De Ramón
- Hematology Department University Hospital of Salamanca, IBSAL Salamanca Spain
| | - Patryk Krzeminski
- Hematology Department University Hospital of Salamanca, IBSAL Salamanca Spain
- Cancer Research Center‐IBMCC (USAL‐CSIC) Salamanca Spain
- Department of Nanobiotechnology and Experimental Ecology, Institute of Biology Warsaw University of Life Sciences Warsaw Poland
| | - Dalia Quwaider
- Hematology Department University Hospital of Salamanca, IBSAL Salamanca Spain
- Cancer Research Center‐IBMCC (USAL‐CSIC) Salamanca Spain
| | - Ramón García‐Sanz
- Hematology Department University Hospital of Salamanca, IBSAL Salamanca Spain
- Cancer Research Center‐IBMCC (USAL‐CSIC) Salamanca Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), CB16/12/00233 Salamanca Spain
- Grupo Español de Mieloma (GEM) Barcelona Spain
| | - Joaquín Martínez‐López
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), CB16/12/00233 Salamanca Spain
- Grupo Español de Mieloma (GEM) Barcelona Spain
- Medicine Department Complutense University Madrid Spain
- Spanish National Cancer Research Center (CNIO) Madrid Spain
| | - Albert Oriol
- Grupo Español de Mieloma (GEM) Barcelona Spain
- University Hospital Germans Trias i Pujol Barcelona Spain
| | - Laura Rosiñol
- Grupo Español de Mieloma (GEM) Barcelona Spain
- Hospital Clinic of Barcelona Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS) Barcelona Spain
| | - Joan Bladé
- Grupo Español de Mieloma (GEM) Barcelona Spain
- Hospital Clinic of Barcelona Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS) Barcelona Spain
| | - Juan José Lahuerta
- Grupo Español de Mieloma (GEM) Barcelona Spain
- Hematology Department University Hospital 12 de Octubre Madrid Spain
| | - Jesús F. San Miguel
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), CB16/12/00233 Salamanca Spain
- Grupo Español de Mieloma (GEM) Barcelona Spain
- Clínica Universidad de Navarra, Centro de Investigaciones Médicas Aplicadas (CIMA) Instituto de Investigación Sanitaria de Navarra (IdiSNA) Pamplona Spain
| | - Marcos González
- Hematology Department University Hospital of Salamanca, IBSAL Salamanca Spain
- Cancer Research Center‐IBMCC (USAL‐CSIC) Salamanca Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), CB16/12/00233 Salamanca Spain
| | - María Victoria Mateos
- Hematology Department University Hospital of Salamanca, IBSAL Salamanca Spain
- Cancer Research Center‐IBMCC (USAL‐CSIC) Salamanca Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), CB16/12/00233 Salamanca Spain
- Grupo Español de Mieloma (GEM) Barcelona Spain
| | | | - Irena Misiewicz‐Krzeminska
- Hematology Department University Hospital of Salamanca, IBSAL Salamanca Spain
- Cancer Research Center‐IBMCC (USAL‐CSIC) Salamanca Spain
- Experimental Hematology Department Institute of Hematology and Transfusion Medicine Warsaw Poland
| | - Norma C. Gutiérrez
- Hematology Department University Hospital of Salamanca, IBSAL Salamanca Spain
- Cancer Research Center‐IBMCC (USAL‐CSIC) Salamanca Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), CB16/12/00233 Salamanca Spain
- Grupo Español de Mieloma (GEM) Barcelona Spain
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10
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Tadijan A, Precazzini F, Hanžić N, Radić M, Gavioli N, Vlašić I, Ozretić P, Pinto L, Škreblin L, Barban G, Slade N, Ciribilli Y. Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma Aggressiveness. Cancers (Basel) 2021; 13:5231. [PMID: 34680379 PMCID: PMC8533715 DOI: 10.3390/cancers13205231] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/07/2021] [Accepted: 10/11/2021] [Indexed: 02/05/2023] Open
Abstract
Cutaneous melanoma is the most aggressive form of skin cancer. Despite the significant advances in the management of melanoma in recent decades, it still represents a challenge for clinicians. The TP53 gene, the guardian of the genome, which is altered in more than 50% of human cancers, is rarely mutated in melanoma. More recently, researchers started to appreciate the importance of shorter p53 isoforms as potential modifiers of the p53-dependent responses. We analyzed the expression of p53 and p73 isoforms both at the RNA and protein level in a panel of melanoma-derived cell lines with different TP53 and BRAF status, in normal conditions or upon treatment with common anti-cancer DNA damaging agents or targeted therapy. Using lentiviral vectors, we also generated stable clones of H1299 p53 null cells over-expressing the less characterized isoforms Δ160p53α, Δ160p53β, and Δ160p53γ. Further, we obtained two melanoma-derived cell lines resistant to BRAF inhibitor vemurafenib. We observed that melanoma cell lines expressed a wide array of p53 and p73 isoforms, with Δ160p53α as the most variable one. We demonstrated for the first time that Δ160p53α, and to a lesser extent Δ160p53β, can be recruited on chromatin, and that Δ160p53γ can localize in perinuclear foci; moreover, all Δ160p53 isoforms can stimulate proliferation and in vitro migration. Lastly, vemurafenib-resistant melanoma cells showed an altered expression of p53 and p73 isoforms, namely an increased expression of potentially pro-oncogenic Δ40p53β and a decrease in tumor-suppressive TAp73β. We therefore propose that p53 family isoforms can play a role in melanoma cells' aggressiveness.
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Affiliation(s)
- Ana Tadijan
- Laboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (A.T.); (N.H.); (M.R.); (I.V.); (L.Š.)
| | - Francesca Precazzini
- Laboratory of Molecular Cancer Genetics, Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, 38123 Povo, TN, Italy; (F.P.); (N.G.); (L.P.); (G.B.)
- Laboratory of RNA Biology and Biotechnology, Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, 38123 Povo, TN, Italy
| | - Nikolina Hanžić
- Laboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (A.T.); (N.H.); (M.R.); (I.V.); (L.Š.)
| | - Martina Radić
- Laboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (A.T.); (N.H.); (M.R.); (I.V.); (L.Š.)
| | - Nicolò Gavioli
- Laboratory of Molecular Cancer Genetics, Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, 38123 Povo, TN, Italy; (F.P.); (N.G.); (L.P.); (G.B.)
| | - Ignacija Vlašić
- Laboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (A.T.); (N.H.); (M.R.); (I.V.); (L.Š.)
| | - Petar Ozretić
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia;
| | - Lia Pinto
- Laboratory of Molecular Cancer Genetics, Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, 38123 Povo, TN, Italy; (F.P.); (N.G.); (L.P.); (G.B.)
| | - Lidija Škreblin
- Laboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (A.T.); (N.H.); (M.R.); (I.V.); (L.Š.)
| | - Giulia Barban
- Laboratory of Molecular Cancer Genetics, Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, 38123 Povo, TN, Italy; (F.P.); (N.G.); (L.P.); (G.B.)
| | - Neda Slade
- Laboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (A.T.); (N.H.); (M.R.); (I.V.); (L.Š.)
| | - Yari Ciribilli
- Laboratory of Molecular Cancer Genetics, Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, 38123 Povo, TN, Italy; (F.P.); (N.G.); (L.P.); (G.B.)
