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1
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R HC, C GPD. Investigation of the impact of R273H and R273C mutations on the DNA binding domain of P53 protein through molecular dynamic simulation. J Biomol Struct Dyn 2025; 43:798-812. [PMID: 39737749 DOI: 10.1080/07391102.2023.2283793] [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: 10/04/2023] [Accepted: 11/09/2023] [Indexed: 01/01/2025]
Abstract
The P53 protein, a cancer-associated transcriptional factor and tumor suppressor, houses a Zn2+ ion in its DNA-binding domain (DBD), essential for sequence-specific DNA binding. However, common mutations at position 273, specifically from Arginine to Histidine and Cysteine, lead to a loss of function as a tumor suppressor, also called DNA contact mutations. The mutant (MT) P53 structure cannot stabilize DNA due to inadequate interaction. To investigate the conformational changes, we performed a comparative molecular dynamic simulation (MDS) to study the effect of the P53-Wildtype (P53-WT) and the DNA contact mutations (R273H and R273C) on the DBD. Our research indicated that the DNA binding bases lose Hydrogen bonds (H bonds) when mutated to P53-R273H and P53-R273C during the simulation. We employed tools, such as PDIviz to highlight the contacts with DNA bases and backbone, major and minor grooves, and various pharmacophore forms of atoms. The contact maps for R273H and R273C were generated using the COZOID tool, which displayed changes in the frequency of the amino acids and DNA bases interaction in the DNA binding domain. These residues have diminished interactions, and the zinc-binding domain shows significant movements by Zn2+ ion binding to the phosphate group of the DNA, moving away from its binding sites. In conclusion, our research suggests that R273H and R273C each have unique stability and self-assembly properties. This understanding might assist researchers in better comprehending the function of the p53 protein and its importance in cancer.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Hephzibah Cathryn R
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, India
| | - George Priya Doss C
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, India
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2
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Chen B, Jin W. A comprehensive review of stroke-related signaling pathways and treatment in western medicine and traditional Chinese medicine. Front Neurosci 2023; 17:1200061. [PMID: 37351420 PMCID: PMC10282194 DOI: 10.3389/fnins.2023.1200061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 05/19/2023] [Indexed: 06/24/2023] Open
Abstract
This review provides insight into the complex network of signaling pathways and mechanisms involved in stroke pathophysiology. It summarizes the historical progress of stroke-related signaling pathways, identifying potential interactions between them and emphasizing that stroke is a complex network disease. Of particular interest are the Hippo signaling pathway and ferroptosis signaling pathway, which remain understudied areas of research, and are therefore a focus of the review. The involvement of multiple signaling pathways, including Sonic Hedgehog (SHH), nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE), hypoxia-inducible factor-1α (HIF-1α), PI3K/AKT, JAK/STAT, and AMPK in pathophysiological mechanisms such as oxidative stress and apoptosis, highlights the complexity of stroke. The review also delves into the details of traditional Chinese medicine (TCM) therapies such as Rehmanniae and Astragalus, providing an analysis of the recent status of western medicine in the treatment of stroke and the advantages and disadvantages of TCM and western medicine in stroke treatment. The review proposes that since stroke is a network disease, TCM has the potential and advantages of a multi-target and multi-pathway mechanism of action in the treatment of stroke. Therefore, it is suggested that future research should explore more treasures of TCM and develop new therapies from the perspective of stroke as a network disease.
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Affiliation(s)
- Binhao Chen
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Weifeng Jin
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
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3
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Kim HJ, Lee SE, Na H, Roe JS, Roh JI, Lee HW. Divergence of the PIERCE1 expression between mice and humans as a p53 target gene. PLoS One 2020; 15:e0236881. [PMID: 32745107 PMCID: PMC7398528 DOI: 10.1371/journal.pone.0236881] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 07/16/2020] [Indexed: 12/23/2022] Open
Abstract
PIERCE1, p53 induced expression 1 in Rb null cells, is a novel p53 target involved in the DNA damage response and cell cycle in mice. These facts prompted us to study the function of PIERCE1 with respect to p53-associated pathophysiology of cancer in humans. Unexpectedly, PIERCE1 did not respond to overexpression and activation of p53 in humans. In this study, we swapped p53 protein expression in human and mouse cells to find the clue of this difference between species. Human p53 expression in mouse cells upregulated PIERCE1 expression, suggesting that p53-responsive elements on the PIERCE1 promoter are crucial, but not the p53 protein itself. Indeed, in silico analyses of PIERCE1 promoters revealed that p53-responsive elements identified in mice are not conserved in humans. Consistently, chromatin immunoprecipitation-sequencing (ChIP-seq) analyses confirmed p53 enrichment against the PIERCE1 promoter region in mice, not in human cells. To complement the p53 study in mice, further promoter analyses suggested that the human PIERCE1 promoter is more similar to guinea pigs, lemurs, and dogs than to rodents. Taken together, our results confirm the differential responsiveness of PIERCE1 expression to p53 due to species differences in PIERCE1 promoters. The results also show partial dissimilarity after p53 induction between mice and humans.
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Affiliation(s)
- Hye Jeong Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Seung Eon Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Heeju Na
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Jae-Seok Roe
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Jae-il Roh
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
- * E-mail: (JIR); (HWL)
| | - Han-Woong Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
- * E-mail: (JIR); (HWL)
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4
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Deutsch MD, Li YQ, Utz G, McDonald JS, Nguyen C, Pavelic L, Wilson KM, Gluckman JL, Pavelic ZP. The Role of the p53 Tumor Suppressor Gene in the Tumorigenesis of Inverting Papilloma of the Nose and Paranasal Sinuses. ACTA ACUST UNITED AC 2018. [DOI: 10.2500/105065896781795012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Inverting Papilloma (IP) is a rare neoplasm of the nose and paranasal sinuses. It is considered to be a premalignant lesion as there is a 7–21% incidence of squamous cell carcinoma (SCC) associated with IP. Although there have been many attempts to assign prognostic significance to various features of IP, there has not been a single reliable prognostic indicator identified. Recently it has been shown that mutations of the p53 tumor suppressor gene (TSG) are commonly involved in the process of cancer development. It has been assumed that cells which stain positive with p53 monoclonal antibody (MAb) contain mutant protein due to its lengthened half-life. To better understand the relationship of IP and carcinoma, we analyzed tumor specimens from 12 patients for p53 gene alterations using immunohistochemistry and DNA sequencing. Seven patients had IP without dysplasia, and five patients had IP with dysplasia or squamous cell carcinoma (SCC). All seven patients with IP only had tumors negative for p53 TSG. Three of five patients with IP and dysplasia or SCC stained positive for p53 TSG. No gene alterations of p53 TSG were detected in this study. The role and significance of p53 TSG in the tumorigenesis of IP is discussed based on these findings.
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Affiliation(s)
- Mark D. Deutsch
- Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Ya-Qin Li
- Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Gary Utz
- Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH
| | - John S. McDonald
- Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Charly Nguyen
- Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Ljiljana Pavelic
- Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Keith M. Wilson
- Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Jack L. Gluckman
- Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Zlatko P. Pavelic
- Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH
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Monti P, Ghiorzo P, Menichini P, Foggetti G, Queirolo P, Izzotti A, Fronza G. TP63 mutations are frequent in cutaneous melanoma, support UV etiology, but their role in melanomagenesis is unclear. Oncol Rep 2017; 38:1985-1994. [PMID: 28849221 PMCID: PMC5652947 DOI: 10.3892/or.2017.5903] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 07/12/2017] [Indexed: 12/18/2022] Open
Abstract
In contrast to TP53, cancer development is rarely associated with mutations in the TP63 and TP73 genes. Recently, next generation sequencing analysis revealed that TP63 mutations are frequent, specifically in cutaneous melanomas. Cutaneous melanoma represents 4% of skin cancers but it is responsible for 80% of skin cancer related deaths. In the present study, we first determined whether all three members of the P53 family of transcription factors were found mutated in cutaneous melanomas by retrieving all TP53, TP63 and TP73 mutations from cBioPortal (http://www.cbioportal.org/). TP53 and TP63 were frequently mutated [15.0% (91/605) and 14.7% (89/605), respectively], while TP73 [1.5% (9/605)] was more rarely mutated (p<0.0001). A UV-mutation fingerprint was recognized for TP63 and TP73 genes. Then, we tried to evaluate the potential role of TP63 mutations as drivers or passengers in the tumorigenic process. In the former case, the amino acid substitutions should cause significant functional consequences on the main biochemical activity of the P63 protein, namely transactivation. The predicted effects of specific amino acid substitutions by two bioinformatics tools were rather different. Using a yeast-based functional assay, the observed hotspot mutant R379CP63 protein exhibited a substantial residual activity compared to the wild-type (>70%). This result does not support a major role of the mutant P63 protein in melanomagenesis while it is still consistent with the TP63 gene being a recorder of UV exposure. The TP63 mutation spectrum from cutaneous melanomas, when compared with that observed at the germinal level in patients affected by P63-associated diseases [ectodermal dysplasia syndromes, (EDs)], revealed significant differences. The TP63 mutations were more frequent at CpGs sites (p<0.0001) in EDs and at PyPy sites (p<0.0001) in cutaneous melanomas. The two spectra differed significantly (p<0.0001). We conclude that TP63 mutations are frequent in cutaneous melanoma, support UV etiology, but their role in melanomagenesis is unclear.
