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Ueda Y, Nakamura T, Nie J, Solivais AJ, Hoffman JR, Daye BJ, Hashino E. Defining developmental trajectories of prosensory cells in human inner ear organoids at single-cell resolution. Development 2023; 150:dev201071. [PMID: 37381908 PMCID: PMC10323240 DOI: 10.1242/dev.201071] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 05/24/2023] [Indexed: 06/29/2023]
Abstract
The inner ear sensory epithelia contain mechanosensitive hair cells and supporting cells. Both cell types arise from SOX2-expressing prosensory cells, but the mechanisms underlying the diversification of these cell lineages remain unclear. To determine the transcriptional trajectory of prosensory cells, we established a SOX2-2A-ntdTomato human embryonic stem cell line using CRISPR/Cas9, and performed single-cell RNA-sequencing analyses with SOX2-positive cells isolated from inner ear organoids at various time points between differentiation days 20 and 60. Our pseudotime analysis suggests that vestibular type II hair cells arise primarily from supporting cells, rather than bi-fated prosensory cells in organoids. Moreover, ion channel- and ion-transporter-related gene sets were enriched in supporting cells versus prosensory cells, whereas Wnt signaling-related gene sets were enriched in hair cells versus supporting cells. These findings provide valuable insights into how prosensory cells give rise to hair cells and supporting cells during human inner ear development, and may provide a clue to promote hair cell regeneration from resident supporting cells in individuals with hearing loss or balance disorders.
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Affiliation(s)
- Yoshitomo Ueda
- Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Takashi Nakamura
- Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Jing Nie
- Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Alexander J. Solivais
- Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - John R. Hoffman
- Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Becca J. Daye
- Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Eri Hashino
- Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Whitfield JF, Rennie K, Chakravarthy B. Alzheimer's Disease and Its Possible Evolutionary Origin: Hypothesis. Cells 2023; 12:1618. [PMID: 37371088 PMCID: PMC10297544 DOI: 10.3390/cells12121618] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/29/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
The enormous, 2-3-million-year evolutionary expansion of hominin neocortices to the current enormity enabled humans to take over the planet. However, there appears to have been a glitch, and it occurred without a compensatory expansion of the entorhinal cortical (EC) gateway to the hippocampal memory-encoding system needed to manage the processing of the increasing volume of neocortical data converging on it. The resulting age-dependent connectopathic glitch was unnoticed by the early short-lived populations. It has now surfaced as Alzheimer's disease (AD) in today's long-lived populations. With advancing age, processing of the converging neocortical data by the neurons of the relatively small lateral entorhinal cortex (LEC) inflicts persistent strain and high energy costs on these cells. This may result in their hyper-release of harmless Aβ1-42 monomers into the interstitial fluid, where they seed the formation of toxic amyloid-β oligomers (AβOs) that initiate AD. At the core of connectopathic AD are the postsynaptic cellular prion protein (PrPC). Electrostatic binding of the negatively charged AβOs to the positively charged N-terminus of PrPC induces hyperphosphorylation of tau that destroys synapses. The spread of these accumulating AβOs from ground zero is supported by Aβ's own production mediated by target cells' Ca2+-sensing receptors (CaSRs). These data suggest that an early administration of a strongly positively charged, AβOs-interacting peptide or protein, plus an inhibitor of CaSR, might be an effective AD-arresting therapeutic combination.
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Affiliation(s)
- James F. Whitfield
- Human Health Therapeutics, National Research Council, Ottawa, ON K1A 0R6, Canada
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Li JK, Zhu PL, Wang Y, Jiang XL, Zhang Z, Zhang Z, Yung KKL. Gracillin exerts anti-melanoma effects in vitro and in vivo: role of DNA damage, apoptosis and autophagy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 108:154526. [PMID: 36334389 DOI: 10.1016/j.phymed.2022.154526] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 09/13/2022] [Accepted: 10/25/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Melanoma is an aggressive cancer. Gracillin has been reported to treat various types of cancer, such as colorectal and lung cancer. However, there is a paucity of research on the anti-melanoma effects of gracillin. PURPOSE The aim of this study was to assess the anti-melanoma effects and mechanisms of action of gracillin in vitro and in vivo. METHODS Cell viability was detected using MTT and crystal violet staining assays. Cell proliferation was examined by EdU staining assays. Cell cycle arrest and apoptosis were analyzed by flow cytometry. Autophagic flux was monitored under a confocal microscope. Protein levels were