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11
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Guo Y, Rall-Scharpf M, Bourdon JC, Wiesmüller L, Biber S. p53 isoforms differentially impact on the POLι dependent DNA damage tolerance pathway. Cell Death Dis 2021; 12:941. [PMID: 34645785 PMCID: PMC8514551 DOI: 10.1038/s41419-021-04224-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 09/17/2021] [Accepted: 09/27/2021] [Indexed: 12/22/2022]
Abstract
The recently discovered p53-dependent DNA damage tolerance (DDT) pathway relies on its biochemical activities in DNA-binding, oligomerization, as well as complex formation with the translesion synthesis (TLS) polymerase iota (POLι). These p53-POLι complexes slow down nascent DNA synthesis for safe, homology-directed bypass of DNA replication barriers. In this study, we demonstrate that the alternative p53-isoforms p53β, p53γ, Δ40p53α, Δ133p53α, and Δ160p53α differentially affect this p53-POLι-dependent DDT pathway originally described for canonical p53α. We show that the C-terminal isoforms p53β and p53γ, comprising a truncated oligomerization domain (OD), bind PCNA. Conversely, N-terminally truncated isoforms have a reduced capacity to engage in this interaction. Regardless of the specific loss of biochemical activities required for this DDT pathway, all alternative isoforms were impaired in promoting POLι recruitment to PCNA in the chromatin and in decelerating DNA replication under conditions of enforced replication stress after Mitomycin C (MMC) treatment. Consistent with this, all alternative p53-isoforms no longer stimulated recombination, i.e., bypass of endogenous replication barriers. Different from the other isoforms, Δ133p53α and Δ160p53α caused a severe DNA replication problem, namely fork stalling even in untreated cells. Co-expression of each alternative p53-isoform together with p53α exacerbated the DDT pathway defects, unveiling impaired POLι recruitment and replication deceleration already under unperturbed conditions. Such an inhibitory effect on p53α was particularly pronounced in cells co-expressing Δ133p53α or Δ160p53α. Notably, this effect became evident after the expression of the isoforms in tumor cells, as well as after the knockdown of endogenous isoforms in human hematopoietic stem and progenitor cells. In summary, mimicking the situation found to be associated with many cancer types and stem cells, i.e., co-expression of alternative p53-isoforms with p53α, carved out interference with p53α functions in the p53-POLι-dependent DDT pathway.
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Affiliation(s)
- Yitian Guo
- grid.6582.90000 0004 1936 9748Department of Obstetrics and Gynecology, Ulm University, Ulm, 89075 Germany
| | - Melanie Rall-Scharpf
- grid.6582.90000 0004 1936 9748Department of Obstetrics and Gynecology, Ulm University, Ulm, 89075 Germany
| | - Jean-Christophe Bourdon
- grid.8241.f0000 0004 0397 2876Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK
| | - Lisa Wiesmüller
- grid.6582.90000 0004 1936 9748Department of Obstetrics and Gynecology, Ulm University, Ulm, 89075 Germany
| | - Stephanie Biber
- grid.6582.90000 0004 1936 9748Department of Obstetrics and Gynecology, Ulm University, Ulm, 89075 Germany
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12
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Hernández Borrero LJ, El-Deiry WS. Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochim Biophys Acta Rev Cancer 2021; 1876:188556. [PMID: 33932560 PMCID: PMC8730328 DOI: 10.1016/j.bbcan.2021.188556] [Citation(s) in RCA: 311] [Impact Index Per Article: 77.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/13/2022]
Abstract
TP53 is the most commonly mutated gene in human cancer with over 100,000 literature citations in PubMed. This is a heavily studied pathway in cancer biology and oncology with a history that dates back to 1979 when p53 was discovered. The p53 pathway is a complex cellular stress response network with multiple diverse inputs and downstream outputs relevant to its role as a tumor suppressor pathway. While inroads have been made in understanding the biology and signaling in the p53 pathway, the p53 family, transcriptional readouts, and effects of an array of mutants, the pathway remains challenging in the realm of clinical translation. While the role of mutant p53 as a prognostic factor is recognized, the therapeutic modulation of its wild-type or mutant activities remain a work-in-progress. This review covers current knowledge about the biology, signaling mechanisms in the p53 pathway and summarizes advances in therapeutic development.
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Affiliation(s)
- Liz J Hernández Borrero
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI 02912, United States of America; Cancer Center at Brown University, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America
| | - Wafik S El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI 02912, United States of America; Cancer Center at Brown University, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America.
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13
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p53/p73 Protein Network in Colorectal Cancer and Other Human Malignancies. Cancers (Basel) 2021; 13:cancers13122885. [PMID: 34207603 PMCID: PMC8227208 DOI: 10.3390/cancers13122885] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary The p53 family of proteins comprises p53, p63, and p73, which share high structural and functional similarity. The two distinct promoters of each locus, the alternative splicing, and the alternative translation initiation sites enable the generation of numerous isoforms with different protein-interacting domains and distinct activities. The co-expressed p53/p73 isoforms have significant but distinct roles in carcinogenesis. Their activity is frequently impaired in human tumors including colorectal carcinoma due to dysregulated expression and a dominant-negative effect accomplished by some isoforms and p53 mutants. The interactions between isoforms are particularly important to understand the onset of tumor formation, progression, and therapeutic response. The understanding of the p53/p73 network can contribute to the development of new targeted therapies. Abstract The p53 tumor suppressor protein is crucial for cell growth control and the maintenance of genomic stability. Later discovered, p63 and p73 share structural and functional similarity with p53. To understand the p53 pathways more profoundly, all family members should be considered. Each family member possesses two promoters and alternative translation initiation sites, and they undergo alternative splicing, generating multiple isoforms. The resulting isoforms have important roles in carcinogenesis, while their expression is dysregulated in several human tumors including colorectal carcinoma, which makes them potential targets in cancer treatment. Their activities arise, at least in part, from the ability to form tetramers that bind to specific DNA sequences and activate the transcription of target genes. In this review, we summarize the current understanding of the biological activities and regulation of the p53/p73 isoforms, highlighting their role in colorectal tumorigenesis. The analysis of the expression patterns of the p53/p73 isoforms in human cancers provides an important step in the improvement of cancer therapy. Furthermore, the interactions among the p53 family members which could modulate normal functions of the canonical p53 in tumor tissue are described. Lastly, we emphasize the importance of clinical studies to assess the significance of combining the deregulation of different members of the p53 family to define the outcome of the disease.
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14
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Niu G, Hellmuth I, Flisikowska T, Pausch H, Rieblinger B, Carrapeiro A, Schade B, Böhm B, Kappe E, Fischer K, Klinger B, Steiger K, Burgkart R, Bourdon JC, Saur D, Kind A, Schnieke A, Flisikowski K. Porcine model elucidates function of p53 isoform in carcinogenesis and reveals novel circTP53 RNA. Oncogene 2021; 40:1896-1908. [PMID: 33603167 PMCID: PMC7946636 DOI: 10.1038/s41388-021-01686-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 01/19/2021] [Accepted: 01/27/2021] [Indexed: 01/31/2023]
Abstract
Recent years have seen an increasing number of genetically engineered pig models of human diseases including cancer. We previously generated pigs with a modified TP53 allele that carries a Cre-removable transcriptional stop signal in intron 1, and an oncogenic mutation TP53R167H (orthologous to human TP53R175H) in exon 5. Pigs with the unrecombined mutant allele (flTP53R167H) develop mainly osteosarcoma but also nephroblastomas and lymphomas. This observation suggested that TP53 gene dysfunction is itself the key initiator of bone tumorigenesis, but raises the question which aspects of the TP53 regulation lead to the development of such a narrow tumour spectrum. Molecular analysis of p53 revealed the presence of two internal TP53 promoters (Pint and P2) equivalent to those found in human. Consequently, both pig and human express TP53 isoforms. Data presented here strongly suggest that P2-driven expression of the mutant R167H-Δ152p53 isoform (equivalent to the human R175H-Δ160p53 isoform) and its circular counterpart circTP53 determine the tumour spectrum and play a critical role in the malignant transformation in flTP53R167H pigs. The detection of Δ152p53 isoform mRNA in serum is indicative of tumorigenesis. Furthermore, we showed a tissue-specific p53-dependent deregulation of the p63 and p73 isoforms in these tumours. This study highlights important species-specific differences in the transcriptional regulation of TP53. Considering the similarities of TP53 regulation between pig and human, these observations provide useful pointers for further investigation into isoform function including the novel circTP53 in both the pig model and human patients.
