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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The study of polyomavirus has benefited immensely from two scientific methodologies, cell culture and in vitro studies on one side and the use of transgenic mice as experimental models on the other. Both approaches allowed us to identify cellular products targeted by the viruses, the consequences of these interactions at the phenotypic and molecular level, and thus the potential roles of the targets within their normal cellular context. In particular, cell culture and in vitro reports suggest a model explaining partially how SV40 large T antigen contributes to oncogenic transformation. In most cases, T antigen induces cell cycle entry by inactivation of the Rb proteins (pRb, p130, and p107), thus activating E2F-dependent transcription and subsequent S-phase entry. Simultaneously, T antigen blocks p53 activity and therefore prevents the ensuing cell-cycle arrest and apoptosis. For the most part, studies of T antigen expression in transgenic mice support this model, but the use of T antigen mutants and their expression in different tissue and cell type settings have expanded our knowledge of the model system and raised important questions regarding tumorigenic mechanisms functioning in vivo.
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PMID:T antigen transgenic mouse models. 1950 50

Mirk/Dyrk1B is a serine/threonine kinase widely expressed in colon cancers. Serum starvation induced HD6 colon carcinoma cells to enter a quiescent G0 state, characterized by a 2N DNA content and a lower RNA content than G1 cells. Compared with cycling cells, quiescent cells exhibited 16-fold higher levels of the retinoblastoma protein p130/Rb2, which sequesters E2F4 to block entry into G1, 10-fold elevated levels of the CDK inhibitor p27kip1, and 10-fold higher levels of Mirk. However, depletion of Mirk did not prevent entry into G0, but enabled quiescent HD6, SW480, and colo320 colon carcinoma cells to acquire some biochemical characteristics of G1 cells, including increased levels of cyclin D1 and cyclin D3 because of slower turnover, increased activity of their CDK4/cyclin D complexes, and increased phosphorylation and decreased E2F4 sequestering ability of the CDK4 target, p130/Rb2. As a result, depletion of Mirk allowed some cells to escape quiescence and enabled cells released from quiescence to traverse G1 more quickly. The kinase activity of Mirk was increased by the chemotherapeutic drug 5-fluorouracil (5-FU). Treatment of p53 mutant colon cancer cells with 5-FU led to an elongated G1 in a Mirk-dependent manner, as G1 was shortened by ectopic overexpression of cyclin D1 mutated at the Mirk phosphorylation site (T288A), but not by wild-type cyclin D1. Mirk, through regulating cyclin D turnover, and the CDK inhibitor p27, as shown by depletion studies, functioned independently and additively to regulate the exit of tumor cells from quiescence.
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PMID:Mirk regulates the exit of colon cancer cells from quiescence. 1954 20

Most cells in the body are in a resting state and undergo cell cycle progression only upon growth factor stimulation or activation. while much research on proliferation and activation has been performed, very little about signals that maintain quiescent cells in G(0) is known, preventing cell cycle entry or apoptosis. In this study, the pathways of apoptosis induction in quiescent peripheral blood cells and fibroblasts mediated by inhibition or downregulation of Dipeptidyl Peptidase 2 (DPP2) have been explored. A decrease in DPP2 activity was found to cause resting cells to exit from G(0), accompanied by a decrease in p130, p27(Kip1) and p21(Cip1) protein levels. In addition, DPP2-inhibited or downregulated cells exhibit an increase in early G(1)/S progressors, with increases in the levels of retinoblastoma (pRb), p107 and cyclin D proteins. Furthermore, decrease of DPP2 activity leads to an increase in c-Myc and a decrease in Bcl-2, two events that have been associated with apoptosis induction. This apoptosis by DPP2 downregulation is prevented in p53(-/-) cells or by ectopic expression of proteins that suppress p53 or c-Myc activity. Thus, DPP2 is essential for maintaining lymphocytes and fibroblasts in G(0), and its inhibition results in apoptosis mediated by induction of c-Myc and p53.
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PMID:Dipeptidyl peptidase 2 is an essential survival factor in the regulation of cell quiescence. 1971 73