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Affiliation(s)
- Paola Monti
- UOC Mutagenesis, Ospedale Policlinico San Martino, I-16132 Genova, Italy
| | - Paola Ghiorzo
- Department of Internal Medicine and Medical Specialties, University of Genova, I-16132 Genova, Italy
- Genetics of Rare Cancers Unit, Ospedale Policlinico San Martino, I-16132 Genova, Italy
| | - Paola Menichini
- UOC Mutagenesis, Ospedale Policlinico San Martino, I-16132 Genova, Italy
| | - Giorgia Foggetti
- UOC Mutagenesis, Ospedale Policlinico San Martino, I-16132 Genova, Italy
| | - Paola Queirolo
- Medical Oncology Unit, Ospedale Policlinico San Martino, I-16132 Genova, Italy
| | - Alberto Izzotti
- UOC Mutagenesis, Ospedale Policlinico San Martino, I-16132 Genova, Italy
- Department of Health Sciences, University of Genova, I-16132 Genova, Italy
| | - Gilberto Fronza
- UOC Mutagenesis, Ospedale Policlinico San Martino, I-16132 Genova, Italy
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6
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Gao W, Jin J, Yin J, Land S, Gaither-Davis A, Christie N, Luketich JD, Siegfried JM, Keohavong P. KRAS and TP53 mutations in bronchoscopy samples from former lung cancer patients. Mol Carcinog 2017; 56:381-388. [PMID: 27182622 DOI: 10.1002/mc.22501] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Revised: 05/06/2016] [Accepted: 05/13/2016] [Indexed: 11/12/2022]
Abstract
Mutations in the KRAS and TP53 genes have been found frequently in lung tumors and specimens from individuals at high risk for lung cancer and have been suggested as predictive markers for lung cancer. In order to assess the prognostic value of these two genes' mutations in lung cancer recurrence, we analyzed mutations in codon 12 of the KRAS gene and in hotspot codons of the TP53 gene in 176 bronchial biopsies obtained from 77 former lung cancer patients. Forty-seven patients (61.0%) showed mutations, including 35/77 (45.5%) in the KRAS gene and 25/77 (32.5%) in the TP53 gene, among them 13/77 (16.9%) had mutations in both genes. When grouped according to past or current smoking status, a higher proportion of current smokers showed mutations, in particular those in the TP53 gene (P = 0.07), compared with ex-smokers. These mutations were found in both abnormal lesions (8/20 or 40%) and histologically normal tissues (70/156 or 44.9%) (P = 0.812). They consisted primarily of G to A transition and G to T transversion in both the KRAS (41/56 or 73.2%) and TP53 (24/34 or 70.6%) genes, consistent with mutations found in lung tumors of smoking lung cancer patients. Overall, recurrence-free survival (RFS) among all subjects could be explained by age at diagnosis, tumor stage, tumor subtype, and smoking (P < 0.05, Cox proportional hazard). Therefore, KRAS and TP53 mutations were frequently detected in bronchial tissues of former lung cancer patients. However, the presence of mutation of bronchial biopsies was not significantly associated with a shorter RFS time. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Weimin Gao
- Department of Environmental Toxicology, The Institute of Environmental and Human Health, Texas Tech University, Lubbock, Texas
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jide Jin
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jinling Yin
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Stephanie Land
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Neil Christie
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - James D Luketich
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jill M Siegfried
- Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Phouthone Keohavong
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
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7
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Carroll BL, Pulkoski-Gross MJ, Hannun YA, Obeid LM. CHK1 regulates NF-κB signaling upon DNA damage in p53- deficient cells and associated tumor-derived microvesicles. Oncotarget 2017; 7:18159-70. [PMID: 26921248 PMCID: PMC4951279 DOI: 10.18632/oncotarget.7566] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 01/23/2016] [Indexed: 12/15/2022] Open
Abstract
The recently discovered CHK1-Suppressed (CS) pathway is activated by inhibition or loss of the checkpoint kinase CHK1, promoting an apoptotic response to DNA damage mediated by caspase-2 in p53-deficient cells. Although functions of the CS-pathway have been investigated biochemically, it remains unclear whether and how CHK1 inhibition can be regulated endogenously and whether this constitutes a key component of the DNA damage response (DDR). Here, we present data that define the first endogenous activation of the CS-pathway whereby, upon DNA damage, wild type p53 acts as an endogenous regulator of CHK1 levels that modulates caspase-2 activation. Moreover, we demonstrate that persistence of CHK1 levels in response to DNA damage in p53-deficient cancer cells, leads to CHK1-mediated activation of NF-κB and induction of NF-κB-regulated genes in cells and in associated tumor-derived microvesicles (TMVs), both of which are abrogated by loss or inhibition of CHK1. These data define a novel role for CHK1 in the DDR pathway as a regulator NF-κB activity. Our data provide evidence that targeting CHK1 in p53-deficient cancers may abrogate NF-κB signaling that is associated with increased cellular survival and chemoresistance.
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Affiliation(s)
- Brittany L Carroll
- Stony Brook Cancer Center and The Department of Medicine, Stony Brook, New York, USA
| | - Michael J Pulkoski-Gross
- Stony Brook Cancer Center and The Department of Medicine, Stony Brook, New York, USA.,Pharmacological Sciences, Stony Brook University, Health Sciences Center, Stony Brook, New York, USA
| | - Yusuf A Hannun
- Stony Brook Cancer Center and The Department of Medicine, Stony Brook, New York, USA
| | - Lina M Obeid
- Stony Brook Cancer Center and The Department of Medicine, Stony Brook, New York, USA.,Northport Veterans Affairs Medical Center, Northport, New York, USA
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8
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ATM/CHK/p53 Pathway Dependent Chemopreventive and Therapeutic Activity on Lung Cancer by Pterostilbene. PLoS One 2016; 11:e0162335. [PMID: 27612029 PMCID: PMC5017581 DOI: 10.1371/journal.pone.0162335] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 08/22/2016] [Indexed: 01/16/2023] Open
Abstract
Among the many stilbenoids found in a variety of berries, resveratrol and pterostilbene are of particular interest given their potential for use in cancer therapeutics and prevention. We purified four stilbenoids from R. undulatum and found that pterostilbene inhibits cancer cell proliferation more efficiently than rhapontigenin, piceatannol and resveratrol. To investigate the underlying mechanism of this superior action of pterostilbene on cancer cells, we utilized a reverse-phase protein array followed by bioinformatic analysis and found that the ATM/CHK pathway is modified by pterostilbene in a lung cancer cell line. Given that ATM/CHK signaling requires p53 for its biological effects, we hypothesized that p53 is required for the anticancer effect of pterostilbene. To test this hypothesis, we used two molecularly defined precancerous human bronchial epithelial cell lines, HBECR and HBECR/p53i, with normal p53 and suppressed p53 expression, respectively, to represent premalignant states of squamous lung carcinogenesis. Pterostilbene inhibited the cell cycle more efficiently in HBECR cells compared to HBECR/p53i cells, suggesting that the presence of p53 is required for the action of pterostilbene. Pterostilbene also activated ATM and CHK1/2, which are upstream of p53, in both cell lines, though pterostilbene-induced senescence was dependent on the presence of p53. Finally, pterostilbene more effectively inhibited p53-dependent cell proliferation compared to the other three stilbenoids. These results strongly support the potential chemopreventive effect of pterostilbene on p53-positive cells during early carcinogenesis.
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9
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Costa MJ, Walls J, Dickerman A, Ames PF, Roth LM, Guinee D. Cell Cycle Control of Ovarian Granulosa Cells in Tumors and Cysts. Int J Surg Pathol 2016. [DOI: 10.1177/106689699600400201] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Ovarian granulosa cell tumors (GCTs) behave unpredictably. Stage I patients suffer recurrences many years after treatment, and histopathologic evaluation of the primary GCT offers few clues. p21IPl/wafl (Waft), the principle downstream effector of the p53-dependent pathway of growth control, inhibits cyclin-dependent kinases responsible for conversion of GI to S in the cell cycle. This study hypothesizes that immunohistochemistry for these proliferation-related markers will help discern granulosa cell growth control and may predict the GCTs' clinical behavior. Paraffin sections from a surgical series of 43 GCTs (34 primary and 9 recurrent: 19 diffuse and 18 typical adult; 6 juvenile type) and 12 benign cysts (8 follicular and 4 corpora luteal) were immunostained for Waft and p53. Ki67 (MIB-1 clone) proliferation index is the percent of nuclei immunoreactive on a count of at least 400. The 43 GCTs stained as follows: 40% Waft + (11 St = < 10%, 4 S2 = 10-50%, and 2 S3 = > 50% of nuclei) and 28% p53 + (2 W = weak, 8 S 1, 2 S2). All p53 + GCTs stained with Waf 1; the number of immunoreactive nuclei correlated (P < .00001). Juvenile more often than adult type GCTs exhibited Waf 1 (6/6) and p53 staining (5/6) (P < .001). No difference in pS3 or Waft staining was present in primary compared with recurrent GCTs. Ki67 proliferation index for GCTs ranged from 1 to 50% (mean, 13.8%; median, 10.9%) and associated with both p53 and Waft (P < .000 1). The 12 benign cysts stained as follows: 100% Waft + (6 S1, 5 S2, 1 S3) and 75% p53+ (4 W, 4 S1, 1 S2). Of the 43 patients, 41 were available for follow-up study: 15 suffered recurrences after 16-133 (mean 59.3, median 55) months, and 26 were disease-free 21-369 (mean 78.2, median 57.5) months after diagnosis. Waft staining of the primary GCT does not help predict recurrence. All GCTs immunoreactive for p53 produce Waft, suggesting detection of an active wild type p53 rather than overproduction of mutant p53. Waft is produced by granulosa cells in all benign functional cysts, suggesting a physiologic role in the ovulation sequence. Waf t's association with proliferation in GCTs suggests possible physiologic feedback. Proliferation (correlated with histopathologic grading) in GCTs may signify appropriate feedback control; thus it is not a predictor of aggressive clinical behavior.
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Affiliation(s)
- Michael J. Costa
- Pathology Department, Building Pat. 1, University of California, Davis, Medical Center, 2315 Stockton Boulevard, Sacramento, CA 95817
| | | | | | - Peter F. Ames
- Pathology Department, University of California, Davis, Davis and Sacramento, California
| | - Lawrence M. Roth
- Pathology Department, Indiana University Medical Center, Indianapolis, Indiana
| | - Donald Guinee
- Pathology Department, University of Utah Medical Center, Salt Lake City, Utah
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Gupta S, Khan H, Kushwaha VS, Husain N, Negi M, Ghatak A, Bhatt M. Impact of EGFR and p53 expressions on survival and quality of life in locally advanced oral squamous cell carcinoma patients treated with chemoradiation. Cancer Biol Ther 2016; 16:1269-80. [PMID: 26177827 DOI: 10.1080/15384047.2015.1070985] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
EGFR and p53 are molecular markers which play important role in tumor progression and development. The objective of this study was to assess the association between EGFR and p53 expression and survival, and to determine whether EGFR and p53 expression levels were associated with differences quality of life in OSCC patients undergoing chemoradiation. A total of 120 OSCC patients aged 20-67 y and stage III/IV were recruited. Treatment response was assessed according to W.H.O. (1979). EGFR and p53 expression in tumor tissue was estimated by immunohistochemical (IHC) method and quantified as percentage positive nuclei. Molecular marker expressions of both EGFR and p53 were found significantly (P < 0.01 or P < 0.001) associated with overall response, survivals and quality of life. Neither EGFR nor p53 expression was associated with hematologic or non-hematologic toxicity. EGFR and p53 molecular marker expressions may have significant association with survival and QOL in OSCC patients undergoing chemoradiation.