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Affiliation(s)
- Guanglin Niu
- Chair of Livestock Biotechnology, Technische Universität München, Munich, Germany
| | - Isabel Hellmuth
- Chair of Livestock Biotechnology, Technische Universität München, Munich, Germany
| | - Tatiana Flisikowska
- Chair of Livestock Biotechnology, Technische Universität München, Munich, Germany
| | | | - Beate Rieblinger
- Chair of Livestock Biotechnology, Technische Universität München, Munich, Germany
| | - Alexander Carrapeiro
- Chair of Livestock Biotechnology, Technische Universität München, Munich, Germany
| | - Benjamin Schade
- Department of Pathology, Bavarian Animal Health Service, Poing, Germany
| | - Brigitte Böhm
- Department of Pathology, Bavarian Animal Health Service, Poing, Germany
| | - Eva Kappe
- Department of Pathology, Bavarian Animal Health Service, Poing, Germany
| | - Konrad Fischer
- Chair of Livestock Biotechnology, Technische Universität München, Munich, Germany
| | - Bernhard Klinger
- Chair of Livestock Biotechnology, Technische Universität München, Munich, Germany
| | - Katja Steiger
- School of Medicine, Institute of Pathology, Technische Universität München, Munich, Germany
| | - Reiner Burgkart
- Klinik und Poliklinik für Orthopädie und Sportorthopädie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | | | - Dieter Saur
- Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Alexander Kind
- Chair of Livestock Biotechnology, Technische Universität München, Munich, Germany
| | - Angelika Schnieke
- Chair of Livestock Biotechnology, Technische Universität München, Munich, Germany
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15
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The Δ133p53 Isoforms, Tuners of the p53 Pathway. Cancers (Basel) 2020; 12:cancers12113422. [PMID: 33218139 PMCID: PMC7698932 DOI: 10.3390/cancers12113422] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 11/12/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary TP53, the most frequently mutated gene in human cancers, has a key role in the maintenance of the genetic stability and, thus, in preventing tumor development. The p53-dependent responses were long thought to be solely driven by canonical p53α. However, it is now known that TP53 physiologically expresses at least 12 p53 isoforms including Δ133p53α, Δ133p53β and Δ133p53γ. The Δ133p53 isoforms are potent modulators of the p53 pathway that regulate critical functions in cancer, physiological and premature aging, neurodegenerative diseases, immunity and inflammation, and tissue repair. This review aims to summarize the current knowledge on the Δ133p53 isoforms and how they contribute to multiple physiological and pathological mechanisms. Critically, further characterization of p53 isoforms may identify novel regulatory modes of p53 pathway functions that contribute to disease progression and facilitate the development of new therapeutic strategies. Abstract The TP53 gene is a critical tumor suppressor and key determinant of cell fate which regulates numerous cellular functions including DNA repair, cell cycle arrest, cellular senescence, apoptosis, autophagy and metabolism. In the last 15 years, the p53 pathway has grown in complexity through the discovery that TP53 differentially expresses twelve p53 protein isoforms in human cells with both overlapping and unique biologic activities. Here, we summarize the current knowledge on the Δ133p53 isoforms (Δ133p53α, Δ133p53β and Δ133p53γ), which are evolutionary derived and found only in human and higher order primates. All three isoforms lack both of the transactivation domains and the beginning of the DNA-binding domain. Despite the absence of these canonical domains, the Δ133p53 isoforms maintain critical functions in cancer, physiological and premature aging, neurodegenerative diseases, immunity and inflammation, and tissue repair. The ability of the Δ133p53 isoforms to modulate the p53 pathway functions underscores the need to include these p53 isoforms in our understanding of how the p53 pathway contributes to multiple physiological and pathological mechanisms. Critically, further characterization of p53 isoforms may identify novel regulatory modes of p53 pathway functions that contribute to disease progression and facilitate the development of new therapeutic strategies.
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16
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Dhalla PS, Kaul A, Garcia J, Bapatla A, Khalid R, Armenta-Quiroga AS, Khan S. Comparing the Role of the p53 Gene and Telomerase Enzyme in 'Accelerated Aging Due to Cancer': A Literature Review. Cureus 2020; 12:e10794. [PMID: 33163298 PMCID: PMC7641464 DOI: 10.7759/cureus.10794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 10/04/2020] [Indexed: 11/05/2022] Open
Abstract
Aging is defined as progressive physiological alterations in an organism that lead to senescence. In response to stress, when proliferative-competent cells undergo permanent, irreversible growth arrest (like replicative dividing limit, oncogene activation, oxidative stress, or deoxyribonucleic acid (DNA) damage), it is termed as cellular senescence. Biomarkers p53, telomerase, and other inflammatory cytokines have a vital link with senescence, and directed use of these markers might be useful in manipulating cancer and the aging process. We included studies related to topics ' accelerated aging due to cancer', telomerase's relation to Aging and Cancer, p53's relation to Aging and Cancer, Atherosclerosis and Cancer from Search databases like PubMed and Google Scholar. We relied on peer-reviewed articles and included literature from the last 10 years written in the English language. Degenerative diseases in humans are usually linked to atherosclerosis, and atherosclerosis is associated with short leukocyte telomere length. Cancer itself and its treatment are linked with accelerated aging by causing progressive shortening of telomeres during cell replication, resulting in cell death. Gene p53 is known to have a dual effect that works as a tumor suppressor and has pro-aging side effects. In experimental studies, when p53 overcomes multiple regulatory mechanisms controlling its activity, then only the pro-aging side effects of p53 manifested. This might be a potential key for treating cancer without causing the side-effects of aging. In this review, we aim to explain and summarize the interdependent nature of p53, telomeres, and other conventional mechanisms of aging and cancer like inflammation, oxidative stress, uncontrolled proliferation, angiogenesis, micro ribonucleic acids (RNAs), and apoptosis, with a more synergistic approach that can help in developing new therapeutics and play a potential role in shaping modern human lifespan and revolutionize cancer treatment.
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Affiliation(s)
| | - Arunima Kaul
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Jian Garcia
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Anusha Bapatla
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Raheela Khalid
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ana S Armenta-Quiroga
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Safeera Khan
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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17
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Marin JJG, Serrano MA, Monte MJ, Sanchez-Martin A, Temprano AG, Briz O, Romero MR. Role of Genetic Variations in the Hepatic Handling of Drugs. Int J Mol Sci 2020; 21:E2884. [PMID: 32326111 PMCID: PMC7215464 DOI: 10.3390/ijms21082884] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 04/09/2020] [Accepted: 04/17/2020] [Indexed: 12/18/2022] Open
Abstract
The liver plays a pivotal role in drug handling due to its contribution to the processes of detoxification (phases 0 to 3). In addition, the liver is also an essential organ for the mechanism of action of many families of drugs, such as cholesterol-lowering, antidiabetic, antiviral, anticoagulant, and anticancer agents. Accordingly, the presence of genetic variants affecting a high number of genes expressed in hepatocytes has a critical clinical impact. The present review is not an exhaustive list but a general overview of the most relevant variants of genes involved in detoxification phases. The available information highlights the importance of defining the genomic profile responsible for the hepatic handling of drugs in many ways, such as (i) impaired uptake, (ii) enhanced export, (iii) altered metabolism due to decreased activation of prodrugs or enhanced inactivation of active compounds, and (iv) altered molecular targets located in the liver due to genetic changes or activation/downregulation of alternative/compensatory pathways. In conclusion, the advance in this field of modern pharmacology, which allows one to predict the outcome of the treatments and to develop more effective and selective agents able to overcome the lack of effect associated with the existence of some genetic variants, is required to step forward toward a more personalized medicine.
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Affiliation(s)
- Jose J. G. Marin
- HEVEFARM Group, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.A.S.); (M.J.M.); (A.S.-M.); (A.G.T.); (O.B.); (M.R.R.)
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18
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The Influence of Quadruplex Structure in Proximity to P53 Target Sequences on the Transactivation Potential of P53 Alpha Isoforms. Int J Mol Sci 2019; 21:ijms21010127. [PMID: 31878115 PMCID: PMC6982142 DOI: 10.3390/ijms21010127] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/22/2019] [Accepted: 12/23/2019] [Indexed: 12/24/2022] Open
Abstract
p53 is one of the most studied tumor suppressor proteins that plays an important role in basic biological processes including cell cycle, DNA damage response, apoptosis, and senescence. The human TP53 gene contains alternative promoters that produce N-terminally truncated proteins and can produce several isoforms due to alternative splicing. p53 function is realized by binding to a specific DNA response element (RE), resulting in the transactivation of target genes. Here, we evaluated the influence of quadruplex DNA structure on the transactivation potential of full-length and N-terminal truncated p53α isoforms in a panel of S. cerevisiae luciferase reporter strains. Our results show that a G-quadruplex prone sequence is not sufficient for transcription activation by p53α isoforms, but the presence of this feature in proximity to a p53 RE leads to a significant reduction of transcriptional activity and changes the dynamics between co-expressed p53α isoforms.