determined by immunoblotting. LY294002 and rapamycin (Rapa) were used to determine the involvement of PI3K/AKT/mTOR signaling in gracillin-mediated autophagy. Signal transducer and activator of transcription 3 (STAT3) was overactivated to explore the contribution of the STAT3 signaling pathway in the anti-melanoma effects of gracillin. A B16F10 allograft mouse model was developed to evaluate the anti-melanoma effects of gracillin in vivo. RESULTS We demonstrated that in melanoma cells, gracillin inhibited proliferation, induced G0/G1 phase cell cycle arrest, evoked apoptosis, and triggered autophagic cell death. Gracillin induced DNA damage in melanoma cells. Moreover, it suppressed the phosphorylation/activation of PI3K, AKT, mTOR, and 4E-BP1 in melanoma cells. Inhibiting PI3K/AKT and mTOR activity using LY294002 and Rapa, respectively, increased the protein level of LC3B-II in gracillin-treated melanoma cells. Furthermore, gracillin downregulated the protein levels of p-JAK2 (Tyr1007/1008), p-Src (Tyr416), and p-STAT3 (Tyr705) in melanoma cells. Over-expression of STAT3 in A375 cells significantly mitigated the cytotoxic and apoptotic effects of gracillin. In vivo studies showed that gracillin (1 mg/kg or 8 mg/kg, administered intraperitoneally for 16 consecutive days) suppressed B16F10 tumor growth and Src/STAT3 and AKT/mTOR signaling in tumors. No overt toxicity was observed in mice. CONCLUSION Induction of DNA damage, inhibition of PI3K/AKT/mTOR signaling and suppression of STAT3 signaling are involved in gracillin-mediated cell cycle arrest, autophagic cell death and apoptosis, respectively, in melanoma cells. These findings provide novel insights into the anti-melanoma molecular mechanisms of gracillin, and suggest a potential role of gracillin in melanoma management.
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Affiliation(s)
- Jun-Kui Li
- Department of Biology, Hong Kong Baptist University (HKBU), Kowloon Tong, Kowloon, Hong Kong, China; Golden Meditech Center for NeuroRegeneration Sciences (GMCNS), HKBU, Kowloon Tong, Hong Kong, China
| | - Pei-Li Zhu
- Department of Biology, Hong Kong Baptist University (HKBU), Kowloon Tong, Kowloon, Hong Kong, China; Golden Meditech Center for NeuroRegeneration Sciences (GMCNS), HKBU, Kowloon Tong, Hong Kong, China
| | - Ying Wang
- Department of Biology, Hong Kong Baptist University (HKBU), Kowloon Tong, Kowloon, Hong Kong, China; Golden Meditech Center for NeuroRegeneration Sciences (GMCNS), HKBU, Kowloon Tong, Hong Kong, China
| | - Xiao-Li Jiang
- Department of Biology, Hong Kong Baptist University (HKBU), Kowloon Tong, Kowloon, Hong Kong, China; Golden Meditech Center for NeuroRegeneration Sciences (GMCNS), HKBU, Kowloon Tong, Hong Kong, China
| | - Zhu Zhang
- Department of Biology, Hong Kong Baptist University (HKBU), Kowloon Tong, Kowloon, Hong Kong, China; Golden Meditech Center for NeuroRegeneration Sciences (GMCNS), HKBU, Kowloon Tong, Hong Kong, China
| | - Zhang Zhang
- Department of Biology, Hong Kong Baptist University (HKBU), Kowloon Tong, Kowloon, Hong Kong, China; Golden Meditech Center for NeuroRegeneration Sciences (GMCNS), HKBU, Kowloon Tong, Hong Kong, China
| | - Ken-Kin-Lam Yung
- Department of Biology, Hong Kong Baptist University (HKBU), Kowloon Tong, Kowloon, Hong Kong, China; Golden Meditech Center for NeuroRegeneration Sciences (GMCNS), HKBU, Kowloon Tong, Hong Kong, China.
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Patra D, Bhavya K, Ramprasad P, Kalia M, Pal D. Anti-cancer drug molecules targeting cancer cell cycle and proliferation. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2023; 135:343-395. [PMID: 37061337 DOI: 10.1016/bs.apcsb.2022.11.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
Cancer, a vicious clinical burden that potentiates maximum fatality for humankind, arises due to unregulated excessive cell division and proliferation through an eccentric expression of cell cycle regulator proteins. A set of evolutionarily conserved machinery controls the cell cycle in an extremely precise manner so that a cell that went through the cycle can produce a genetically identical copy. To achieve perfection, several checkpoints were placed in the cycle for surveillance; so, errors during the division were rectified by the repair strategies. However, irreparable damage leads to exit from the cell cycle and induces programmed cell death. In comparison to a normal cell, cancer cells facilitate the constitutive activation of many dormant proteins and impede negative regulators of the checkpoint. Extensive studies in the last few decades on cell division and proliferation of cancer cells elucidate the molecular mechanism of the cell-cycle regulators that are often targeted for the development of anti-cancer therapy. Each phase of the cell cycle has been regulated by a unique set of proteins including master regulators Cyclins, and CDKs, along with the accessory proteins such as CKI, Cdc25, error-responsive proteins, and various kinase proteins mainly WEE1 kinases, Polo-like kinases, and Aurora kinases that control cell division. Here in this chapter, we have analytically discussed the role of cell cycle regulators and proliferation factors in cancer progression and the rationale of using various cell cycle-targeting drug molecules as anti-cancer therapy.