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Affiliation(s)
- Seema Gupta
- a Department of Radiotherapy ; King George's Medical University ; Lucknow , UP , India
| | - Huma Khan
- a Department of Radiotherapy ; King George's Medical University ; Lucknow , UP , India
| | | | - Nuzhat Husain
- b Department of Pathology ; RMLIMS ; Lucknow , UP , India
| | - Mps Negi
- c Clinical and Experimental Medicine Division; CSIR-Central Drug Research Institute ; Lucknow , UP , India
| | - Ashim Ghatak
- c Clinical and Experimental Medicine Division; CSIR-Central Drug Research Institute ; Lucknow , UP , India
| | - Mlb Bhatt
- a Department of Radiotherapy ; King George's Medical University ; Lucknow , UP , India
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11
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Imazawa T, Nishikawa A, Toyoda K, Furukawa F, Mitsui M, Hirose M. Sequential Alteration of Apoptosis, p53 Expression, and Cell Proliferation in the Rat Pancreas Treated with 4-Hydroxyaminoquinoline 1-Oxide. Toxicol Pathol 2016; 31:625-31. [PMID: 14585730 DOI: 10.1080/01926230390241855] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Changes in p53 expression, apoptosis and cell proliferation after treatment with 4-hydroxyaminoquinoline 1-oxide (4HAQO) were investigated in the rat pancreas and liver, target and nontarget organs for tumorigenesis, respectively. Male rats were given a single intravenous injection of 4HAQO at a dose of 20 mg/kg body weight and control rats received vehicle alone and were euthanized after 2—72 hours. Pancreata and livers were removed for histopathological examination, immunohistochemistry for p53 protein, PCNA and Ki-67, and TUNEL labeling and electron microscopic observation for detecting apoptosis. In the pancreas, p53 expression and apoptosis were significantly increased first at 4 and 6 hours, respectively, while no change was evident in the liver. The rates peaked at 24 hours, consistent with the peak for PCNA-labeling, while Ki-67-labeling rates peaked at 72 hours. Electron microscopically, apoptotic changes in pancreatic acinar cells were observed after 2 hours. No significant apoptosis, p53 expression or cell proliferation were noted in the pancreatic tissues of the control rats nor in liver cells regardless of 4HAQO treatment. Taken together with our previous data, the results suggest that apoptosis, p53 expression, and enhanced cell replication are closely related phenomena involved in the carcinogenesis of 4HAQO following DNA adduct formation.
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Affiliation(s)
- Takayoshi Imazawa
- Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
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12
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Trump BF. Mechanisms of Toxicity and Carcinogenesis. Toxicol Pathol 2016. [DOI: 10.1177/019262339502300616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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13
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Perz E, Kuhn JG. Review : p53 in the pathogenesis, diagnosis, and treatment of cancer. J Oncol Pharm Pract 2016. [DOI: 10.1177/107815529800400201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Objective. The cellular functions of p53, the conse quences of the loss of p53 function, and the potential impact of p53 in oncology are reviewed within the framework of an overview of the molecular basis of cancer and cell cycle control. Data Sources. A MEDLINE search of articles from 1976 to the present was conducted using the terms p53 protein and p53 gene. The search was restricted to the English language. Oncology and molecular biology textbooks were used as additional references. Data Extraction. We reviewed the literature to discuss the cellular function of p53, the mechanisms of p53 inactivation, the cellular consequences of the loss of p53 function, the role of p53 loss in tumori genesis, and the potential applications of this knowl edge. Data Synthesis. p53 mutations are found in ~ 50% of human cancers. Knowledge of p53 functions and defects provides the basis for potential applica tions in the areas of cancer epidemiology, cancer diagnosis, and determination of prognosis. An under standing of the functions and defects of p53 also presents a host of opportunities for the design of novel cancer therapies. Therapeutic approaches be ing studied include the restoration of p53 by gene therapy, the alteration of mutant p53 expression by antisense therapy, and the use of p53 mutations as a target for directing therapy to cancer cells; some of these approaches are already under phase I investiga tion. As knowledge of p53 unfolds, additional thera peutic approaches will certainly be developed. The story of p53 illustrates that the manipulation of mo lecular interactions is a new frontier in therapeutics and offers an additional role for oncology pharmacy specialists.
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Affiliation(s)
- Elizabeth Perz
- Department of Pharmacology, The University of Texas Health Science Center at San Antonio, College of Pharmacy, The University of Texas at Austin, Austin, Texas
| | - John G. Kuhn
- Department of Pharmacology, The University of Texas Health Science Center at San Antonio, Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, College of Pharmacy, The University of Texas at Austin, Austin, Texas
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Novel Implications of DNA Damage Response in Drug Resistance of Malignant Cancers Obtained from the Functional Interaction between p53 Family and RUNX2. Biomolecules 2015; 5:2854-76. [PMID: 26512706 PMCID: PMC4693260 DOI: 10.3390/biom5042854] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 09/17/2015] [Accepted: 10/16/2015] [Indexed: 12/31/2022] Open
Abstract
During the lifespan of cells, their genomic DNA is continuously exposed to the endogenous and exogenous DNA insults. Thus, the appropriate cellular response to DNA damage plays a pivotal role in maintaining genomic integrity and also acts as a molecular barrier towards DNA legion-mediated carcinogenesis. The tumor suppressor p53 participates in an integral part of proper regulation of DNA damage response (DDR). p53 is frequently mutated in a variety of human cancers. Since mutant p53 displays a dominant-negative behavior against wild-type p53, cancers expressing mutant p53 sometimes acquire drug-resistant phenotype, suggesting that mutant p53 prohibits the p53-dependent cell death pathway following DNA damage, and thereby contributing to the acquisition and/or maintenance of drug resistance of malignant cancers. Intriguingly, we have recently found that silencing of pro-oncogenic RUNX2 enhances drug sensitivity of aggressive cancer cells regardless of p53 status. Meanwhile, cancer stem cells (CSCs) have stem cell properties such as drug resistance. Therefore, the precise understanding of the biology of CSCs is quite important to overcome their drug resistance. In this review, we focus on molecular mechanisms behind DDR as well as the serious drug resistance of malignant cancers and discuss some attractive approaches to improving the outcomes of patients bearing drug-resistant cancers.
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Correlation between expressions of Cyclin-D1, EGFR and p53 with chemoradiation response in patients of locally advanced oral squamous cell carcinoma. BBA CLINICAL 2014; 3:11-7. [PMID: 26675419 PMCID: PMC4661497 DOI: 10.1016/j.bbacli.2014.11.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Revised: 11/10/2014] [Accepted: 11/14/2014] [Indexed: 11/24/2022]
Abstract
Introduction Cyclin-D1, p53 and EGFR are molecular markers that regulate the cell cycle and play an important role in tumor progression and development. The present study evaluates the prognostic significance of these markers with chemoradiation response in patients of locally advanced oral squamous cell carcinoma (OSCC). Material and method A total of 97 OSCC patients (females = 19 and males = 78), aged 20–67 years and stage III/IV were recruited. Treatment response was assessed according to WHO criteria. Cyclin-D1, p53 and EGFR expressions in tumor tissue was estimated by immunohistochemical (IHC) method and quantified as percentage positive nuclei. Results The positive expression rates of molecular markers were 86.6% for Cyclin-D1, 92.8% for EGFR and 85.6% for p53. The strong positive expressions of both Cyclin-D1 and p53 showed significant association with poor response. The Cox multivariate regression analysis showed coexpressions of Cyclin-D1 and p53 a significant and independent predictor of overall survival (OR = 1.90, 95% CI = 1.45–4.82, p = 0.046) after adjusting the demographic, clinicopathological and radiological response. The strong positive expressions of Cyclin-D1 and p53 and coexpressions of Cyclin-D1, EGFR and p53 showed significant (p < 0.05 or p < 0.01 or p < 0.001) and lower survival as compared to negative or moderate positive expressions and coexpressions, respectively. Conclusion Expressions and coexpressions of Cyclin-D1 and p53 may serve as a prognostic marker in OSCC patients.
Cyclin-D1, p53 and EGFR are molecular markers that regulate the cell cycle. Coexpressions of Cyclin-D1, EGFR & p53 serve as prognostic marker in advanced OSCC. p53 alone may serve as prognostic marker in patients of locally advanced OSCC.
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Ozaki T, Sugimoto H, Nakamura M, Hiraoka K, Yoda H, Sang M, Fujiwara K, Nagase H. Runt-related transcription factor 2 attenuates the transcriptional activity as well as DNA damage-mediated induction of pro-apoptotic TAp73 to regulate chemosensitivity. FEBS J 2014; 282:114-28. [PMID: 25331851 PMCID: PMC4368372 DOI: 10.1111/febs.13108] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Revised: 09/26/2014] [Accepted: 09/30/2014] [Indexed: 12/22/2022]
Abstract
Although runt-related transcription factor 2 (RUNX2) is known to be an essential key transcription factor for osteoblast differentiation and bone formation, RUNX2 also plays a pivotal role in the regulation of p53-dependent DNA damage response. In the present study, we report that, in addition to p53, RUNX2 downregulates pro-apoptotic TAp73 during DNA damage-dependent cell death. Upon adriamycin (ADR) exposure, human osteosarcoma-derived U2OS cells underwent cell death in association with an upregulation of TAp73 and various p53/TAp73-target gene products together with RUNX2. Small interfering RNA-mediated silencing of p73 resulted in a marked reduction in ADR-induced p53/TAp73-target gene expression, suggesting that TAp73 is responsible for the ADR-dependent DNA damage response. Immunoprecipitation and transient transfection experiments demonstrated that RUNX2 forms a complex with TAp73 and impairs its transcriptional activity. Notably, knockdown of RUNX2 stimulated ADR-induced cell death accompanied by a massive induction of TAp73 expression, indicating that RUNX2 downregulates TAp73 expression. Consistent with this notion, the overexpression of RUNX2 suppressed ADR-dependent cell death, which was associated with a remarkable downregulation of TAp73 and p53/TAp73-target gene expression. Collectively, our present findings strongly suggest that RUNX2 attenuates the transcriptional activity and ADR-mediated induction of TAp73, and may provide novel insights into understanding the molecular basis behind the development and/or maintenance of chemoresistance. Thus, we propose that the silencing of RUNX2 might be an attractive strategy for improving the chemosensitivity of malignant cancers.