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19
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The Emerging Landscape of p53 Isoforms in Physiology, Cancer and Degenerative Diseases. Int J Mol Sci 2019; 20:ijms20246257. [PMID: 31835844 PMCID: PMC6941119 DOI: 10.3390/ijms20246257] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 11/26/2019] [Accepted: 12/09/2019] [Indexed: 12/13/2022] Open
Abstract
p53, first described four decades ago, is now established as a master regulator of cellular stress response, the “guardian of the genome”. p53 contributes to biological robustness by behaving in a cellular-context dependent manner, influenced by several factors (e.g., cell type, active signalling pathways, the type, extent and intensity of cellular damage, cell cycle stage, nutrient availability, immune function). The p53 isoforms regulate gene transcription and protein expression in response to the stimuli so that the cell response is precisely tuned to the cell signals and cell context. Twelve isoforms of p53 have been described in humans. In this review, we explore the interactions between p53 isoforms and other proteins contributing to their established cellular functions, which can be both tumour-suppressive and oncogenic in nature. Evidence of p53 isoform in human cancers is largely based on RT-qPCR expression studies, usually investigating a particular type of isoform. Beyond p53 isoform functions in cancer, it is implicated in neurodegeneration, embryological development, progeroid phenotype, inflammatory pathology, infections and tissue regeneration, which are described in this review.
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20
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Zhang YX, Pan WY, Chen J. p53 and its isoforms in DNA double-stranded break repair. J Zhejiang Univ Sci B 2019; 20:457-466. [PMID: 31090271 DOI: 10.1631/jzus.b1900167] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
DNA double-stranded break (DSB) is one of the most catastrophic damages of genotoxic insult. Inappropriate repair of DNA DSBs results in the loss of genetic information, mutation, and the generation of harmful genomic rearrangements, which predisposes an organism to immunodeficiency, neurological damage, and cancer. The tumor repressor p53 plays a key role in DNA damage response, and has been found to be mutated in 50% of human cancer. p53, p63, and p73 are three members of the p53 gene family. Recent discoveries have shown that human p53 gene encodes at least 12 isoforms. Different p53 members and isoforms play various roles in orchestrating DNA damage response to maintain genomic integrity. This review briefly explores the functions of p53 and its isoforms in DNA DSB repair.
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Affiliation(s)
- Yu-Xi Zhang
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wen-Ya Pan
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jun Chen
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
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21
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Fujita K. p53 Isoforms in Cellular Senescence- and Ageing-Associated Biological and Physiological Functions. Int J Mol Sci 2019; 20:ijms20236023. [PMID: 31795382 PMCID: PMC6928910 DOI: 10.3390/ijms20236023] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/22/2019] [Accepted: 11/27/2019] [Indexed: 12/12/2022] Open
Abstract
Cellular senescence, a term originally used to define the characteristics of normal human fibroblasts that reached their replicative limit, is an important factor for ageing, age-related diseases including cancer, and cell reprogramming. These outcomes are mediated by senescence-associated changes in gene expressions, which sometimes lead to the secretion of pro-inflammatory factors, or senescence-associated secretory phenotype (SASP) that contribute to paradoxical pro-tumorigenic effects. p53 functions as a transcription factor in cell-autonomous responses such as cell-cycle control, DNA repair, apoptosis, and cellular senescence, and also non-cell-autonomous responses to DNA damage by mediating the SASP function of immune system activation. The human TP53 gene encodes twelve protein isoforms, which provides an explanation for the pleiotropic p53 function on cellular senescence. Recent reports suggest that some short isoforms of p53 may modulate gene expressions in a full-length p53-dependent and -independent manner, in other words, some p53 isoforms cooperate with full-length p53, whereas others operate independently. This review summarizes our current knowledge about the biological activities and functions of p53 isoforms, especially Δ40p53, Δ133p53α, and p53β, on cellular senescence, ageing, age-related disorder, reprogramming, and cancer. Numerous cellular and animal model studies indicate that an unbalance in p53 isoform expression in specific cell types causes age-related disorders such as cancer, premature ageing, and degenerative diseases.
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Affiliation(s)
- Kaori Fujita
- Cell Induction and Regulation Field, Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
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22
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Wu HY, Wei Y, Liu LM, Chen ZB, Hu QP, Pan SL. Construction of a model to predict the prognosis of patients with cholangiocarcinoma using alternative splicing events. Oncol Lett 2019; 18:4677-4690. [PMID: 31611977 PMCID: PMC6781777 DOI: 10.3892/ol.2019.10838] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 08/13/2019] [Indexed: 12/15/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a type of malignant tumor that originates in the mucosal epithelial cells of the biliary system. It is a highly aggressive cancer that progresses rapidly, has low surgical resection rates and a high recurrence. At present, no prognostic molecular biomarker for CCA has been identified. However, CCA progression is affected by mRNA precursors that modify gene expression levels and protein structures through alternative splicing (AS) events, which create molecular indicators that may potentially be used to predict CCA outcomes. The present study aimed to construct a model to predict CCA prognosis based on AS events. Using prognostic data available from The Cancer Genome Atlas, including the percent spliced index of AS events obtained from TCGASpliceSeq in 32 CCA cases, univariate and multivariate Cox regression analyses were performed to assess the associations between AS events and the overall survival (OS) rates of patients with CCA. Additional multivariate Cox regression analyses were used to identify AS events that were significantly associated with prognosis, which were used to construct a prediction model with a prognostic index (PI). A receiver operating characteristic (ROC) curve was used to determine the predictive value of the PI, and Pearson's correlation analysis was used to determine the association between OS-related AS events and splicing factors. A total of 38,804 AS events were identified in 9,673 CCA genes, among which univariate Cox regression analysis identified 1,639 AS events associated with OS (P<0.05); multivariate Cox regression analysis narrowed this list to 23 CCA AS events (P<0.001). The final PI model was constructed to predict the survival of patients with CCA; the ROC curve demonstrated that it had a high predictive power for CCA prognosis, with a highest area under the curve of 0.986. Correlations between 23 OS-related AS events and splicing factors were also noted, and may thus, these AS events may be used to improve predictions of OS. In conclusion, AS events exhibited potential for predicting the prognosis of patients with CCA, and thus, the effects of AS events in CCA required further examination.
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Affiliation(s)
- Hua-Yu Wu
- Department of Pathophysiology, School of Pre-Clinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.,Department of Cell Biology and Genetics, School of Pre-Clinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Yi Wei
- Department of Pathophysiology, School of Pre-Clinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Li-Min Liu
- Department of Toxicology, College of Pharmacy, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Zhong-Biao Chen
- Department of General Surgery, The First People's Hospital of Yulin, Yulin, Guangxi 537000, P.R. China
| | - Qi-Ping Hu
- Department of Cell Biology and Genetics, School of Pre-Clinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Shang-Ling Pan
- Department of Pathophysiology, School of Pre-Clinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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23
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Ozretić P, Hanžić N, Proust B, Sabol M, Trnski D, Radić M, Musani V, Ciribilli Y, Milas I, Puljiz Z, Bosnar MH, Levanat S, Slade N. Expression profiles of p53/p73, NME and GLI families in metastatic melanoma tissue and cell lines. Sci Rep 2019; 9:12470. [PMID: 31462745 PMCID: PMC6713730 DOI: 10.1038/s41598-019-48882-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 08/01/2019] [Indexed: 02/08/2023] Open
Abstract
Unlike other tumours, TP53 is rarely mutated in melanoma; however, it fails to function as a tumour suppressor. We assume that its functions might be altered through interactions with several families of proteins, including p53/p73, NME and GLI. To elucidate the potential interplay among these families we analysed the expression profiles of aforementioned genes and proteins in a panel of melanoma cell lines, metastatic melanoma specimens and healthy corresponding tissue. Using qPCR a higher level of NME1 gene expression and lower levels of Δ40p53β, ΔNp73, GLI1, GLI2 and PTCH1 were observed in tumour samples compared to healthy tissue. Protein expression of Δ133p53α, Δ160p53α and ΔNp73α isoforms, NME1 and NME2, and N'ΔGLI1, GLI1FL, GLI2ΔN isoforms was elevated in tumour tissue, whereas ∆Np73β was downregulated. The results in melanoma cell lines, in general, support these findings. In addition, we correlated expression profiles with clinical features and outcome. Higher Δ133p53β and p53α mRNA and both GLI1 mRNA and GLI3R protein expression had a negative impact on the overall survival. Shorter overall survival was also connected with lower p53β and NME1 gene expression levels. In conclusion, all examined genes may have implications in melanoma development and functional inactivity of TP53.