The tumour suppressor ARF (alternative reading frame), which is mutated or silenced in various tumours, has a crucial role in tumour surveillance to suppress unwarranted cell growth and proliferation. ARF has also been linked to the DNA-damage-induced response of p53 because of its ability to inhibit murine double minute 2 (MDM2). Here, however, we provide genetic evidence for a role of ARF in nucleotide excision repair (NER) that is independent of p53. Cells lacking ARF are deficient in NER. Expression of ARF restores the repair activity, which coincides with increased expression of the damaged-DNA recognition protein xeroderma pigmentosum, complementation group C (XPC). We provide evidence that, by disrupting the interaction between E2F transcription factor 4 (E2F4) and DRTF polypeptide 1 (DP1), ARF reduces the interaction of the E2F4-p130 repressor complex with the promoter of XPC to ensure high-level expression of XPC. Together, our results point to an important 'care-taker'-type tumour-suppression function for ARF in NER through the increased expression of XPC.
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PMID:ARF stimulates XPC to trigger nucleotide excision repair by regulating the repressor complex of E2F4. 1964

Cellular senescence is a stress-induced state of irreversible growth arrest thought to act as a barrier to cancer development. The p53 tumor suppressor is a critical mediator of senescence and recent in vivo studies have suggested that p53-induced senescence may contribute to tumor clearance by the immune system. Recently developed MDM2 antagonists, the nutlins, are effective p53 activators and potent antitumor agents in cells with functional apoptotic pathways. However, they only block cell cycle progression in cancer cells with compromised p53 apoptotic signaling. We use nutlin-3a as a selective probe to study the role of p53 activation in senescence using a panel of eight epithelial cancer cell lines and primary epithelial cells. Our results reveal that the MDM2 antagonist can induce a senescence-like state in all tested cell lines, but it is reversible and cells resume proliferation upon drug removal and normalization of p53 control. Retinoblastoma family members (pRb, p107, and p130) previously implicated in gene silencing during fibroblasts senescence were found down-regulated in cells with nutlin-induced senescence-like phenotype, suggesting a mechanism for its reversibility. Therefore, selective p53 pathway activation is insufficient for induction of true senescence in epithelial cells in vitro. However, elevated expression of several inflammatory cytokines in cancer cells with nutlin-induced senescence-like phenotype suggests a possible in vivo benefit of p53-activating therapies.
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PMID:Pharmacologic p53 activation blocks cell cycle progression but fails to induce senescence in epithelial cancer cells. 1973 73

HPV type 58 (HPV-58) is the third most common HPV type in cervical cancer from Eastern Asia, yet little is known about how it promotes carcinogenesis. In this study, we demonstrate that HPV-58 E7 significantly promoted the proliferation and extended the lifespan of primary human keratinocytes (PHKs). HPV-58 E7 abrogated the G1 and the postmitotic checkpoints, although less efficiently than HPV-16 E7. Consistent with these observations, HPV-58 E7 down-regulated the cellular tumor suppressor pRb to a lesser extent than HPV-16 E7. Similar to HPV-16 E7 expressing PHKs, Cdk2 remained active in HPV-58 E7 expressing PHKs despite the presence of elevated levels of p53 and p21. Interestingly, HPV-58 E7 down-regulated p130 more efficiently than HPV-16 E7. Our study demonstrates a correlation between the ability of down-regulating pRb/p130 and abrogating cell cycle checkpoints by HPV-58 E7, which also correlates with the biological risks of cervical cancer progression associated with HPV-58 infection.
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PMID:The human papillomavirus type 58 E7 oncoprotein modulates cell cycle regulatory proteins and abrogates cell cycle checkpoints. 1994 33