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Affiliation(s)
- Toshinori Ozaki
- Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba, Japan
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Structural basis for inhibition of the MDM2:p53 interaction by an optimized MDM2-binding peptide selected with mRNA display. PLoS One 2014; 9:e109163. [PMID: 25275651 PMCID: PMC4183577 DOI: 10.1371/journal.pone.0109163] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Accepted: 08/29/2014] [Indexed: 12/21/2022] Open
Abstract
The oncoprotein MDM2 binds to tumor suppressor protein p53 and inhibits its anticancer activity, which leads to promotion of tumor cell growth and tumor survival. Abrogation of the p53:MDM2 interaction reportedly results in reactivation of the p53 pathway and inhibition of tumor cell proliferation. We recently performed rigorous selection of MDM2-binding peptides by means of mRNA display and identified an optimal 12-mer peptide (PRFWEYWLRLME), named MDM2 Inhibitory Peptide (MIP), which shows higher affinity for MDM2 (and also its homolog, MDMX) and higher tumor cell proliferation suppression activity than known peptides. Here we determined the NMR solution structure of a MIP-MDM2 fusion protein to elucidate the structural basis of the tight binding of MIP to MDM2. A region spanning from Phe3 to Met11 of MIP forms a single α-helix, which is longer than those of the other MDM2-binding peptides. MIP shares a conserved Phe3-Trp7-Leu10 triad, whose side chains are oriented towards and fit into the hydrophobic pockets of MDM2. Additionally, hydrophobic surface patches that surround the hydrophobic pockets of MDM2 are covered by solvent-exposed MIP residues, Trp4, Tyr6, and Met11. Their hydrophobic interactions extend the interface of the two molecules and contribute to the strong binding. The potential MDM2 inhibition activity observed for MIP turned out to originate from its enlarged binding interface. The structural information obtained in the present study provides a road map for the rational design of strong inhibitors of MDM2:p53 binding.
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Yeudall WA, Miyazaki H. Chemokines and squamous cancer of the head and neck: targets for therapeutic intervention? Expert Rev Anticancer Ther 2014; 7:351-60. [PMID: 17338654 DOI: 10.1586/14737140.7.3.351] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The biological properties of squamous carcinoma cells are intimately regulated by a multitude of cytokines and growth factors; the most well studied of these include epidermal growth factor receptor agonists and members of the transforming growth factor-beta family. The recent explosion of research in the field of chemokine function as a mediator of tumor progression has led to the possibility that these small, immunomodulatory proteins also play key roles in squamous carcinogenesis and may, therefore, be potential targets for novel therapeutic approaches.
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MESH Headings
- Amino Acid Motifs
- Amino Acid Sequence
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Carcinoma, Squamous Cell/blood supply
- Carcinoma, Squamous Cell/drug therapy
- Carcinoma, Squamous Cell/physiopathology
- Cell Survival
- Cell Transformation, Neoplastic
- Chemokines/antagonists & inhibitors
- Chemokines/physiology
- Chemokines, CXC/antagonists & inhibitors
- Chemokines, CXC/physiology
- Disease Progression
- Drug Design
- ErbB Receptors/antagonists & inhibitors
- ErbB Receptors/physiology
- Head and Neck Neoplasms/blood supply
- Head and Neck Neoplasms/drug therapy
- Head and Neck Neoplasms/physiopathology
- Humans
- Molecular Sequence Data
- Neoplasm Invasiveness
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/physiology
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/physiopathology
- Receptors, Chemokine/drug effects
- Receptors, Chemokine/physiology
- Sequence Alignment
- Sequence Homology, Amino Acid
- Signal Transduction
- Transforming Growth Factor beta/antagonists & inhibitors
- Transforming Growth Factor beta/physiology
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Affiliation(s)
- W Andrew Yeudall
- Virginia Commonwealth University School of Dentistry, Philips Institute for Oral & Craniofacial Molecular Biology, Department of Biochemistry and Massey Cancer Center, Richmond, VA 23298, USA.
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19
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Bruno A, Pagani A, Magnani E, Rossi T, Noonan DM, Cantelmo AR, Albini A. Inflammatory angiogenesis and the tumor microenvironment as targets for cancer therapy and prevention. Cancer Treat Res 2014; 159:401-426. [PMID: 24114493 DOI: 10.1007/978-3-642-38007-5_23] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
In addition to aberrant transformed cells, tumors are tissues that contain host components, including stromal cells, vascular cells (ECs) and their precursors, and immune cells. All these constituents interact with each other at the cellular and molecular levels, resulting in the production of an intricate and heterogeneous complex of cells and matrix defined as the tumor microenvironment. Several pathways involved in these interactions have been investigated both in pathological and physiological scenarios, and diverse molecules are currently targets of chemotherapeutic and preventive drugs. Many phytochemicals and their derivatives show the ability to inhibit tumor progression, angiogenesis, and metastasis, exerting effects on the tumor microenvironment. In this review, we will outline the principal players and mechanisms involved in the tumor microenvironment network and we will discuss some interesting compounds aimed at interrupting these interactions and blocking tumor insurgence and progression. The considerations provided will be crucial for the design of new preventive approaches to the reduction in cancer risk that need to be applied to large populations composed of apparently healthy individuals.
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Affiliation(s)
- Antonino Bruno
- Polo Scientifico e Tecnologico, MultiMedica Onlus, Milano, Italy
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20
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miR-16 and miR-26a target checkpoint kinases Wee1 and Chk1 in response to p53 activation by genotoxic stress. Cell Death Dis 2013; 4:e953. [PMID: 24336073 PMCID: PMC3877554 DOI: 10.1038/cddis.2013.483] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Revised: 10/31/2013] [Accepted: 11/04/2013] [Indexed: 01/07/2023]
Abstract
The tumour suppressor p53 is a crucial regulator of cell cycle arrest and apoptosis by acting as a transcription factor to regulate a variety of genes. At least in part, this control is exerted by p53 via regulating expression of numerous microRNAs. We identified two abundantly expressed microRNAs, miR-16 and miR-26a, whose expression is regulated by p53 during the checkpoint arrest induced by the genotoxic drug, doxorubicin. Importantly, among the targets of these miRs are two critical checkpoint kinases, Chk1 and Wee1. The p53-dependent augmentation of miR-16 and miR-26a expression levels led to the cell cycle arrest of tumour cells in G1/S and increased apoptosis. Strikingly, the bioinformatics analysis of survival times for patients with breast and prostate cancers has revealed that co-expression of mir-16 and miR-26a correlated with a better survival outcome. Collectively, our data provide a novel mechanism whereby p53 represses Chk1 and Wee1 expression, at least partially, via upregulation of miR-16 and miR-26a and thus sensitizes tumour cells to genotoxic therapies.
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21
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Sung YH, Jin Y, Kang Y, Devkota S, Lee J, Roh JI, Lee HW. Ei24, a novel E2F target gene, affects p53-independent cell death upon ultraviolet C irradiation. J Biol Chem 2013; 288:31261-7. [PMID: 24014029 DOI: 10.1074/jbc.m113.477570] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
The deficiency of retinoblastoma (Rb) gene deregulates E2F transcription factors and thus induces E2F target genes directly or p53 target genes indirectly via mouse p19(Arf) (or p14(ARF) in humans), an E2F target gene. Here, we identified that etoposide-induced 2.4 mRNA (Ei24)/p53-induced gene 8 (Pig8), a p53 target gene involved in apoptosis and autophagy, was up-regulated in Rb(-/-) mouse embryonic fibroblasts (MEFs). The Ei24 promoter was activated by E2F1 via multiple E2F-responsive elements, independently of the previously reported p53-responsive element. Chromatin immunoprecipitation assays revealed that E2F1 directly acts on the mouse Ei24 promoter. We observed that Ei24 expression was suppressed in p53(-/-) MEFs upon UVC irradiation, which was exacerbated in p53(-/-) E2f1(-/-) MEFs, supporting the positive role of E2F1 on Ei24 transcription. Furthermore, Ei24 knockdown sensitized p53(-/-) MEFs against UVC irradiation. Together, our data indicate that Ei24 is a novel E2F target gene contributing to the survival of p53-deficient cells upon UVC irradiation and thus may have a potential significance as a therapeutic target of certain chemotherapy for treating p53-deficient tumors.
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Affiliation(s)
- Young Hoon Sung
- From the Department of Biochemistry, College of Life Science and Biotechnology, and Laboratory Animal Research Center, Yonsei University, Seoul 120-749, Korea and
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22
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Moraes VWR, Caires ACF, Paredes-Gamero EJ, Rodrigues T. Organopalladium compound 7b targets mitochondrial thiols and induces caspase-dependent apoptosis in human myeloid leukemia cells. Cell Death Dis 2013; 4:e658. [PMID: 23744358 PMCID: PMC3702286 DOI: 10.1038/cddis.2013.190] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Revised: 05/04/2013] [Accepted: 05/07/2013] [Indexed: 12/11/2022]
Abstract
The advances in the treatment of chronic myeloid leukemia (CML) during the last years were also accompanied by the development of evading strategies by tumor cells, resulting in chemotherapy resistance in some patients. Patented organopalladium compounds derived from the reaction of N,N-dimethyl-1-phenethylamine (dmpa) with [1,2-ethanebis(diphenylphosphine)] (dppe) exhibited a potent antitumor activity in vivo and in vitro in melanoma cells. We showed here that the cyclopalladated derivative [Pd2(R(+))C(2), N-dmpa)2(μ-dppe)Cl2], named compound 7b, was highly effective to promote cell death in the K562 human leukemia cells and its mechanisms of action were investigated. It was shown that compound 7b was able to promote exclusively apoptotic cell death in K562 cells associated to cytochrome c release and caspase 3 activation. This cytotoxic effect was not observed in normal peripheral mononuclear blood cells. The compound 7b-induced intrinsic apoptotic pathway was triggered by the protein thiol oxidation that resulted in the dissipation of the mitochondrial transmembrane potential. The preventive effect of the dithiothreitol on the compound 7b-induced cell death and all downstream events associated to apoptosis confirmed that death signal was elicited by the thiol oxidation. These findings contribute to the elucidation of the palladacycle 7b-induced cell death mechanism and present this compound as a promising drug in the CML antitumor chemotherapy.