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Affiliation(s)
- Petar Ozretić
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb, Croatia
| | - Nikolina Hanžić
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb, Croatia
| | - Bastien Proust
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb, Croatia
| | - Maja Sabol
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb, Croatia
| | - Diana Trnski
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb, Croatia
| | - Martina Radić
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb, Croatia
| | - Vesna Musani
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb, Croatia
| | - Yari Ciribilli
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, Povo (Trento), IT-38123, Italy
| | - Ivan Milas
- Sestre milosrdnice University Hospital Center, Vinogradska cesta 29, HR-10000, Zagreb, Croatia
| | - Zvonimir Puljiz
- Sestre milosrdnice University Hospital Center, Vinogradska cesta 29, HR-10000, Zagreb, Croatia
| | - Maja Herak Bosnar
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb, Croatia
| | - Sonja Levanat
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb, Croatia
| | - Neda Slade
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb, Croatia.
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24
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Yosudjai J, Wongkham S, Jirawatnotai S, Kaewkong W. Aberrant mRNA splicing generates oncogenic RNA isoforms and contributes to the development and progression of cholangiocarcinoma. Biomed Rep 2019; 10:147-155. [PMID: 30906543 PMCID: PMC6403481 DOI: 10.3892/br.2019.1188] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 01/04/2019] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinoma is a lethal biliary cancer, with an unclear molecular pathogenesis. Alternative splicing is a post-transcriptional modification that generates mature mRNAs, which are subsequently translated into proteins. Aberrant alternative splicing has been reported to serve a role in tumor initiation, maintenance and metastasis in several types of human cancer, including cholangiocarcinoma. In this review, the aberrant splicing of genes and the functional contributions of the spliced genes, in the carcinogenesis, progression and aggressiveness of cholangiocarcinoma are summarized. In addition, factors that influence this aberrant splicing that may be relevant as therapeutic targets or prognosis markers for cholangiocarcinoma are discussed.
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Affiliation(s)
- Juthamas Yosudjai
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Siwanon Jirawatnotai
- Siriraj Center for Research of Excellence (SiCORE) for System Pharmacology, Department of Pharmacology, Faculty of Medicine, Siriraj Medical School, Mahidol University, Bangkok 10700, Thailand
| | - Worasak Kaewkong
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand
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25
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p53 Isoforms and Their Implications in Cancer. Cancers (Basel) 2018; 10:cancers10090288. [PMID: 30149602 PMCID: PMC6162399 DOI: 10.3390/cancers10090288] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 08/18/2018] [Accepted: 08/18/2018] [Indexed: 01/10/2023] Open
Abstract
In this review we focus on the major isoforms of the tumor-suppressor protein p53, dysfunction of which often leads to cancer. Mutations of the TP53 gene, particularly in the DNA binding domain, have been regarded as the main cause for p53 inactivation. However, recent reports demonstrating abundance of p53 isoforms, especially the N-terminally truncated ones, in the cancerous tissues suggest their involvement in carcinogenesis. These isoforms are ∆40p53, ∆133p53, and ∆160p53 (the names indicate their respective N-terminal truncation). Due to the lack of structural and functional characterizations the modes of action of the p53 isoforms are still unclear. Owing to the deletions in the functional domains, these isoforms can either be defective in DNA binding or more susceptive to altered ‘responsive elements’ than p53. Furthermore, they may exert a ‘dominant negative effect’ or induce more aggressive cancer by the ‘gain of function’. One possible mechanism of p53 inactivation can be through tetramerization with the ∆133p53 and ∆160p53 isoforms—both lacking part of the DNA binding domain. A recent report and unpublished data from our laboratory also suggest that these isoforms may inactivate p53 by fast aggregation—possibly due to ectopic overexpression. We further discuss the evolutionary significance of the p53 isoforms.
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26
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A mouse model of the Δ133p53 isoform: roles in cancer progression and inflammation. Mamm Genome 2018; 29:831-842. [PMID: 29992419 DOI: 10.1007/s00335-018-9758-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Accepted: 07/05/2018] [Indexed: 01/19/2023]
Abstract
This review paper outlines studies on the Δ122p53 mouse, a model of the human Δ133p53 isoform, together with studies in other model organisms, cell culture, and where available, clinical investigations. In general, these studies imply that, in contrast to the canonical p53 tumor suppressor, Δ133p53 family members have oncogenic capability. Δ122p53 is multi-functional, conferring survival and proliferative advantages on cells, promoting invasion, metastasis and vascularization, as does Δ133p53. Cancers with high levels of Δ133p53 often have poor prognosis. Δ122p53 mediates its effects through the JAK-STAT and RhoA-ROCK signaling pathways. We propose that Δ133p53 isoforms have evolved as inflammatory signaling molecules to deal with the consequent tissue damage of p53 activation. However, if sustained expression of the isoforms occur, pathologies may result.
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27
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Srijiwangsa P, Ponnikorn S, Na-Bangchang K. Effect of β-Eudesmol on NQO1 suppression-enhanced sensitivity of cholangiocarcinoma cells to chemotherapeutic agents. BMC Pharmacol Toxicol 2018; 19:32. [PMID: 29914576 PMCID: PMC6006851 DOI: 10.1186/s40360-018-0223-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Accepted: 06/10/2018] [Indexed: 01/17/2023] Open
Abstract
Background Cholangiocarcinoma (CCA), an epithelial malignancy of the biliary tree, is one of the aggressive cancers with poor prognosis and unsatisfactory response to chemotherapy with acquired resistance. NAD(P)H-quinone oxidoreductase 1 (NQO1), an antioxidant/detoxifying enzyme, plays important roles in chemo-resistance and proliferation in several cancer cells. The study aimed to investigate the inhibitory effect of β-eudesmol on NQO1 enhanced chemotherapeutic effects of 5-fluorouracil (5-FU) and doxorubicin (DOX) in the high NQO1-expressing human CCA cell line, NQO1-KKU-100. In addition, the molecular events associated with the inhibition of the cell proliferation, cell migration, and induction of apoptosis were investigated. Methods Human CCA KKU-100 cells were exposed to β-eudesmol at various concentrations. NQO1 enzyme activity and protein expression were measured by enzymatic assay and Western blot analysis, respectively. Sulforhodamine B (SRB) assay and wound healing assay were performed to detect the inhibitory effect of β-eudesmol on cell proliferation, cell migration, and sensitivity to 5-FU and DOX. Apoptotic induction was detected by flow cytometry with annexin V/PI and DAPI nuclear staining. Caspase 3/7 activation was determined by fluorescence microscopy. The mechanism of enhanced chemo-sensitivity was evaluated by Western blot analysis. Results β-Eudesmol significantly suppressed NQO1 enzyme activity (both in KKU-100 cells and cell lysates) and protein expression in KKU-100 cells in a concentration-dependent manner. β-Eudesmol exhibited potent cytotoxicity on KKU-100 cells with mean ± SD IC50 values of 47.62 ± 9.54 and 37.46 ± 12.58 μM at 24 and 48 h, respectively. In addition, it also potentiated the cytotoxic activities and inhibitory activities of 5-FU and DOX on cell migration through induction of cell apoptosis and activation of caspase 3/7. Western blot analysis suggested that β-eudesmol enhanced chemosensitivity was associated with the suppression of NQO1 protein and activation of Bax/Bcl-2 protein expression ratio in CCA cells. Conclusions β-Eudesmol may serve as a potential anti-CCA candidate particularly when used in combination with conventional chemotherapeutics. The mechanisms involved may be mediated via NQO1 suppression-related apoptosis pathway.