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Affiliation(s)
- Debarun Patra
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab, India
| | - Kumari Bhavya
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab, India
| | - Palla Ramprasad
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab, India
| | - Moyna Kalia
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab, India
| | - Durba Pal
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab, India.
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Transcriptome Analysis of the Anti-Proliferative Effects of Ginsenoside Rh3 on HCT116 Colorectal Cancer Cells. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27155002. [PMID: 35956952 PMCID: PMC9370307 DOI: 10.3390/molecules27155002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/27/2022] [Accepted: 08/03/2022] [Indexed: 11/16/2022]
Abstract
The mechanism of ginsenoside Rh3 activity against cancer remains unclear. This study aimed to investigate the underlying mechanism. The effects of Rh3 on the cell proliferation, migration and invasion, and cycle and apoptosis were analyzed using CCK-8 assay, transwell migration assay and flow cytometry, respectively. The RNA transcriptome was sequenced and data were analyzed by R software. Protein expression and protein-protein interactions were determined by Western blotting and co-immunoprecipitation, respectively. The results showed Rh3 inhibited HCT116 cell proliferation, invasion, and migration, arrested cells at G1 phase; and increased apoptosis. Rh3 downregulated 314 genes and upregulated 371 genes. Gene Set Enrichment Analysis (GSEA) using The Kyoto Encyclopedia of Genes Genomics ranked DNA replication first, while GSEA using Gene Ontology ranked the initiation of DNA replication first. Compared with tumor data from The Cancer Genome Atlas (TCGA), most of genes related to DNA replication were oppositely regulated by Rh3. Furthermore, Rh3 down-regulated key protein expression related to DNA replication (Orc6, Cdt1, and Mcm2), but did not affect the loading of Mcm complexes onto ORC complexes nor the phosphorylation at ser139 of Mcm2. Therefore, Rh3 may inhibit colorectal cancer HCT116 cells by downregulation of genes related to DNA replication.
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G1/S restriction point coordinates phasic gene expression and cell differentiation. Nat Commun 2022; 13:3696. [PMID: 35760790 PMCID: PMC9237072 DOI: 10.1038/s41467-022-31101-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 05/31/2022] [Indexed: 01/19/2023] Open
Abstract
Pluripotent embryonic stem cells have a unique cell cycle structure with a suppressed G1/S restriction point and little differential expression across the cell cycle phases. Here, we evaluate the link between G1/S restriction point activation, phasic gene expression, and cellular differentiation. Expression analysis reveals a gain in phasic gene expression across lineages between embryonic days E7.5 and E9.5. Genetic manipulation of the G1/S restriction point regulators miR-302 and P27 respectively accelerates or delays the onset of phasic gene expression in mouse embryos. Loss of miR-302-mediated p21 or p27 suppression expedites embryonic stem cell differentiation, while a constitutive Cyclin E mutant blocks it. Together, these findings uncover a causal relationship between emergence of the G1/S restriction point with a gain in phasic gene expression and cellular differentiation.
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Clinical characteristics and outcomes of phase I cancer patients with CCNE1 amplification: MD Anderson experiences. Sci Rep 2022; 12:8701. [PMID: 35610322 PMCID: PMC9130298 DOI: 10.1038/s41598-022-12669-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 05/13/2022] [Indexed: 11/25/2022] Open
Abstract
Cyclin E is frequently encoded by CCNE1 gene amplification in various malignancies. We reviewed the medical records of patients with solid tumors displaying CCNE1 amplification to determine the effect of this amplification for future therapeutic development. We reviewed the medical records of patients with advanced solid tumors harboring CCNE1 amplification who were seen at the phase I clinic between September 1, 2012, and December 31, 2019. Among 79 patients with solid tumors harboring CCNE1 amplification, 56 (71%) received phase 1 clinical trial therapy, 39 (49%) had 3 or more concurrent genomic aberrances, and 52 (66%) had a concurrent TP53 mutation. The median overall survival (OS) after patients’ initial phase I visit was 8.9 months and after their initial metastasis diagnosis was 41.4 months. We identified four factors associated with poor risk: age < 45 years, body mass index ≥ 25 kg/m2, presence of the TP53 mutation, and elevated LDH > upper limit of normal. In patients treated with gene aberration-related therapy, anti-angiogenic therapy led to significantly longer OS after their initial phase I trial therapy than those who did not: 26 months versus 7.4 months, respectively (P = 0.04). This study provided preliminary evidence that CCNE1 amplification was associated with frequent TP53 mutation and aggressive clinical outcomes. Survival benefit was observed in patients who received antiangiogenic therapy and gene aberration-related treatment, supporting the future development of a personalized approach to combine gene aberration-related therapy with antiangiogenesis for the treatment of advanced malignancies harboring CCNE1 amplification.