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Affiliation(s)
- V W R Moraes
- Centro de Ciências Naturais e Humanas, Universidade Federal do ABC (UFABC), São Paulo, Brazil
| | - A C F Caires
- Centro Interdisciplinar de Investigação Bioquímica (CIIB), Universidade de Mogi das Cruzes, São Paulo, Brazil
| | - E J Paredes-Gamero
- Departamento de Bioquímica, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - T Rodrigues
- Centro de Ciências Naturais e Humanas, Universidade Federal do ABC (UFABC), São Paulo, Brazil
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23
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Runt-related transcription factor 2 (RUNX2) inhibits p53-dependent apoptosis through the collaboration with HDAC6 in response to DNA damage. Cell Death Dis 2013; 4:e610. [PMID: 23618908 PMCID: PMC3641350 DOI: 10.1038/cddis.2013.127] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Runt-related transcription factor 2 (RUNX2) is the best known as an essential protein for osteoblast differentiation. In this study, we have found for the first time that RUNX2 acts as a negative regulator for p53 in response to DNA damage. On DNA damage mediated by adriamycin (ADR) exposure, p53 as well as RUNX2 was induced at protein and mRNA level in human osteosarcoma-derived U2OS cells in association with a significant upregulation of various p53-target genes. Indirect immunostaining and co-immunoprecipitation experiments demonstrated that RUNX2 colocalizes with p53 in cell nucleus and forms a complex with p53 following ADR treatment. Chromatin immunoprecipitation assays revealed that RUNX2/p53 complex is efficiently recruited onto p53-target promoters in response to ADR, suggesting that RUNX2 might be involved in the regulation of transcriptional activation mediated by p53. Indeed, forced expression of RUNX2 resulted in a remarkable downregulation of p53-target genes. Consistent with these observations, knockdown of RUNX2 enhanced ADR-mediated apoptosis and also elevated p53-target gene expression in response to ADR. On the other hand, depletion of RUNX2 in p53-deficient human lung carcinoma-derived H1299 cells had an undetectable effect on p53-target gene expression regardless of ADR treatment, indicating that RUNX2-mediated downregulation of p53-target genes is dependent on p53. Furthermore, RUNX2/p53 complex included histone deacetylase 6 (HDAC6) and HDAC6 was also recruited onto p53-target promoters following ADR exposure. Of note, HDAC6-specific chemical inhibitor tubacin treatment enhanced ADR-mediated upregulation of p53-target gene expression, indicating that deacetylase activity of HDAC6 is required for RUNX2-mediated downregulation of p53-target gene. Taken together, our present findings strongly suggest that RUNX2 inhibits DNA damage-induced transcriptional as well as pro-apoptotic activity of p53 through the functional collaboration with HDAC6 and therefore might be an attractive therapeutic target for cancer treatment.
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Association between the p53 codon 72 Arg/Pro polymorphism and hepatocellular carcinoma risk. Tumour Biol 2013; 34:1451-9. [PMID: 23564481 DOI: 10.1007/s13277-013-0649-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2012] [Accepted: 01/03/2013] [Indexed: 01/17/2023] Open
Abstract
Previous studies regarding the association of p53 codon 72 Arg/Pro polymorphism with hepatocellular carcinoma (HCC) risk have provided conflicting and inconclusive findings. Thus, a meta-analysis of all currently available publications was performed to address this issue. Eleven individual case-control studies involving a total of 2,718 cases and 3,752 controls were identified after a systematic search of the PubMed, Embase, Web of Science, and Wanfang databases. The strength of the association of p53 codon 72 Arg/Pro polymorphism with HCC risk was estimated by the pooled odds ratio (OR) with its corresponding 95 % confidence interval (95 % CI). Subgroup analyses stratified by ethnicity, source of controls, gender, hepatitis virus infection status, and family history of HCC were also conducted to assess the association. Overall, significantly increased risk of HCC was identified among carriers of the homozygous genotype ProPro (ORProPro vs. ArgArg=1.38 (95 % CI, 1.03-1.85), P OR=0.033; ORProPro vs. ArgArg + ArgPro =1.28 (95 % CI, 1.03-1.59), P OR=0.026). In subgroup analysis by ethnicity, the pooled results suggested that the p53 codon 72 Arg/Pro polymorphism was associated with an increased risk of HCC in Asians and Caucasians (for Asians, ORProPro vs. ArgArg + ArgPro=1.17 (95 % CI, 1.02-1.34), P OR=0.025; for Caucasians, ORProPro vs. ArgArg = 1.65 (95 % CI, 1.07-2.56), P OR=0.025; ORProPro vs. ArgArg + ArgPro=1.74 (95 % CI, 1.14-2.66), P OR=0.010). Subgroup analyses by source of controls and hepatitis virus infection status further demonstrated the significant association, whereas stratification factors involving gender and family history of HCC did not modify the association between p53 codon 72 Arg/Pro polymorphism and HCC risk. This meta-analysis suggests that the p53 codon 72 Arg/Pro polymorphism may play a critical role in the development of HCC, and gender and family history of HCC may not modulate the effect of p53 codon 72 Arg/Pro in HCC risk.
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Kubo N, Wu D, Yoshihara Y, Sang M, Nakagawara A, Ozaki T. Co-chaperon DnaJC7/TPR2 enhances p53 stability and activity through blocking the complex formation between p53 and MDM2. Biochem Biophys Res Commun 2012; 430:1034-9. [PMID: 23261415 DOI: 10.1016/j.bbrc.2012.11.121] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2012] [Accepted: 11/20/2012] [Indexed: 01/27/2023]
Abstract
Tumor suppressor p53 plays a critical role in the regulation of DNA damage response. Upon severe DNA damage, p53 promotes apoptosis to eliminate cells with seriously damaged DNA to maintain genomic integrity. Pro-apoptotic function of p53 is tightly linked to its sequence-specific transactivation ability. In the present study, we have identified co-chaperon DnaJC7/TPR2 as a novel binding partner of p53 by yeast-based two-hybrid screening. In the two-hybrid screening, we used the central DNA-binding domain of p53 as a bait. Co-immunoprecipitation experiments demonstrated that DnaJC7 is associated with p53 in mammalian cells. Luciferase reporter and colony formation assays revealed that DnaJC7 enhances p53-dependent transcriptional as well as growth-suppressive activity. Forced expression of DnaJC7 induced to extend a half-life of p53, indicating that DnaJC7-mediated activation of p53 might be at least in part due to its prolonged half-life. Consistent with these observations, the amount of p53/MDM2 complex was markedly reduced in the presence of DnaJC7, suggesting that DnaJC7 dissociates MDM2 from p53. Taken together, our present findings strongly suggest that DnaJC7 participates in p53/MDM2 negative feedback regulatory pathway, and thereby enhancing the stability and activity of p53.
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Affiliation(s)
- Natsumi Kubo
- Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan
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Wu D, Ozaki T, Yoshihara Y, Kubo N, Nakagawara A. Runt-related transcription factor 1 (RUNX1) stimulates tumor suppressor p53 protein in response to DNA damage through complex formation and acetylation. J Biol Chem 2012; 288:1353-64. [PMID: 23148227 DOI: 10.1074/jbc.m112.402594] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Representative tumor suppressor p53 plays a critical role in the regulation of proper DNA damage response. In this study, we have found for the first time that Runt-related transcription factor 1 (RUNX1) contributes to p53-dependent DNA damage response. Upon adriamycin (ADR) exposure, p53 as well as RUNX1 were strongly induced in p53-proficient HCT116 and U2OS cells, which were closely associated with significant transactivation of p53 target genes, such as p21(WAF)(1), BAX, NOXA, and PUMA. RUNX1 was exclusively expressed in the cell nucleus and formed a complex with p53 in response to ADR. Chromatin immunoprecipitation assay demonstrated that p53 together with RUNX1 are efficiently recruited onto p53 target gene promoters following ADR exposure, indicating that RUNX1 is involved in p53-mediated transcriptional regulation. Indeed, forced expression of RUNX1 stimulated the transcriptional activity of p53 in response to ADR. Consistent with these observations, knockdown of RUNX1 attenuated ADR-mediated induction of p53 target genes and suppressed ADR-dependent apoptosis. Furthermore, RUNX1 was associated with p300 histone acetyltransferase, and ADR-dependent acetylation of p53 at Lys-373/382 was markedly inhibited in RUNX1 knockdown cells. In addition, knockdown of RUNX1 resulted in a significant decrease in the amount of p53-p300 complex following ADR exposure. Taken together, our present results strongly suggest that RUNX1 is required for the stimulation of p53 in response to DNA damage and also provide novel insight into understanding the molecular mechanisms behind p53-dependent DNA damage response.