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Affiliation(s)
- Pimradasiri Srijiwangsa
- Chulabhorn International College of Medicine, Thammasat University, (Rangsit Campus), Pathum Thani, 12121, Thailand
| | - Saranyoo Ponnikorn
- Chulabhorn International College of Medicine, Thammasat University, (Rangsit Campus), Pathum Thani, 12121, Thailand
| | - Kesara Na-Bangchang
- Chulabhorn International College of Medicine, Thammasat University, (Rangsit Campus), Pathum Thani, 12121, Thailand. .,Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand.
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28
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p73 coordinates with Δ133p53 to promote DNA double-strand break repair. Cell Death Differ 2018; 25:1063-1079. [PMID: 29511339 PMCID: PMC5988805 DOI: 10.1038/s41418-018-0085-8] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 01/18/2018] [Accepted: 02/07/2018] [Indexed: 12/16/2022] Open
Abstract
Tumour repressor p53 isoform Δ133p53 is a target gene of p53 and an antagonist of p53-mediated apoptotic activity. We recently demonstrated that Δ133p53 promotes DNA double-strand break (DSB) repair by upregulating transcription of the repair genes RAD51, LIG4 and RAD52 in a p53-independent manner. However, Δ133p53 lacks the transactivation domain of full-length p53, and the mechanism by which it exerts transcriptional activity independently of full-length p53 remains unclear. In this report, we describe the accumulation of high levels of both Δ133p53 and p73 (a p53 family member) at 24 h post γ-irradiation (hpi). Δ133p53 can form a complex with p73 upon γ-irradiation. The co-expression of Δ133p53 and p73, but not either protein alone, can significantly promote DNA DSB repair mechanisms, including homologous recombination (HR), non-homologous end joining (NHEJ) and single-strand annealing (SSA). p73 and Δ133p53 act synergistically to promote the expression of RAD51, LIG4 and RAD52 by joining together to bind to region containing a Δ133p53-responsive element (RE) and a p73-RE in the promoters of all three repair genes. In addition to its accumulation at 24 hpi, p73 protein expression also peaks at 4 hpi. The depletion of p73 not only reduces early-stage apoptotic frequency (4–6 hpi), but also significantly increases later-stage DNA DSB accumulation (48 hpi), leading to cell cycle arrest in the G2 phase and, ultimately, cell senescence. In summary, the apoptotic regulator p73 also coordinates with Δ133p53 to promote DNA DSB repair, and the loss of function of p73 in DNA DSB repair may underlie spontaneous and carcinogen-induced tumorigenesis in p73 knockout mice.
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29
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Li N, Xie C, Lu NH. p53, a potential predictor of Helicobacter pylori infection-associated gastric carcinogenesis? Oncotarget 2018; 7:66276-66286. [PMID: 27556187 PMCID: PMC5323233 DOI: 10.18632/oncotarget.11414] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Accepted: 08/13/2016] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori (H. pylori) is an ancient and persistent inhabitant of the human stomach that is closely linked to the development of gastric cancer (GC). . Emerging evidence suggests that H. pylori strain interactions with gastric epithelial cells subvert the best- characterized p53 tumour suppressor pathway. A high prevalence of p53 mutations is related to H. pylori infection. H. pylori also accelerates p53 protein degradation by disturbing the MDM2-P53 feedback loop. Additionally, H. pylori triggers the alteration of other p53 isoforms. Dysregulation of p53 by H. pylori infection contributes to gastric carcinogenesis by mediating cell proliferation and apoptosis. This review focuses on the regulation of p53 in H. pylori infection-associated GC.
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Affiliation(s)
- Nianshuang Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Chuan Xie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Nong-Hua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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30
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Sae-Lao T, Tohtong R, Bates DO, Wongprasert K. Sulfated Galactans from Red Seaweed Gracilaria fisheri Target EGFR and Inhibit Cholangiocarcinoma Cell Proliferation. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2017; 45:615-633. [DOI: 10.1142/s0192415x17500367] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Cholangiocarcinoma (CCA) is increasing in incidence worldwide and is resistant to chemotherapeutic agents, making treatment of CCA a major challenge. Previous studies reported that natural sulfated polysaccharides (SPs) disrupted growth factor receptor activation in cancer cells. The present study, therefore, aimed at investigating the antiproliferation effect of sulfated galactans (SG) isolated from the red seaweed Gracilaria fisheri (G. fisheri) on CCA cell lines. Direct binding activity of SG to CCA cells, epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) were determined. The effect of SG on proliferation of CCA cells was investigated. Cell cycle analyses and expression of signaling molecules associated with proliferation were also determined. The results demonstrated that SG bound directly to EGFR. SG inhibited proliferation of various CCA cell lines by inhibiting EGFR and extracellular signal-regulated kinases (ERK) phosphorylation, and inhibited EGF-induced increased cell proliferation. Cell cycle analyses showed that SG induced cell cycle arrest at the G0/G1 phase, down-regulated cell cycle genes and proteins (cyclin-D, cyclin-E, cdk-4, cdk-2), and up-regulated the tumor suppressor protein P53 and the cyclin-dependent kinase inhibitor P21. Taken together, these data demonstrate that SG from G. fisheri inhibited proliferation of CCA cells, and its mechanism of inhibition is mediated, to some extent, by inhibitory effects on EGFR activation and EGFR/ERK signaling pathway. SG presents a potential EGFR targeted molecule, which may be further clinically developed in a combination therapy for CCA treatment.
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Affiliation(s)
| | - Rutaiwan Tohtong
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - David O. Bates
- Cancer Biology, Division of Cancer Stem Cells, School of Medicine, University of Nottingham, Queen Medical Centre, Nottingham NG7 2UH, UK
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31
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p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure-Function Continuum Concept. Int J Mol Sci 2016; 17:ijms17111874. [PMID: 27834926 PMCID: PMC5133874 DOI: 10.3390/ijms17111874] [Citation(s) in RCA: 132] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 10/27/2016] [Accepted: 11/03/2016] [Indexed: 01/10/2023] Open
Abstract
Although it is one of the most studied proteins, p53 continues to be an enigma. This protein has numerous biological functions, possesses intrinsically disordered regions crucial for its functionality, can form both homo-tetramers and isoform-based hetero-tetramers, and is able to interact with many binding partners. It contains numerous posttranslational modifications, has several isoforms generated by alternative splicing, alternative promoter usage or alternative initiation of translation, and is commonly mutated in different cancers. Therefore, p53 serves as an important illustration of the protein structure–function continuum concept, where the generation of multiple proteoforms by various mechanisms defines the ability of this protein to have a multitude of structurally and functionally different states. Considering p53 in the light of a proteoform-based structure–function continuum represents a non-canonical and conceptually new contemplation of structure, regulation, and functionality of this important protein.
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32
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Mehta S, Tsai P, Lasham A, Campbell H, Reddel R, Braithwaite A, Print C. A Study of TP53 RNA Splicing Illustrates Pitfalls of RNA-seq Methodology. Cancer Res 2016; 76:7151-7159. [PMID: 27913434 DOI: 10.1158/0008-5472.can-16-1624] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Revised: 09/02/2016] [Accepted: 09/27/2016] [Indexed: 11/16/2022]
Abstract
TP53 undergoes multiple RNA-splicing events, resulting in at least nine mRNA transcripts encoding at least 12 functionally different protein isoforms. Antibodies specific to p53 protein isoforms have proven difficult to develop, thus researchers must rely on the transcript information to infer isoform abundance. In this study, we used deep RNA-seq, droplet digital PCR (ddPCR), and real-time quantitative reverse transcriptase PCR (RT-qPCR) from nine human cell lines and RNA-seq data available for tumors in The Cancer Genome Atlas to analyze TP53 splice variant expression. All three methods detected expression of the FL/40TP53α_T1 variant in most human tumors and cell lines. However, other less abundant variants were only detected with PCR-based methods. Using RNA-seq simulation analysis, we determined why RNA-seq is unable to detect less abundant TP53 transcripts and discuss the implications of these findings for the general interpretation of RNA-seq data. Cancer Res; 76(24); 7151-9. ©2016 AACR.