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Hydroxyurea-The Good, the Bad and the Ugly. Genes (Basel) 2021; 12:genes12071096. [PMID: 34356112 PMCID: PMC8304116 DOI: 10.3390/genes12071096] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/13/2021] [Accepted: 07/16/2021] [Indexed: 01/23/2023] Open
Abstract
Hydroxyurea (HU) is mostly referred to as an inhibitor of ribonucleotide reductase (RNR) and as the agent that is commonly used to arrest cells in the S-phase of the cycle by inducing replication stress. It is a well-known and widely used drug, one which has proved to be effective in treating chronic myeloproliferative disorders and which is considered a staple agent in sickle anemia therapy and—recently—a promising factor in preventing cognitive decline in Alzheimer’s disease. The reversibility of HU-induced replication inhibition also makes it a common laboratory ingredient used to synchronize cell cycles. On the other hand, prolonged treatment or higher dosage of hydroxyurea causes cell death due to accumulation of DNA damage and oxidative stress. Hydroxyurea treatments are also still far from perfect and it has been suggested that it facilitates skin cancer progression. Also, recent studies have shown that hydroxyurea may affect a larger number of enzymes due to its less specific interaction mechanism, which may contribute to further as-yet unspecified factors affecting cell response. In this review, we examine the actual state of knowledge about hydroxyurea and the mechanisms behind its cytotoxic effects. The practical applications of the recent findings may prove to enhance the already existing use of the drug in new and promising ways.
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9
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Replication initiation: Implications in genome integrity. DNA Repair (Amst) 2021; 103:103131. [PMID: 33992866 DOI: 10.1016/j.dnarep.2021.103131] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/07/2021] [Accepted: 05/07/2021] [Indexed: 02/01/2023]
Abstract
In every cell cycle, billions of nucleotides need to be duplicated within hours, with extraordinary precision and accuracy. The molecular mechanism by which cells regulate the replication event is very complicated, and the entire process begins way before the onset of S phase. During the G1 phase of the cell cycle, cells prepare by assembling essential replication factors to establish the pre-replicative complex at origins, sites that dictate where replication would initiate during S phase. During S phase, the replication process is tightly coupled with the DNA repair system to ensure the fidelity of replication. Defects in replication and any error must be recognized by DNA damage response and checkpoint signaling pathways in order to halt the cell cycle before cells are allowed to divide. The coordination of these processes throughout the cell cycle is therefore critical to achieve genomic integrity and prevent diseases. In this review, we focus on the current understanding of how the replication initiation events are regulated to achieve genome stability.
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Hydroxyurea and Caffeine Impact pRb-like Protein-Dependent Chromatin Architecture Profiles in Interphase Cells of Vicia faba. Int J Mol Sci 2021; 22:ijms22094572. [PMID: 33925461 PMCID: PMC8123844 DOI: 10.3390/ijms22094572] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/06/2021] [Accepted: 04/23/2021] [Indexed: 01/04/2023] Open
Abstract
The survival of cells depends on their ability to replicate correctly genetic material. Cells exposed to replication stress can experience a number of problems that may lead to deregulated proliferation, the development of cancer, and/or programmed cell death. In this article, we have induced prolonged replication arrest via hydroxyurea (HU) treatment and also premature chromosome condensation (PCC) by co-treatment with HU and caffeine (CF) in the root meristem cells of Vicia faba. We have analyzed the changes in the activities of retinoblastoma-like protein (RbS807/811ph). Results obtained from the immunocytochemical detection of RbS807/811ph allowed us to distinguish five unique activity profiles of pRb. We have also performed detailed 3D modeling using Blender 2.9.1., based on the original data and some final conclusions. 3D models helped us to visualize better the events occurring within the nuclei and acted as a high-resolution aid for presenting the results. We have found that, despite the decrease in pRb activity, its activity profiles were mostly intact and clearly recognizable, with some local alterations that may correspond to the increased demand in transcriptional activity. Our findings suggest that Vicia faba’s ability to withstand harsh environments may come from its well-developed and highly effective response to replication stress.