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Affiliation(s)
- Dan Wu
- Laboratory of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chiba 260-8717, Japan
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Loeb KR, Asgari MM, Hawes SE, Feng Q, Stern JE, Jiang M, Argenyi ZB, de Villiers EM, Kiviat NB. Analysis of Tp53 codon 72 polymorphisms, Tp53 mutations, and HPV infection in cutaneous squamous cell carcinomas. PLoS One 2012; 7:e34422. [PMID: 22545084 PMCID: PMC3335843 DOI: 10.1371/journal.pone.0034422] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2011] [Accepted: 02/28/2012] [Indexed: 12/26/2022] Open
Abstract
Background Non-melanoma skin cancers are one of the most common human malignancies accounting for 2–3% of tumors in the US and represent a significant health burden. Epidemiology studies have implicated Tp53 mutations triggered by UV exposure, and human papilloma virus (HPV) infection to be significant causes of non-melanoma skin cancer. However, the relationship between Tp53 and cutaneous HPV infection is not well understood in skin cancers. In this study we assessed the association of HPV infection and Tp53 polymorphisms and mutations in lesional specimens with squamous cell carcinomas. Methods We studied 55 cases of histologically confirmed cutaneous squamous cell carcinoma and 41 controls for the presence of HPV infection and Tp53 genotype (mutations and polymorphism). Results We found an increased number of Tp53 mutations in the squamous cell carcinoma samples compared with perilesional or control samples. There was increased frequency of homozygous Tp53-72R polymorphism in cases with squamous cell carcinomas, while the Tp53-72P allele (Tp53-72R/P and Tp53-72P/P) was more frequent in normal control samples. Carcinoma samples positive for HPV showed a decreased frequency of Tp53 mutations compared to those without HPV infection. In addition, carcinoma samples with a Tp53-72P allele showed an increased incidence of Tp53 mutations in comparison carcinomas samples homozygous for Tp53-72R. Conclusions These studies suggest there are two separate pathways (HPV infection and Tp53 mutation) leading to cutaneous squamous cell carcinomas stratified by the Tp53 codon-72 polymorphism. The presence of a Tp53-72P allele is protective against cutaneous squamous cell carcinoma, and carcinoma specimens with Tp53-72P are more likely to have Tp53 mutations. In contrast Tp53-72R is a significant risk factor for cutaneous squamous cell carcinoma and is frequently associated with HPV infection instead of Tp53 mutations. Heterozygosity for Tp53-72R/P is protective against squamous cell carcinomas, possibly reflecting a requirement for both HPV infection and Tp53 mutations.
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Affiliation(s)
- Keith R. Loeb
- Divisions of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Pathology, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - Maryam M. Asgari
- Department of Epidemiology, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - Stephen E. Hawes
- Department of Epidemiology, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - Qinghua Feng
- Department of Pathology, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - Joshua E. Stern
- Department of Pathology, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - Mingjun Jiang
- Institute of Dermatology, National Academy of Medical Sciences, Nanjing, People’s Republic of China
| | - Zsolt B. Argenyi
- Department of Pathology, University of Washington School of Medicine, Seattle, Washington, United States of America
- Division of Dermatology, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - Ethel-Michele de Villiers
- Division for the Characterization of Tumorviruses, Deutsches Krebsforschungszentrum, Heidelberg, Germany
| | - Nancy B. Kiviat
- Department of Pathology, University of Washington School of Medicine, Seattle, Washington, United States of America
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America
- * E-mail:
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Yoshihara Y, Wu D, Kubo N, Sang M, Nakagawara A, Ozaki T. Inhibitory role of E2F-1 in the regulation of tumor suppressor p53 during DNA damage response. Biochem Biophys Res Commun 2012; 421:57-63. [DOI: 10.1016/j.bbrc.2012.03.108] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2012] [Accepted: 03/21/2012] [Indexed: 10/28/2022]
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Abstract
The characterization of functional CD8(+) inhibitory or regulatory T cells and their gene regulation remains a critical challenge in the field of tolerance and autoimmunity. Investigating the genes induced in regulatory cells and the regulatory networks and pathways that underlie mechanisms of immune resistance and prevent apoptosis in the CD8(+) T cell compartment are crucial to understanding tolerance mechanisms in systemic autoimmunity. Little is currently known about the genetic control that governs the ability of CD8(+) Ti or regulatory cells to suppress anti-DNA Ab production in B cells. Silencing genes with siRNA or shRNA and overexpression of genes with lentiviral cDNA transduction are established approaches to identifying and understanding the function of candidate genes in tolerance and immunity. Elucidation of interactions between genes and proteins, and their synergistic effects in establishing cell-cell cross talk, including receptor modulation/antagonism, are essential for delineating the roles of these cells. In this review, we will examine recent reports which describe the modulation of cells from lupus prone mice or lupus patients to confer anti-inflammatory and protective gene expression and novel associated phenotypes. We will highlight recent findings on the role of selected genes induced by peptide tolerance in CD8(+) Ti.
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Liu J, Shao C, Tan ML, Mu D, Ferris RL, Ha PK. Molecular biology of adenoid cystic carcinoma. Head Neck 2011; 34:1665-77. [PMID: 22006498 DOI: 10.1002/hed.21849] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/19/2011] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Adenoid cystic carcinoma (ACC) is an unusual salivary gland malignancy that remains poorly understood. Standard treatment, including surgery with postoperative radiation therapy, has attained reasonable local control rates, but the propensity for distant metastases has limited any improvement in survival over time. Our understanding of the molecular mechanisms driving ACC is quite rudimentary, due to the infrequent nature of its occurrence. METHODS An extensive literature review was performed on salivary gland ACCs and basic science research findings. RESULTS This review highlights many findings that are emerging about the carcinogenesis of ACC including cytogenetics, tumor suppressor genes, oncogenes, epigenetic alterations, mitochondrial alterations, and biomarker studies. CONCLUSION Although there have been many discoveries, much still remains unknown about this rare malignancy. © 2011 Wiley Periodicals, Inc. Head Neck, 2011.
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Affiliation(s)
- Jia Liu
- University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Taylor ATS, Rogers JC. The ethical implications of genetic testing in the classroom. BIOCHEMISTRY AND MOLECULAR BIOLOGY EDUCATION : A BIMONTHLY PUBLICATION OF THE INTERNATIONAL UNION OF BIOCHEMISTRY AND MOLECULAR BIOLOGY 2011; 39:253-260. [PMID: 21774053 DOI: 10.1002/bmb.20521] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
The development of classroom experiments where students examine their own DNA is frequently described as an innovative teaching practice. Often these experiences involve students analyzing their genes for various polymorphisms associated with disease states, like an increased risk for developing cancer. Such experiments can muddy the distinction between classroom investigation and medical testing. Although the goals and issues surrounding classroom genotyping do not directly align with those of clinical testing, instructors can use the guidelines and standards established by the medical genetics community when evaluating the ethics of human genotyping. We developed a laboratory investigation and discussion which allowed undergraduate science students to explore current DNA manipulation techniques to isolate their p53 gene, followed by a dialogue probing the ethical implications of examining their sample for various polymorphisms. Students never conducted genotyping on their samples because of the ethical concerns presented in this paper, so the discussion replaced the actual genetic testing in the class. A science faculty member led the laboratory portion, while a genetic counselor facilitated the discussion of the ethical concepts underlying genetic counseling: autonomy, beneficence, confidentiality, and justice. In their final papers, students demonstrated an understanding of the practice guidelines established by the genetics community and acknowledged the ethical considerations inherent in p53 genotyping. Given the burgeoning market for personalized medicine, teaching undergraduates about the psychosocial and ethical dimensions of human genetic testing is important and timely. Moreover, incorporating a genetic counselor in the classroom discussion provided a rich and dynamic discussion of human genetic testing.
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Affiliation(s)
- Ann T S Taylor
- Department of Chemistry, Wabash College, Crawfordsville, Indiana 47933, USA.
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Affiliation(s)
- Rao N. Jaladanki
- University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center
| | - Jian-Ying Wang
- University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center
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33
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Rogers JC, Taylor ATS. Teaching about genetic testing issues in the undergraduate classroom: a case study. J Genet Couns 2011; 20:231-40. [PMID: 21373958 DOI: 10.1007/s10897-011-9352-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Accepted: 01/14/2011] [Indexed: 11/30/2022]
Abstract
Educating undergraduates about current genetic testing and genomics can involve novel and creative teaching practices. The higher education literature describes numerous pedagogical approaches in the laboratory designed to engage science and liberal arts students. Often these experiences involve students analyzing their own genes for various polymorphisms, some of which are associated with disease states such as an increased risk for developing cancer. While the literature acknowledges possible ethical ramifications of such laboratory exercises, authors do not present recommendations or rubrics for evaluating whether or not the testing is, in fact, ethical. In response, we developed a laboratory investigation and discussion which allowed undergraduate science students to explore current DNA manipulation techniques to isolate their p53 gene, followed by a dialogue probing the ethical implications of examining their sample for various polymorphisms. Students never conducted genotyping on their samples because of ethical concerns, so the discussion served to replace actual genetic testing in the class. A basic scientist led the laboratory portion of the assignment. A genetic counselor facilitated the discussion, which centered around existing ethical guidelines for clinical genetic testing and possible challenges of human genotyping outside the medical setting. In their final papers, students demonstrated an understanding of the practice guidelines established by the genetics community and acknowledged the ethical considerations inherent in p53 genotyping. Given the burgeoning market for personalized medicine, teaching undergraduates about the psychosocial and ethical dimensions of human gene testing seems important and timely, and introduces an additional role genetic counselors can play in educating consumers about genomics.
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Sung YH, Kim HJ, Devkota S, Roh J, Lee J, Rhee K, Bahk YY, Lee HW. Pierce1, a Novel p53 Target Gene Contributing to the Ultraviolet-Induced DNA Damage Response. Cancer Res 2010; 70:10454-63. [DOI: 10.1158/0008-5472.can-10-0031] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Wei Y, Lin Y, Zhang AQ, Guo LH, Cao J. Evaluation of the noncovalent binding interactions between polycyclic aromatic hydrocarbon metabolites and human p53 cDNA. THE SCIENCE OF THE TOTAL ENVIRONMENT 2010; 408:6285-90. [PMID: 20932552 DOI: 10.1016/j.scitotenv.2010.09.024] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2009] [Revised: 09/10/2010] [Accepted: 09/13/2010] [Indexed: 05/22/2023]
Abstract
The binding of reactive polycyclic aromatic hydrocarbon (PAH) metabolites, formed enzymatically, to DNA is a crucial step in PAH carcinogenesis in vivo. We investigated the noncovalent binding interactions between 11 PAH metabolites and human p53 complementary DNA (p53 cDNA) using the fluorescence displacement method and molecular docking analysis. All of the examined metabolites predominantly interacted with p53 cDNA by intercalation instead of groove binding. The dissociation constants ranged from 0.02 to 12.34μM. Of the metabolites tested, 1-hydroxypyrene and 3-hydroxybenzo[a]pyrene showed the strongest binding affinities to DNA, while 2-naphthol was the weakest DNA intercalator. The intercalation of the metabolites was stabilized by stacking the PAH phenyl rings with the DNA base pairs and the formation of hydrogen bonds between the oxide or hydroxyl groups on the metabolites, and DNA bases or backbones. The binding of the metabolites to DNA showed some sequence selectivity. The binding affinities and hydrogen bonds for 3-hydroxybenzo[a]pyrene, benzo[a]pyrene-4,5-dihydroepoxide (BPE) and benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide (BPDE) differed. It seems that the functional groups on the periphery of the PAH aromatic ring play crucial roles in regulating its binding affinity with DNA. Although it was difficult to determine the correlation between DNA noncovalent binding affinity and carcinogenicity for some of the PAH metabolites, the present study improved our understanding of the formation of PAH metabolite-DNA adducts.