Defects in pRb tumor suppressor pathway occur in approximately 50% of the deadly muscle-invasive urothelial carcinomas in humans and urothelial carcinoma is the most prevalent epithelial cancer in long-term survivors of hereditary retinoblastomas caused by loss-of-function RB1 mutations. Here, we show that conditional inactivation of both RB1 alleles in mouse urothelium failed to accelerate urothelial proliferation. Instead, it profoundly activated the p53 pathway, leading to extensive apoptosis, and selectively induced pRb family member p107. Thus, pRb loss triggered multiple fail-safe mechanisms whereby urothelial cells evade tumorigenesis. Additional loss of p53 in pRb-deficient urothelial cells removed these p53-dependent tumor barriers, resulting in late-onset hyperplasia, umbrella cell nuclear atypia, and rare-occurring low-grade, superficial papillary bladder tumors, without eliciting invasive carcinomas. Importantly, mice deficient in both pRb and p53, but not those deficient in either protein alone, were highly susceptible to subthreshold carcinogen exposure and developed invasive urothelial carcinomas that strongly resembled the human counterparts. The invasive lesions had a marked reduction of p107 but not p130 of the pRb family. Our data provide compelling evidence, indicating that urothelium, one of the slowest cycling epithelia, is remarkably resistant to transformation by pRb or p53 deficiency; that concurrent loss of these two tumor suppressors is necessary but insufficient to initiate urothelial tumorigenesis along the invasive pathway; that p107 may play a critical role in suppressing invasive urothelial tumor formation; and that replacing/restoring the function of pRb, p107, or p53 could be explored as a potential therapeutic strategy to block urothelial tumor progression.
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PMID:Deficiency of pRb family proteins and p53 in invasive urothelial tumorigenesis. 1995 92

The RB protein family (RB, p107, and p130) has overlapping and compensatory functions in cell-cycle control. However, cancer-associated mutations are almost exclusively found in RB, implying that RB has a nonredundant role in tumor suppression. We demonstrate that RB preferentially associates with E2F target genes involved in DNA replication and is uniquely required to repress these genes during senescence but not other growth states. Consequently, RB loss leads to inappropriate DNA synthesis following a senescence trigger and, together with disruption of a p21-mediated cell-cycle checkpoint, enables extensive proliferation and rampant genomic instability. Our results identify a nonredundant RB effector function that may contribute to tumor suppression and reveal how loss of RB and p53 cooperate to bypass senescence.
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PMID:Dissecting the unique role of the retinoblastoma tumor suppressor during cellular senescence. 2038 55

Small-cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer. Although SCLC patients often initially respond to therapy, tumors nearly always recur, resulting in a 5-year survival rate of less than 10%. A mouse model has been developed based on the fact that the RB and p53 tumor suppressor genes are mutated in more than 90% of human SCLCs. Emerging evidence in patients and mouse models suggests that p130, a gene related to RB, may act as a tumor suppressor in SCLC cells. To test this idea, we used conditional mutant mice to delete p130 in combination with Rb and p53 in adult lung epithelial cells. We found that loss of p130 resulted in increased proliferation and significant acceleration of SCLC development in this triple-knockout mouse model. The histopathologic features of the triple-mutant mouse tumors closely resembled that of human SCLC. Genome-wide expression profiling experiments further showed that Rb/p53/p130-mutant mouse tumors were similar to human SCLC. These findings indicate that p130 plays a key tumor suppressor role in SCLC. Rb/p53/p130-mutant mice provide a novel preclinical mouse model to identify novel therapeutic targets against SCLC.
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PMID:Loss of p130 accelerates tumor development in a mouse model for human small-cell lung carcinoma. 2040 86

The tumor suppressor p53 is a central regulator of cell-cycle arrest and apoptosis by acting as a transcription factor to regulate numerous genes. We identified all human p53-regulated mRNAs by microarray analyses and searched for protein-coding genes which contain intronic miRNAs. Among others, this analysis yielded the panthothenate kinase 1 (PANK1) gene and its intronic miRNA-107. We showed that miRNA-107 and PANK1 are coregulated by p53 in different cell systems. The PANK1 protein, which catalyzes the rate-limiting step of coenzyme A biosynthesis, is also upregulated by p53. We observed that p53 directly activates PANK1 and miRNA-107 transcription through a binding site in the PANK1 promoter. Furthermore, p53 is recruited to the PANK1 promoter after DNA damage. In order to get more insight into miRNA-107 function we investigated its potential target genes. Cell-cycle regulators are significantly enriched among predicted miRNA-107 targets. We found miRNA-107-dependent regulation of two important regulators of G(1)/S progression, CDK6 and the RB-related 2 gene RBL2 (p130). CDK6 and p130 proteins are downregulated upon miRNA-107 expression. Our results uncover a novel miRNA-dependent signaling pathway which leads to downregulation of cell cycle proteins in the absence of transcriptional repression.
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PMID:p53 activates the PANK1/miRNA-107 gene leading to downregulation of CDK6 and p130 cell cycle proteins. 2083 36


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