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Zhang P, Katzaroff AJ, Buttitta LA, Ma Y, Jiang H, Nickerson DW, Øvrebø JI, Edgar BA. The Krüppel-like factor Cabut has cell cycle regulatory properties similar to E2F1. Proc Natl Acad Sci U S A 2021; 118:e2015675118. [PMID: 33558234 PMCID: PMC7896318 DOI: 10.1073/pnas.2015675118] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Using a gain-of-function screen in Drosophila, we identified the Krüppel-like factor Cabut (Cbt) as a positive regulator of cell cycle gene expression and cell proliferation. Enforced cbt expression is sufficient to induce an extra cell division in the differentiating fly wing or eye, and also promotes intestinal stem cell divisions in the adult gut. Although inappropriate cell proliferation also results from forced expression of the E2f1 transcription factor or its target, Cyclin E, Cbt does not increase E2F1 or Cyclin E activity. Instead, Cbt regulates a large set of E2F1 target genes independently of E2F1, and our data suggest that Cbt acts via distinct binding sites in target gene promoters. Although Cbt was not required for cell proliferation during wing or eye development, Cbt is required for normal intestinal stem cell divisions in the midgut, which expresses E2F1 at relatively low levels. The E2F1-like functions of Cbt identify a distinct mechanism for cell cycle regulation that may be important in certain normal cell cycles, or in cells that cycle inappropriately, such as cancer cells.
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Affiliation(s)
- Peng Zhang
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112
| | - Alexia J Katzaroff
- Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195
- Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
| | - Laura A Buttitta
- Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
| | - Yiqin Ma
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112
| | - Huaqi Jiang
- Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
| | - Derek W Nickerson
- Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
| | - Jan Inge Øvrebø
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112
| | - Bruce A Edgar
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112;
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112
- Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
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Sirtuin 5 Is Regulated by the SCF Cyclin F Ubiquitin Ligase and Is Involved in Cell Cycle Control. Mol Cell Biol 2021; 41:MCB.00269-20. [PMID: 33168699 DOI: 10.1128/mcb.00269-20] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 11/03/2020] [Indexed: 12/31/2022] Open
Abstract
The ubiquitin-proteasome system is essential for cell cycle progression. Cyclin F is a cell cycle-regulated substrate adapter F-box protein for the Skp1, CUL1, and F-box protein (SCF) family of E3 ubiquitin ligases. Despite its importance in cell cycle progression, identifying cyclin F-bound SCF complex (SCFCyclin F) substrates has remained challenging. Since cyclin F overexpression rescues a yeast mutant in the cdc4 gene, we considered the possibility that other genes that genetically modify cdc4 mutant lethality could also encode cyclin F substrates. We identified the mitochondrial and cytosolic deacylating enzyme sirtuin 5 (SIRT5) as a novel cyclin F substrate. SIRT5 has been implicated in metabolic processes, but its connection to the cell cycle is not known. We show that cyclin F interacts with and controls the ubiquitination, abundance, and stability of SIRT5. We show SIRT5 knockout results in a diminished G1 population and a subsequent increase in both S and G2/M. Global proteomic analyses reveal cyclin-dependent kinase (CDK) signaling changes congruent with the cell cycle changes in SIRT5 knockout cells. Together, these data demonstrate that SIRT5 is regulated by cyclin F and suggest a connection between SIRT5, cell cycle regulation, and metabolism.
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Maloney SM, Hoover CA, Morejon-Lasso LV, Prosperi JR. Mechanisms of Taxane Resistance. Cancers (Basel) 2020; 12:E3323. [PMID: 33182737 PMCID: PMC7697134 DOI: 10.3390/cancers12113323] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 10/30/2020] [Accepted: 11/06/2020] [Indexed: 12/17/2022] Open
Abstract
The taxane family of chemotherapy drugs has been used to treat a variety of mostly epithelial-derived tumors and remain the first-line treatment for some cancers. Despite the improved survival time and reduction of tumor size observed in some patients, many have no response to the drugs or develop resistance over time. Taxane resistance is multi-faceted and involves multiple pathways in proliferation, apoptosis, metabolism, and the transport of foreign substances. In this review, we dive deeper into hypothesized resistance mechanisms from research during the last decade, with a focus on the cancer types that use taxanes as first-line treatment but frequently develop resistance to them. Furthermore, we will discuss current clinical inhibitors and those yet to be approved that target key pathways or proteins and aim to reverse resistance in combination with taxanes or individually. Lastly, we will highlight taxane response biomarkers, specific genes with monitored expression and correlated with response to taxanes, mentioning those currently being used and those that should be adopted. The future directions of taxanes involve more personalized approaches to treatment by tailoring drug-inhibitor combinations or alternatives depending on levels of resistance biomarkers. We hope that this review will identify gaps in knowledge surrounding taxane resistance that future research or clinical trials can overcome.
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Affiliation(s)
- Sara M. Maloney
- Harper Cancer Research Institute, South Bend, IN 46617, USA;
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, South Bend, IN 46617, USA
| | - Camden A. Hoover
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA; (C.A.H.); (L.V.M.-L.)
| | - Lorena V. Morejon-Lasso
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA; (C.A.H.); (L.V.M.-L.)
| | - Jenifer R. Prosperi
- Harper Cancer Research Institute, South Bend, IN 46617, USA;
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, South Bend, IN 46617, USA
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA; (C.A.H.); (L.V.M.-L.)