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Affiliation(s)
- Yin Wei
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, Beijing 100085, China.
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36
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Soares AB, Altemani A, de Araújo VC. Study of histopathological, morphological and immunohistochemical features of recurrent pleomorphic adenoma: an attempt to predict recurrence of pleomorphic adenoma. J Oral Pathol Med 2010; 40:352-8. [PMID: 20969626 DOI: 10.1111/j.1600-0714.2010.00956.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Recurrent pleomorphic adenoma (RPA) is an uncommon and challenging disease. The aim of this study was to review the clinical information obtained by examining RPA patients, to determine its histomorphological features and to verify the expression of the Mcm-2 markers of cell proliferation and the expression of p-53 in pleomorphic adenoma (PA), RPA, and RPA with malignant transformation (TRPA). METHODS A total of 10 cases of PA and 29 cases of RPA were examined in detail for the presence of nodules and their histomorphological features. Cell proliferation and expression of p-53 were detected by the immunohistochemical technique using the antibodies against Mcm-2 and p-53. RESULTS Histopathologically, RPA is very similar to PA; the only difference found was that all the cases of RPA were multinodular. When comparing primary and recurrent tumor, no significant difference was found in terms of cell proliferation and the expression of p-53; however, in the RPA with areas of malignant transformation there was an increased expression of these proteins. CONCLUSION This study showed that recurrences were multinodular, with nodules varying in numbers and sizes. No significant difference in histological features was found between RPA and PA. Moreover, the immunohistochemical study showed a low expression of p-53 and Mcm-2 in PA and RPA and an increased expression of these proteins in the RPA with areas of malignant transformation.
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Abstract
Cancer recapitulates Darwinian evolution. Mutations acquired during life that provide cells with a growth or survival advantage will preferentially multiply to form a tumor. As a result of The Cancer Genome Atlas Project, we have gathered detailed information on the nucleotide sequence changes in a number of human cancers. The sources of mutations in cancer are diverse, and the complexity of those found to be clonally present in tumors has increasingly made it difficult to identify key rate-limiting genes for tumor growth that could serve as potential targets for directed therapies. The impact of DNA sequencing on future cancer research and personalized therapy is likely to be profound and merits critical evaluation.
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Affiliation(s)
- Jesse J Salk
- Joseph Gottstein Memorial Cancer Research Laboratory, Department of Pathology, University of Washington, Seattle, Washington 98195, USA
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38
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Salem MMAEL, Shalbaf M, Gibbons NCJ, Chavan B, Thornton JM, Schallreuter KU. Enhanced DNA binding capacity on up‐regulated epidermal wild‐type p53 in vitiligo by H
2
O
2
‐mediated oxidation: a possible repair mechanism for DNA damage. FASEB J 2009; 23:3790-807. [PMID: 19641144 DOI: 10.1096/fj.09-132621] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Mohamed M. A. E. L. Salem
- Clinical and Experimental Dermatology Department of Biomedical Sciences/Centre for Skin Sciences School of Life Sciences University of Bradford Bradford UK
| | - Mohammad Shalbaf
- Clinical and Experimental Dermatology Department of Biomedical Sciences/Centre for Skin Sciences School of Life Sciences University of Bradford Bradford UK
| | - Nicholas C. J. Gibbons
- Clinical and Experimental Dermatology Department of Biomedical Sciences/Centre for Skin Sciences School of Life Sciences University of Bradford Bradford UK
- University of Bradford Bradford UK
| | - Bhaven Chavan
- Clinical and Experimental Dermatology Department of Biomedical Sciences/Centre for Skin Sciences School of Life Sciences University of Bradford Bradford UK
| | - J. M. Thornton
- Clinical and Experimental Dermatology Department of Biomedical Sciences/Centre for Skin Sciences School of Life Sciences University of Bradford Bradford UK
| | - Karin U. Schallreuter
- Clinical and Experimental Dermatology Department of Biomedical Sciences/Centre for Skin Sciences School of Life Sciences University of Bradford Bradford UK
- Institute for Pigmentary Disorders in association with E. M. Arndt University Greifswald Germany
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Abstract
With the publishing of the first complete whole genome of a human cancer and its paired normal, we have passed a key milestone in the cancer genome sequencing strategy. The generation of such data will, thanks to technical advances, soon become commonplace. As a significant number of proof-of-concept studies have been published, it is important to analyze now the likely implications of these data and how this information might frame cancer research in the near future. The diversity of genes mutated within individual tumor types, the most striking feature of all studies reported to date, challenges gene-centric models of tumorigenesis. Although cancer genome sequencing will revolutionize certain aspects of personalized care, the value of these studies in facilitating the development of new therapies, their primary goal, seems less promising. Most significantly, however, the cancer genome sequencing strategy, as currently applied, fails to characterize the most relevant genomic features of cancer-the mutational heterogeneity within individual tumors.
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Affiliation(s)
- Edward J Fox
- Joseph Gottstein Memorial Laboratory, Department of Pathology, University of Washington, Seattle, Washington 98195, USA
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40
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Hong HHL, Ton TVT, Kim Y, Wakamatsu N, Clayton NP, Chan PC, Sills RC, Lahousse SA. Genetic alterations in K-ras and p53 cancer genes in lung neoplasms from B6C3F1 mice exposed to cumene. Toxicol Pathol 2008; 36:720-6. [PMID: 18648094 DOI: 10.1177/0192623308320280] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The incidences of alveolar/bronchiolar adenomas and carcinomas in cumene-treated B6C3F1 mice were significantly greater than those of the control animals. We evaluated these lung neoplasms for point mutations in the K-ras and p53 genes that are often mutated in humans. K-ras and p53 mutations were detected by cycle sequencing of PCR-amplified DNA isolated from paraffin-embedded neoplasms. K-ras mutations were detected in 87% of cumene-induced lung neoplasms, and the predominant mutations were exon 1 codon 12 G to T transversions and exon 2 codon 61 A to G transitions. P53 protein expression was detected by immunohistochemistry in 56% of cumene-induced neoplasms, and mutations were detected in 52% of neoplasms. The predominant mutations were exon 5, codon 155 G to A transitions, and codon 133 C to T transitions. No p53 mutations and one of seven (14%) K-ras mutations were detected in spontaneous neoplasms. Cumene-induced lung carcinomas showed loss of heterozygosity (LOH) on chromosome 4 near the p16 gene (13%) and on chromosome 6 near the K-ras gene (12%). No LOH was observed in spontaneous carcinomas or normal lung tissues examined. The pattern of mutations identified in the lung tumors suggests that DNA damage and genomic instability may be contributing factors to the mutation profile and development of lung cancer in mice exposed to cumene.
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Affiliation(s)
- Hue-Hua L Hong
- 1 Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
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41
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Bodmer W, Bielas JH, Beckman RA. Genetic instability is not a requirement for tumor development. Cancer Res 2008; 68:3558-60; discussion 3560-1. [PMID: 18483234 DOI: 10.1158/0008-5472.can-07-6544] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Walter Bodmer
- Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom
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42
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Rogers CJ, Colbert LH, Greiner JW, Perkins SN, Hursting SD. Physical activity and cancer prevention : pathways and targets for intervention. Sports Med 2008; 38:271-96. [PMID: 18348589 DOI: 10.2165/00007256-200838040-00002] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The prevalence of obesity, an established epidemiological risk factor for many cancers, has risen steadily for the past several decades in the US and many other countries. Particularly alarming are the increasing rates of obesity among children, portending continuing increases in the rates of obesity and obesity-related cancers for many years to come. Modulation of energy balance, via increased physical activity, has been shown in numerous comprehensive epidemiological reviews to reduce cancer risk. Unfortunately, the effects and mechanistic targets of physical activity interventions on the carcinogenesis process have not been thoroughly characterized. Studies to date suggest that exercise can exert its cancer-preventive effects at many stages during the process of carcinogenesis, including both tumour initiation and progression. As discussed in this review, exercise may be altering tumour initiation events by modifying carcinogen activation, specifically by enhancing the cytochrome P450 system and by enhancing selective enzymes in the carcinogen detoxification pathway, including, but not limited to, glutathione-S-transferases. Furthermore, exercise may reduce oxidative damage by increasing a variety of anti-oxidant enzymes, enhancing DNA repair systems and improving intracellular protein repair systems. In addition to altering processes related to tumour initiation, exercise may also exert a cancer-preventive effect by dampening the processes involved in the promotion and progression stages of carcinogenesis, including scavenging reactive oxygen species (ROS); altering cell proliferation, apoptosis and differentiation; decreasing inflammation; enhancing immune function; and suppressing angiogenesis. A paucity of data exists as to whether exercise may be working as an anti-promotion strategy via altering ROS in initiated or preneoplastic models; therefore, no conclusions can be made about this possible mechanism. The studies directly examining cell proliferation and apoptosis have shown that exercise can enhance both processes, which is difficult to interpret in the context of carcinogenesis. Studies examining the relationship between exercise and chronic inflammation suggest that exercise may reduce pro-inflammatory mediators and reduce the state of low-grade, chronic inflammation. Additionally, exercise has been shown to enhance components of the innate immune response (i.e. macrophage and natural killer cell function). Finally, only a limited number of studies have explored the relationship between exercise and angiogenesis; therefore, no conclusions can be made currently about the role of exercise in the angiogenesis process as it relates to tumour progression. In summary, exercise can alter biological processes that contribute to both anti-initiation and anti-progression events in the carcinogenesis process. However, more sophisticated, detailed studies are needed to examine each of the potential mechanisms contributing to an exercise-induced decrease in carcinogenesis in order to determine the minimum dose, duration and frequency of exercise needed to yield significant cancer-preventive effects, and whether exercise can be used prescriptively to reverse the obesity-induced physiological changes that increase cancer risk.