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Affiliation(s)
- Sunali Mehta
- Department of Pathology, University of Otago, Dunedin, New Zealand. .,Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, University of Otago, Dunedin, New Zealand
| | - Peter Tsai
- Department of Molecular Medicine and Pathology, Faculty of Medicine, University of Auckland, Auckland, New Zealand.,Bioinformatics Institute, University of Auckland, Auckland, New Zealand
| | - Annette Lasham
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, University of Otago, Dunedin, New Zealand.,Department of Molecular Medicine and Pathology, Faculty of Medicine, University of Auckland, Auckland, New Zealand
| | - Hamish Campbell
- Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia
| | - Roger Reddel
- Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia
| | - Antony Braithwaite
- Department of Pathology, University of Otago, Dunedin, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, University of Otago, Dunedin, New Zealand.,Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia
| | - Cristin Print
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, University of Otago, Dunedin, New Zealand.,Department of Molecular Medicine and Pathology, Faculty of Medicine, University of Auckland, Auckland, New Zealand.,Bioinformatics Institute, University of Auckland, Auckland, New Zealand
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33
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Abstract
It is poorly understood how a single protein, p53, can be responsive to so many stress signals and orchestrates very diverse cell responses to maintain/restore cell/tissue functions. The uncovering that TP53 gene physiologically expresses, in a tissue-dependent manner, several p53 splice variants (isoforms) provides an explanation to its pleiotropic biological activities. Here, we summarize a decade of research on p53 isoforms. The clinical studies and the diverse cellular and animal models of p53 isoforms (zebrafish, Drosophila, and mouse) lead us to realize that a p53-mediated cell response is, in fact, the sum of the intrinsic activities of the coexpressed p53 isoforms and that unbalancing expression of different p53 isoforms leads to cancer, premature aging, (neuro)degenerative diseases, inflammation, embryo malformations, or defects in tissue regeneration. Cracking the p53 isoforms' code is, thus, a necessary step to improve cancer treatment. It also opens new exciting perspectives in tissue regeneration.
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Affiliation(s)
- Sebastien M Joruiz
- Dundee Cancer Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom
| | - Jean-Christophe Bourdon
- Dundee Cancer Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom
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34
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Abstract
p53 is a master regulatory protein that is involved in diverse cellular metabolic processes such as apoptosis, DNA repair, and cell cycle arrest. The protective function of p53 (in its homotetrameric form) as a tumor suppressor is lost in more than 50% of human cancers.Despite considerable experimental evidence suggesting the presence of multiple p53 states, it has been difficult to correlate the status of p53 with cancer response to treatments and clinical outcomes, which suggest the importance of complex but essential p53 regulatory pathways.Recent studies have indicated that the expression pattern of p53 isoforms may play a crucial role in regulating normal and cancer cell fates in response to diverse stresses. The human TP53 gene encodes at least 12 p53 isoforms, which are produced in normal tissue through alternative initiation of translation, usage of alternative promoters, and alternative splicing. Furthermore, some researchers have suggested that the formation of mutant p53 aggregates may be associated with cancer pathogenesis due to loss-of function (LoF), dominant-negative (DN), and gain-of function (GoF) effects.As different isoforms or the aggregation state of p53 may influence tumorigenesis, this review aims to examine the correlation of p53 isoforms and aggregation with cancer.
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Affiliation(s)
| | - Seong Soo A. An
- Department of Bionano Technology, Gachon University, Gyeonggi-do, Republic of Korea
- Correspondence: Seong Soo A. An, Department of Bionano Techonology, Gachon University65 San Bokjung-dong, Sujung-gu, Seongnam-si, Gyeonggi-do 461-701, Republic of Korea (e-mail: )
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The Δ133p53 isoform and its mouse analogue Δ122p53 promote invasion and metastasis involving pro-inflammatory molecules interleukin-6 and CCL2. Oncogene 2016; 35:4981-9. [PMID: 26996665 DOI: 10.1038/onc.2016.45] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 12/17/2016] [Accepted: 02/08/2016] [Indexed: 12/12/2022]
Abstract
A number of naturally occurring isoforms of the tumour suppressor protein p53 have been discovered, which appear to have differing roles in tumour prevention or promotion. We are investigating the tumour-promoting activities of the Δ133p53 isoform using our mouse model of Δ133p53 (Δ122p53). Here, we report that tumours from Δ122p53 homozygous mice show evidence of invasion and metastasis and that Δ122p53 promotes migration though a 3-dimensional collagen matrix. We also show that Δ122p53 and Δ133p53 promote cell migration in scratch wound and Transwell assays, similar to the 'gain-of-function' phenotypes seen with mutant p53. Using the well-defined B16 mouse melanoma metastatic model, we show that Δ122p53 leads to faster generation of lung metastases. The increased migratory phenotypes are dependent on secreted factors, including the cytokine interleukin-6 and the chemokine CCL2. We propose that Δ122p53 (and Δ133p53) acts in a similar manner to 'gain-of-function' mutant p53 proteins to promote migration, invasion and metastasis, which may contribute to poor survival in patients with Δ133p53-expressing tumours.
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NUTTHASIRIKUL NICHAPAVEE, HAHNVAJANAWONG CHARIYA, TECHASEN ANCHALEE, LIMPAIBOON TEMDUANG, LEELAYUWAT CHANVIT, CHAU-IN SIRI, JEARANAIKOON PATCHAREE. Targeting the Δ133p53 isoform can restore chemosensitivity in 5-fluorouracil-resistant cholangiocarcinoma cells. Int J Oncol 2015; 47:2153-64. [DOI: 10.3892/ijo.2015.3188] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2015] [Accepted: 09/17/2015] [Indexed: 11/05/2022] Open
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Δ122p53, a mouse model of Δ133p53α, enhances the tumor-suppressor activities of an attenuated p53 mutant. Cell Death Dis 2015; 6:e1783. [PMID: 26068791 PMCID: PMC4669831 DOI: 10.1038/cddis.2015.149] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Revised: 04/09/2015] [Accepted: 05/06/2015] [Indexed: 01/29/2023]
Abstract
Growing evidence suggests the Δ133p53α isoform may function as an oncogene. It is overexpressed in many tumors, stimulates pathways involved in tumor progression, and inhibits some activities of wild-type p53, including transactivation and apoptosis. We hypothesized that Δ133p53α would have an even more profound effect on p53 variants with weaker tumor-suppressor capability. We tested this using a mouse model heterozygous for a Δ133p53α-like isoform (Δ122p53) and a p53 mutant with weak tumor-suppressor function (mΔpro). The Δ122p53/mΔpro mice showed a unique survival curve with a wide range of survival times (92-495 days) which was much greater than mΔpro/- mice (range 120-250 days) and mice heterozygous for the Δ122p53 and p53 null alleles (Δ122p53/-, range 78-150 days), suggesting Δ122p53 increased the tumor-suppressor activity of mΔpro. Moreover, some of the mice that survived longest only developed benign tumors. In vitro analyses to investigate why some Δ122p53/mΔpro mice were protected from aggressive tumors revealed that Δ122p53 stabilized mΔpro and prolonged the response to DNA damage. Similar effects of Δ122p53 and Δ133p53α were observed on wild-type of full-length p53, but these did not result in improved biological responses. The data suggest that Δ122p53 (and Δ133p53α) could offer some protection against tumors by enhancing the p53 response to stress.
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Sawhney S, Hood K, Shaw A, Braithwaite AW, Stubbs R, Hung NA, Royds JA, Slatter TL. Alpha-enolase is upregulated on the cell surface and responds to plasminogen activation in mice expressing a ∆133p53α mimic. PLoS One 2015; 10:e0116270. [PMID: 25643152 PMCID: PMC4313950 DOI: 10.1371/journal.pone.0116270] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 12/05/2014] [Indexed: 01/11/2023] Open
Abstract
The p53 protein is a master regulator of the stress response. It acts as a tumor suppressor by inducing transcriptional activation of p53 target genes, with roles in apoptosis, cell cycle arrest and metabolism. The discovery of at least 12 isoforms of p53, some of which have tumor-promoting properties, has opened new avenues of research. Our previous work studied tumor phenotypes in four mouse models with different p53 backgrounds: wild-type p53, p53 null, mutant p53 lacking the proline domain (mΔpro), and a mimic for the human Δ133p53α p53 isoform (Δ122p53). To identify the major proteins affected by p53 function early in the response to DNA damage, the current study investigated the entire proteome of bone marrow, thymus, and lung in the four p53 models. Protein extracts from untreated controls and those treated with amsacrine were analyzed using two-dimensional fluorescence difference gel electrophoresis. In the bone marrow, reactive proteins were universally decreased by wild-type p53, including α-enolase. Further analysis of α-enolase in the p53 models revealed that it was instead increased in Δ122p53 hematopoietic and tumor cell cytosol and on the cell surface. Alpha-enolase on the surface of Δ122p53 cells acted as a plasminogen receptor, with tumor necrosis factor alpha induced upon plasminogen stimulation. Taken together, these data identified new proteins associated with p53 function. One of these proteins, α-enolase, is regulated differently by wild-type p53 and Δ122p53 cells, with reduced abundance as part of a wild-type p53 response and increased abundance with Δ122p53 function. Increased cell surface α-enolase on Δ122p53 cells provides a possible explanation for the model’s pro-inflammatory features and suggests that p53 isoforms may direct an inflammatory response by increasing the amount of α-enolase on the cell surface.