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Emanuele MJ, Enrico TP, Mouery RD, Wasserman D, Nachum S, Tzur A. Complex Cartography: Regulation of E2F Transcription Factors by Cyclin F and Ubiquitin. Trends Cell Biol 2020; 30:640-652. [PMID: 32513610 PMCID: PMC7859860 DOI: 10.1016/j.tcb.2020.05.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/01/2020] [Accepted: 05/06/2020] [Indexed: 02/07/2023]
Abstract
The E2F family of transcriptional regulators sits at the center of cell cycle gene expression and plays vital roles in normal and cancer cell cycles. Whereas control of E2Fs by the retinoblastoma family of proteins is well established, much less is known about their regulation by ubiquitin pathways. Recent studies placed the Skp1-Cul1-F-box-protein (SCF) family of E3 ubiquitin ligases with the F-box protein Cyclin F at the center of E2F regulation, demonstrating temporal proteolysis of both activator and atypical repressor E2Fs. Importantly, these E2F members, in particular activator E2F1 and repressors E2F7 and E2F8, form a feedback circuit at the crossroads of cell cycle and cell death. Moreover, Cyclin F functions in a reciprocal circuit with the cell cycle E3 ligase anaphase-promoting complex/cyclosome (APC/C), which also controls E2F7 and E2F8. This review focuses on the complex contours of feedback within this circuit, highlighting the deep crosstalk between E2F, SCF-Cyclin F, and APC/C in regulating the oscillator underlying human cell cycles.
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Affiliation(s)
- Michael J Emanuele
- Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Taylor P Enrico
- Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Ryan D Mouery
- Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Genetics and Molecular Biology Program, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Danit Wasserman
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan 5290002, Israel
| | - Sapir Nachum
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan 5290002, Israel
| | - Amit Tzur
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan 5290002, Israel.
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15
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Zluhan-Martínez E, Pérez-Koldenkova V, Ponce-Castañeda MV, Sánchez MDLP, García-Ponce B, Miguel-Hernández S, Álvarez-Buylla ER, Garay-Arroyo A. Beyond What Your Retina Can See: Similarities of Retinoblastoma Function between Plants and Animals, from Developmental Processes to Epigenetic Regulation. Int J Mol Sci 2020; 21:E4925. [PMID: 32664691 PMCID: PMC7404004 DOI: 10.3390/ijms21144925] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/29/2020] [Accepted: 07/07/2020] [Indexed: 12/15/2022] Open
Abstract
The Retinoblastoma protein (pRb) is a key cell cycle regulator conserved in a wide variety of organisms. Experimental analysis of pRb's functions in animals and plants has revealed that this protein participates in cell proliferation and differentiation processes. In addition, pRb in animals and its orthologs in plants (RBR), are part of highly conserved protein complexes which suggest the possibility that analogies exist not only between functions carried out by pRb orthologs themselves, but also in the structure and roles of the protein networks where these proteins are involved. Here, we present examples of pRb/RBR participation in cell cycle control, cell differentiation, and in the regulation of epigenetic changes and chromatin remodeling machinery, highlighting the similarities that exist between the composition of such networks in plants and animals.
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Affiliation(s)
- Estephania Zluhan-Martínez
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de Mexico, 3er Circuito Ext. Junto a J. Botánico, Ciudad Universitaria, UNAM 04510, Mexico; (E.Z.-M.); (M.d.l.P.S.); (B.G.-P.)
- Posgrado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Av. Universidad 3000, Coyoacán 04510, Mexico
| | - Vadim Pérez-Koldenkova
- Laboratorio Nacional de Microscopía Avanzada, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc, 330. Col. Doctores, Alc. Cuauhtémoc 06720, Mexico;
| | - Martha Verónica Ponce-Castañeda
- Unidad de Investigación Médica en Enfermedades Infecciosas, Centro Médico Nacional SXXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico;
| | - María de la Paz Sánchez
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de Mexico, 3er Circuito Ext. Junto a J. Botánico, Ciudad Universitaria, UNAM 04510, Mexico; (E.Z.-M.); (M.d.l.P.S.); (B.G.-P.)
| | - Berenice García-Ponce
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de Mexico, 3er Circuito Ext. Junto a J. Botánico, Ciudad Universitaria, UNAM 04510, Mexico; (E.Z.-M.); (M.d.l.P.S.); (B.G.-P.)
| | - Sergio Miguel-Hernández
- Laboratorio de Citopatología Ambiental, Departamento de Morfología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Campus Zacatenco, Calle Wilfrido Massieu Esquina Cda, Manuel Stampa 07738, Mexico;
| | - Elena R. Álvarez-Buylla
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de Mexico, 3er Circuito Ext. Junto a J. Botánico, Ciudad Universitaria, UNAM 04510, Mexico; (E.Z.-M.); (M.d.l.P.S.); (B.G.-P.)
| | - Adriana Garay-Arroyo
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de Mexico, 3er Circuito Ext. Junto a J. Botánico, Ciudad Universitaria, UNAM 04510, Mexico; (E.Z.-M.); (M.d.l.P.S.); (B.G.-P.)