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Affiliation(s)
- Connie J Rogers
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
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Benjamin CL, Ullrich SE, Kripke ML, Ananthaswamy HN. p53 tumor suppressor gene: a critical molecular target for UV induction and prevention of skin cancer. Photochem Photobiol 2008; 84:55-62. [PMID: 18173701 DOI: 10.1111/j.1751-1097.2007.00213.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The relationship between exposure to UV radiation and development of skin cancer has been well established. Several studies have shown that UVB induces unique mutations (C-->T and CC-->TT transitions) in the p53 tumor suppressor gene that are not commonly induced by other carcinogens. Our studies have demonstrated that UV-induced mouse skin cancers contain p53 mutations at a high frequency and that these mutations can be detected in UV-irradiated mouse skin well before the appearance of skin tumors. This observation suggested that it might be possible to use p53 mutations as a biologic endpoint for testing the efficacy of sunscreens in photoprotection studies. Indeed, application of SPF 15 sunscreens to mouse skin before each UVB irradiation resulted in reduction in the number of p53 mutations. Because p53 mutations represent an early essential step in photocarcinogenesis, these results imply that inhibition of this event may protect against skin cancer development. This hypothesis was confirmed by our finding that sunscreens used in p53 mutation inhibition experiments also protected mice against UVB-induced skin cancer.
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Affiliation(s)
- Cara L Benjamin
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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44
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Bingham SA. Epidemiology and Mechanisms Relating Diet to Risk of Colorectal Cancer. Nutr Res Rev 2007; 9:197-239. [DOI: 10.1079/nrr19960012] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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45
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Bodmer WF, Tomlinson I. Population genetics of tumours. CIBA FOUNDATION SYMPOSIUM 2007; 197:181-9; discussion 189-93. [PMID: 8827374 DOI: 10.1002/9780470514887.ch10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The available evidence suggests that cancer is essentially a somatic evolutionary process involving a series of mutations. Each mutation gives some advantage to a selected clone, and expansion then occurs within that selected clone. The advantages are associated with both growth rate and factors leading to independent growth. The aim of this paper is first to give some background information on genetic changes in tumours, using colorectal cancer as an example. We will then introduce a mathematical model that explains many phenomena associated with the development of benign tumours and the long lag periods that are characteristic of the development of human tumours. The model addresses populations of cells and not populations of people.
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Affiliation(s)
- W F Bodmer
- Imperial Cancer Research Fund, London, UK
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46
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Ivanov GS, Ivanova T, Kurash J, Ivanov A, Chuikov S, Gizatullin F, Herrera-Medina EM, Rauscher F, Reinberg D, Barlev NA. Methylation-acetylation interplay activates p53 in response to DNA damage. Mol Cell Biol 2007; 27:6756-69. [PMID: 17646389 PMCID: PMC2099237 DOI: 10.1128/mcb.00460-07] [Citation(s) in RCA: 145] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
p53, an important tumor suppressor protein, exerts its function mostly as a sequence-specific transcription factor and is subjected to multiple posttranslational modifications in response to genotoxic stress. Recently, we discovered that lysine methylation of p53 at K372 by Set7/9 (also known as SET7 and Set9) is important for transcriptional activation and stabilization of p53. In this report we provide a molecular mechanism for the effect of p53 methylation on transcription. We demonstrate that Set7/9 activity toward p53, but not the nucleosomal histones, is modulated by DNA damage. Significantly, we show that lysine methylation of p53 is important for its subsequent acetylation, resulting in stabilization of the p53 protein. These p53 modification events can be observed on the promoter of p21 gene, a known transcriptional target of p53. Finally, we show that methylation-acetylation interplay in p53 augments acetylation of histone H4 in the promoter of p21 gene, resulting in its subsequent transcriptional activation and, hence, cell cycle arrest. Collectively, these results suggest that the cross talk between lysine methylation and acetylation is critical for p53 activation in response to DNA damage and that Set7/9 may play an important role in tumor suppression.
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Affiliation(s)
- Gleb S Ivanov
- Molecular Oncology Research Institute, NEMC-Tufts, Boston, MA 02111, USA
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Takeba Y, Kumai T, Matsumoto N, Nakaya S, Tsuzuki Y, Yanagida Y, Kobayashi S. Irinotecan activates p53 with its active metabolite, resulting in human hepatocellular carcinoma apoptosis. J Pharmacol Sci 2007; 104:232-42. [PMID: 17609585 DOI: 10.1254/jphs.fp0070442] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The topoisomerase I inhibitor irinotecan is widely used in anticancer therapy, although the detailed mechanism is still unclear. We investigated the apoptotic mechanisms of irinotecan in human hepatocellular carcinoma (HCC) cell lines (Huh7). SN-38 caused a significant decrease in cell proliferation and induced apoptosis in Huh7 cells and HepG2 cells. SN-38 significantly increased the expression of p53 protein and its phosphorylation at Ser(15) in the nucleus and apoptosis-inducing proteins Bax, caspase-9, and caspase-3, while it significantly decreased the antiapoptosis protein Bcl-xL of Huh7 cells. SN-38-induced apoptosis was recovered after p53 antisense oligodeoxynucleotide (AS ODN) pretreatment, while Huh7 cells were precultured with p53 AS ODN, followed by the addition of SN-38 for 24 h. Furthermore, increases in p53 DNA-binding activity were observed in the nuclei of Huh7 cells after SN-38 treatment as shown by electrophoretic mobility shift analysis. SN-38 binding motifs were detected in the proximal promoter of p53 (bases -433 to -317 and -814 to -711). These results suggest that the p53-mediated apoptosis pathway is important in the anticancer effects of irinotecan in hepatocellular carcinoma.
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Affiliation(s)
- Yuko Takeba
- Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaski, Kanagawa 216-8511, Japan.
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Zhang AH, Rao JN, Zou T, Liu L, Marasa BS, Xiao L, Chen J, Turner DJ, Wang JY. p53-Dependent NDRG1 expression induces inhibition of intestinal epithelial cell proliferation but not apoptosis after polyamine depletion. Am J Physiol Cell Physiol 2007; 293:C379-89. [PMID: 17442733 DOI: 10.1152/ajpcell.00547.2006] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Normal intestinal mucosal growth requires polyamines that regulate expression of various genes involved in cell proliferation, growth arrest, and apoptosis. Our previous studies have shown that polyamine depletion stabilizes p53, resulting in inhibition of intestinal epithelial cell (IEC) proliferation, but the exact downstream targets of induced p53 are still unclear. The NDRG1 (N- myc downregulated gene-1) gene encodes a growth-related protein, and its transcription can be induced in response to stress. The current study tests the hypothesis that induced p53 inhibits IEC proliferation by upregulating NDRG1 expression following polyamine depletion. Depletion of cellular polyamines by inhibiting ornithine decarboxylase (ODC) with α-difluoromethylornithine not only induced p53 but also increased NDRG1 transcription as indicated by induction of the NDRG1 promoter activity and increased levels of NDRG1 mRNA and protein, all of which were prevented by using specific p53 siRNA and in cells with a targeted deletion of p53. In contrast, increased levels of cellular polyamines by ectopic expression of the ODC gene decreased p53 and repressed expression of NDRG1. Consistently, polyamine depletion-induced activation of the NDRG1-promoter was decreased when p53-binding sites within the NDRG1 proximal promoter region were deleted. Ectopic expression of the wild-type NDRG1 gene inhibited DNA synthesis and decreased final cell numbers regardless of the presence or absence of endogenous p53, whereas silencing NDRG1 promoted cell growth. However, overexpression of NDRG1 failed to directly induce cell death and to alter susceptibility to apoptosis induced by tumor necrosis factor-α/cycloheximide. These results indicate that NDRG1 is one of the direct mediators of induced p53 following polyamine depletion and that p53-dependent NDRG1 expression plays a critical role in the negative control of IEC proliferation.
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Affiliation(s)
- Ai-Hong Zhang
- Dept. of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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Yazici AC, Karabulut AA, Ozen O, Ekşioğlu M, Ustün H. Expression of p53 in lesions and unaffected skin of patients with plaque-type and guttate psoriasis: A quantitative comparative study. J Dermatol 2007; 34:367-74. [PMID: 17535401 DOI: 10.1111/j.1346-8138.2007.00290.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Psoriasis is a common inflammatory and hyperproliferative skin disease characterized by hyperproliferation of keratinocytes. The pathogenesis of psoriasis has yet to be determined. The control of cell growth is a delicately balanced process, regulated by external signals or the internal genetic program of an individual cell. In psoriasis, these processes are disturbed and some candidate genes like p53 are suspected of being involved in the pathogenesis of the disease. The p53 protein is essential for the regulation of cell proliferation. The study was performed on 32 patients with psoriasis (24 plaque type, eight guttate type). Biopsy specimens for immunohistochemical determination of p53 protein expression were collected from both the lesional and the nonlesional skin sites that were not exposed to sun in all of the patients (n = 32). Taking the ultraviolet (UV) exposure of the skin into consideration, a third skin sample was taken from each patient (n = 7) who had lesions on the sun-exposed areas. Immunohistochemical assessment of p53 expression in skin was determined as p53 protein expression per 1000 cells (keratinocytes). The statistical analysis revealed that the expressions of p53 per 1000 cells were higher in non-sun-exposed lesional skin than the non-sun-exposed nonlesional skin, also in plaque-type psoriasis than guttate-type psoriasis (P = 0.000, P = 0.046, P = 0.037, respectively). There was a positive correlation between the p53 expression in non-sun-exposed lesional skin versus expression in sun-exposed lesional skin (cubic centimeters = 0.811, P = 0.027). Our results show a stronger association of elevated p53 expression with chronic rather than acute inflammatory psoriasis. This may indicate a mechanistic difference between plaque-type and guttate psoriasis. Alternatively, this could reflect a chronological course as the disease transitions from an acute to a chronic phase.
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Affiliation(s)
- Ayça Cordan Yazici
- Department of Dermatology, Faculty of Medicine, Mersin University, Mersin, Turkey.
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Gélis C, Mavon A, Vicendo P. The Contribution of Calpains in the Down-regulation of Mdm2 and p53 Proteolysis in Reconstructed Human Epidermis in Response to Solar Irradiation¶. Photochem Photobiol 2007. [DOI: 10.1111/j.1751-1097.2005.tb01472.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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