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Affiliation(s)
- Sonal Sawhney
- Wakefield Biomedical Research Unit, University of Otago, Wellington, New Zealand
| | - Kylie Hood
- Wakefield Biomedical Research Unit, University of Otago, Wellington, New Zealand
| | - Alisha Shaw
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Antony W. Braithwaite
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
- Children’s Medical Research Institute, University of Sydney, Westmead, Australia
| | - Richard Stubbs
- Wakefield Biomedical Research Unit, University of Otago, Wellington, New Zealand
| | - Noelyn A. Hung
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Janice A. Royds
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Tania L. Slatter
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
- * E-mail:
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Sanada Y, Kawashita Y, Okada S, Azuma T, Matsuo S. Review to better understand the macroscopic subtypes and histogenesis of intrahepatic cholangiocarcinoma. World J Gastrointest Pathophysiol 2014; 5:188-199. [PMID: 25133021 PMCID: PMC4133518 DOI: 10.4291/wjgp.v5.i3.188] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 03/18/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Intrahepatic cholangiocarcinoma is macroscopically classified into three subtypes, mass-forming-type, periductal infiltrating-type, and intraductal growth-type. Each subtype should be preoperatively differentiated to perform the valid surgical resection. Recent researches have revealed the clinical, radiologic, pathobiological characteristics of each subtype. We reviewed recently published studies covering various aspects of intrahepatic cholangiocarcinoma (ICC), focusing especially on the macroscopic subtypes and stem cell features to better understand the pathophysiology of ICC and to establish the valid therapeutic strategy.
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Skipworth JRA, Timms JF, Pereira SP. Novel diagnostic and prognostic biomarkers in biliary tract cancer. ACTA ACUST UNITED AC 2014; 7:487-99. [PMID: 23971898 DOI: 10.1517/17530059.2013.826646] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The worldwide incidence of biliary tract carcinoma (BTC, tumours of the bile ducts and gall-bladder) continues to rise, with the only potentially curative treatment remaining surgical resection or transplantation, possible in only a minority of patients. Late presentation and a paucity of effective treatments mandate the development of techniques for early lesion detection. AREAS COVERED This article reviews currently available biomarkers for the diagnosis and prognosis of BTC, as well as recently published studies describing novel serum, bile and urinary biomarkers. EXPERT OPINION The incorporation of novel analysis techniques, such as digital image analysis and fluorescence in situ hybridization, into existing management algorithms enhances the accuracy of brush cytology taken at the time of therapeutic endoscopy. However, a key goal is the discovery of reliable non-invasive biomarkers with high sensitivity and specificity. Recent advances in gene sequencing and expression, clonal evolution and tumour heterogeneity in other cancers should advance understanding of BTC tumour biology and facilitate biomarker discovery.
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Affiliation(s)
- James R A Skipworth
- University College London, Division of Surgery and Interventional Science, 4th Floor, 74 Huntley Street, London, WC1E6AU, UK
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Zeekpudsa P, Kukongviriyapan V, Senggunprai L, Sripa B, Prawan A. Suppression of NAD(P)H-quinone oxidoreductase 1 enhanced the susceptibility of cholangiocarcinoma cells to chemotherapeutic agents. J Exp Clin Cancer Res 2014; 33:11. [PMID: 24460787 PMCID: PMC3922744 DOI: 10.1186/1756-9966-33-11] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 01/21/2014] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is highly resistant to most of the known chemotherapeutic treatments. NAD(P)H-quinone oxidoreductase 1 (NQO1) is an antioxidant/detoxifying enzyme recently recognized as an important contributor to chemoresistance in some human cancers. However, the contribution of NQO1 to chemotherapy resistance in CCA is unknown. METHODS Two CCA cell lines, KKU-100 and KKU-M214, with high and low NQO1 expression levels, respectively, were used to evaluate the sensitivity to chemotherapeutic agents; 5-fluorouracil (5-FU), doxorubicin (Doxo), and gemcitabine (Gem). NQO1 and/or p53 expression in KKU-100 cells were knocked down by siRNA. NQO1 was over-expressed in KKU-M214 cells by transfection with pCMV6-XL5-NQO1 expression vector. CCA cells with modulated NQO1 and/or p53 expression were treated with chemotherapeutic agents, and the cytotoxicity was assessed by SRB assay. The mechanism of enhanced chemosensitivity was evaluated by Western blot analysis. RESULTS When NQO1 was knocked down, KKU-100 cells became more susceptible to all chemotherapeutic agents. Conversely, with over-expression of NQO1 made KKU-M214 cells more resistant to chemotherapeutic agents. Western blot analysis suggested that enhanced chemosensitivity was probably due to the activation of p53-mediated cell death. Enhanced susceptibility to chemotherapeutic agents by NQO1 silencing was abolished by knockdown of p53. CONCLUSIONS These results suggest that inhibition of NQO1 could enhance the susceptibility of CCA to an array of chemotherapeutic agents.
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Affiliation(s)
- Ponsilp Zeekpudsa
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, Thailand
| | - Veerapol Kukongviriyapan
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, Thailand
| | - Laddawan Senggunprai
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, Thailand
| | - Banchob Sripa
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, Thailand
| | - Auemduan Prawan
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, Thailand
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Surget S, Khoury MP, Bourdon JC. Uncovering the role of p53 splice variants in human malignancy: a clinical perspective. Onco Targets Ther 2013; 7:57-68. [PMID: 24379683 PMCID: PMC3872270 DOI: 10.2147/ott.s53876] [Citation(s) in RCA: 176] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Thirty-five years of research on p53 gave rise to more than 68,000 articles and reviews, but did not allow the uncovering of all the mysteries that this major tumor suppressor holds. How p53 handles the different signals to decide the appropriate cell fate in response to a stress and its implication in tumorigenesis and cancer progression remains unclear. Nevertheless, the uncovering of p53 isoforms has opened new perspectives in the cancer research field. Indeed, the human TP53 gene encodes not only one but at least twelve p53 protein isoforms, which are produced in normal tissues through alternative initiation of translation, usage of alternative promoters, and alternative splicing. In recent years, it became obvious that the different p53 isoforms play an important role in regulating cell fate in response to different stresses in normal cells by differentially regulating gene expression. In cancer cells, abnormal expression of p53 isoforms contributes actively to cancer formation and progression, regardless of TP53 mutation status. They can also be associated with response to treatment, depending on the cell context. The determination of p53 isoform expression and p53 mutation status helps to define different subtypes within a particular cancer type, which would have different responses to treatment. Thus, the understanding of the regulation of p53 isoform expression and their biological activities in relation to the cellular context would constitute an important step toward the improvement of the diagnostic, prognostic, and predictive values of p53 in cancer treatment. This review aims to summarize the involvement of p53 isoforms in cancer and to highlight novel potential therapeutic targets.
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Affiliation(s)
- Sylvanie Surget
- Dundee Cancer Centre, University of Dundee, Dundee, UK ; Jacqui Wood Cancer Centre, Ninewells Hospital, University of Dundee, Dundee, UK
| | - Marie P Khoury
- Dundee Cancer Centre, University of Dundee, Dundee, UK ; Jacqui Wood Cancer Centre, Ninewells Hospital, University of Dundee, Dundee, UK
| | - Jean-Christophe Bourdon
- Dundee Cancer Centre, University of Dundee, Dundee, UK ; Jacqui Wood Cancer Centre, Ninewells Hospital, University of Dundee, Dundee, UK
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