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16
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Pennycook BR, Barr AR. Restriction point regulation at the crossroads between quiescence and cell proliferation. FEBS Lett 2020; 594:2046-2060. [PMID: 32564372 DOI: 10.1002/1873-3468.13867] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 06/08/2020] [Accepted: 06/10/2020] [Indexed: 02/11/2024]
Abstract
The coordination of cell proliferation with reversible cell cycle exit into quiescence is crucial for the development of multicellular organisms and for tissue homeostasis in the adult. The decision between quiescence and proliferation occurs at the restriction point, which is widely thought to be located in the G1 phase of the cell cycle, when cells integrate accumulated extracellular and intracellular signals to drive this binary cellular decision. On the molecular level, decision-making is exerted through the activation of cyclin-dependent kinases (CDKs). CDKs phosphorylate the retinoblastoma (Rb) transcriptional repressor to regulate the expression of cell cycle genes. Recently, the classical view of restriction point regulation has been challenged. Here, we review the latest findings on the activation of CDKs, Rb phosphorylation and the nature and position of the restriction point within the cell cycle.
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Affiliation(s)
- Betheney R Pennycook
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
- MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Alexis R Barr
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
- MRC London Institute of Medical Sciences, Imperial College London, London, UK
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17
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Gorski JW, Ueland FR, Kolesar JM. CCNE1 Amplification as a Predictive Biomarker of Chemotherapy Resistance in Epithelial Ovarian Cancer. Diagnostics (Basel) 2020; 10:diagnostics10050279. [PMID: 32380689 PMCID: PMC7277958 DOI: 10.3390/diagnostics10050279] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 04/28/2020] [Accepted: 05/03/2020] [Indexed: 12/15/2022] Open
Abstract
Ovarian cancer is the most-deadly gynecologic malignancy, with greater than 14,000 women expected to succumb to the disease this year in the United States alone. In the front-line setting, patients are treated with a platinum and taxane doublet. Although 40–60% of patients achieve complete clinical response to first-line chemotherapy, 25% are inherently platinum-resistant or refractory with a median overall survival of about one year. More than 80% of women afflicted with ovarian cancer will recur. Many attempts have been made to understand the mechanism of platinum and taxane based chemotherapy resistance. However, despite decades of research, few predictive markers of chemotherapy resistance have been identified. Here, we review the current understanding of one of the most common genetic alterations in epithelial ovarian cancer, CCNE1 (cyclin E1) amplification, and its role as a potential predictive marker of cytotoxic chemotherapy resistance. CCNE1 amplification has been identified as a primary oncogenic driver in a subset of high grade serous ovarian cancer that have an unmet clinical need. Understanding the interplay between cyclin E1 amplification and other common ovarian cancer genetic alterations provides the basis for chemotherapeutic resistance in CCNE1 amplified disease. Exploration of the effect of cyclin E1 amplification on the cellular machinery that causes dysregulated proliferation in cancer cells has allowed investigators to explore promising targeted therapies that provide the basis for emerging clinical trials.
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Affiliation(s)
- Justin W. Gorski
- Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Kentucky Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-0263, USA;
- Correspondence:
| | - Frederick R. Ueland
- Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Kentucky Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-0263, USA;
| | - Jill M. Kolesar
- Department of Pharmacy Practice & Science, University of Kentucky College of Pharmacy, 567 TODD Building, 789 South Limestone Street, Lexington, KY 40539-0596, USA;
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18
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Whitaker RH, Placzek WJ. MCL1 binding to the reverse BH3 motif of P18INK4C couples cell survival to cell proliferation. Cell Death Dis 2020; 11:156. [PMID: 32111816 PMCID: PMC7048787 DOI: 10.1038/s41419-020-2351-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 02/11/2020] [Indexed: 12/20/2022]
Abstract
Commitment to cell cycle entry and cellular duplication is a tightly coordinated and regulated process. Once initiated, a series of multiple checkpoints ensure both accurate genomic replication and chromosomal separation. In the event of unsuccessful cell division, parallel pathways exist that induce the cell to undergo programmed cell death, or apoptosis. At the center of such stress-induced, intrinsic apoptotic regulation lies the BCL2 family of pro- and anti-apoptotic regulatory proteins. In a proliferative state the balance of pro- and anti-apoptotic signaling proteins would be expected to favor an excess population of anti-apoptotic members. While the anti-apoptotic BCL2 family member, MCL1, has been identified to oversee mitotic progression, direct communication between the BCL2 family and cell proliferation has not been observed. In this study, we demonstrate a direct protein–protein interaction between MCL1 and the G1/S checkpoint protein, P18INK4C. This interaction is mediated by a reverse BH3 (rBH3) motif located in P18INK4C’s C-terminal ankyrin repeat. MCL1 is further shown to decrease P18INK4C expression and thereby regulate cell cycle entry in a retinoblastoma (RB1)-dependent manner. Our findings establish a mechanism for translation independent and direct communication between the BCL2 family regulation of apoptosis and CDK4/6-RB regulation of early G1/S transition during cellular division/growth.
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Affiliation(s)
- Robert H Whitaker
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - William J Placzek
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
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19
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Pérez-Benavente B, Nasresfahani AF, Farràs R. Ubiquitin-Regulated Cell Proliferation and Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1233:3-28. [PMID: 32274751 DOI: 10.1007/978-3-030-38266-7_1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ubiquitin ligases (E3) play a crucial role in the regulation of different cellular processes such as proliferation and differentiation via recognition, interaction, and ubiquitination of key cellular proteins in a spatial and temporal regulated manner. The type of ubiquitin chain formed determines the fate of the substrates. The ubiquitinated substrates can be degraded by the proteasome, display altered subcellular localization, or can suffer modifications on their interaction with functional protein complexes. Deregulation of E3 activities is frequently found in various human pathologies, including cancer. The illegitimated or accelerated degradation of oncosuppressive proteins or, inversely, the abnormally high accumulation of oncoproteins, contributes to cell proliferation and transformation. Anomalies in protein abundance may be related to mutations that alter the direct or indirect recognition of proteins by the E3 enzymes or alterations in the level of expression or activity of ubiquitin ligases. Through a few examples, we illustrate here the complexity and diversity of the molecular mechanisms related to protein ubiquitination involved in cell cycle regulation. We will discuss the role of ubiquitin-dependent degradation mediated by the proteasome, the role of non-proteolytic ubiquitination during cell cycle progression, and the consequences of this deregulation on cellular transformation. Finally, we will highlight the novel opportunities that arise from these studies for therapeutic intervention.
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Affiliation(s)
| | | | - Rosa Farràs
- Oncogenic Signaling Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain.
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20
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Stallaert W, Kedziora KM, Chao HX, Purvis JE. Bistable switches as integrators and actuators during cell cycle progression. FEBS Lett 2019; 593:2805-2816. [PMID: 31566708 DOI: 10.1002/1873-3468.13628] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 09/20/2019] [Accepted: 09/26/2019] [Indexed: 12/14/2022]
Abstract
Progression through the cell cycle is driven by bistable switches-specialized molecular circuits that govern transitions from one cellular state to another. Although the mechanics of bistable switches are relatively well understood, it is less clear how cells integrate multiple sources of molecular information to engage these switches. Here, we describe how bistable switches act as hubs of information processing and examine how variability, competition, and inheritance of molecular signals determine the timing of the Rb-E2F bistable switch that controls cell cycle entry. Bistable switches confer both robustness and plasticity to cell cycle progression, ensuring that cell cycle events are performed completely and in the correct order, while still allowing flexibility to cope with ongoing stress and changing environmental conditions.
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Affiliation(s)
- Wayne Stallaert
- Department of Genetics, Computational Medicine Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Katarzyna M Kedziora
- Department of Genetics, Computational Medicine Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Hui Xiao Chao
- Department of Genetics, Computational Medicine Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Jeremy E Purvis
- Department of Genetics, Computational Medicine Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
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21
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Limas JC, Cook JG. Preparation for DNA replication: the key to a successful S phase. FEBS Lett 2019; 593:2853-2867. [PMID: 31556113 PMCID: PMC6817399 DOI: 10.1002/1873-3468.13619] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/09/2019] [Accepted: 09/17/2019] [Indexed: 12/13/2022]
Abstract
Successful genome duplication is required for cell proliferation and demands extraordinary precision and accuracy. The mechanisms by which cells enter, progress through, and exit S phase are intense areas of focus in the cell cycle and genome stability fields. Key molecular events in the G1 phase of the cell division cycle, especially origin licensing, are essential for pre-establishing conditions for efficient DNA replication during the subsequent S phase. If G1 events are poorly regulated or disordered, then DNA replication can be compromised leading to genome instability, a hallmark of tumorigenesis. Upon entry into S phase, coordinated origin firing and replication progression ensure complete, timely, and precise chromosome replication. Both G1 and S phase progressions are controlled by master cell cycle protein kinases and ubiquitin ligases that govern the activity and abundance of DNA replication factors. In this short review, we describe current understanding and recent developments related to G1 progression and S phase entrance and exit with a particular focus on origin licensing regulation in vertebrates.
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Affiliation(s)
- Juanita C Limas
- Department of Pharmacology, University of North Carolina at Chapel Hill, NC, USA
| | - Jeanette Gowen Cook
- Department of Pharmacology, University of North Carolina at Chapel Hill, NC, USA
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, NC, USA
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