Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The WAF1/CIP1 gene, a potential tumor suppressor gene, has recently been cloned and identified as a p53 mediator and an inhibitor for G1 cyclin-dependent kinases (CDKs). We undertook this study to investigate the possible role of the WAF1/CIP1 gene in human prostatic carcinoma. Matched normal and cancer tissues from 18 patients with prostate cancer were screened for WAF1/CIP1 mutation by nested reverse transcription-polymerase chain reaction/single strand conformational polymorphism (RT-PCR/SSCP) and DNA sequencing. Shifted bands from three tumor, but not the matched normal specimens, were observed. Subsequent direct DNA sequencing of the PCR fragments identified four sequence alterations including a cytosine (C) to adenine (A) transversion and a guanine (G) to A transition and two A insertions. Our results demonstrated that mutations of the WAF1/CIP1 gene occur and may be important during the pathogenesis of human prostate cancer. This is the first report of WAF1/CIP1 mutation in a primary human cancer.
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PMID:Somatic mutations of the WAF1/CIP1 gene in primary prostate cancer. 747 62

The tumor-suppressor p53 inhibits cell cycle progression by direct transactivation of the p21WAF1/CIP1/SDI1 gene, which encodes a universal inhibitor of cyclin dependent kinases (cdk). The proto-oncogene product c-Myc induces cell cycle progression and, in the absence of survival factors, apoptosis. However, a direct link between the cell cycle machinery and c-Myc has not yet been established. We show that c-Myc has not yet been established. We show that c-Myc abrogates a p53-induced G1-arrest without elevating the expression of cdks or cyclins involved in the G1/S-transition. Instead, the results suggest that c-Myc interferes with the inhibitory action of p21 on cdk/cyclin-complexes by inducing a heat-labile inhibitor of p21. The inactivation of p21 and related cdk-inhibitors may explain several of the oncogenic actions of c-Myc, including the induction of proliferation, immortalisation and the inhibition of differentiation. Modulation of cdk activity by the induction of an inhibitor of cdk-inhibitors represents a novel mechanism of cell cycle regulation in mammalian cells.
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PMID:Abrogation of p53-induced cell cycle arrest by c-Myc: evidence for an inhibitor of p21WAF1/CIP1/SDI1. 747 65

The inducible response of the tumour suppressor gene p53 has been examined following exposure to DNA-damaging agents in Ataxia telangiectasia (AT) cell lines, an autosomal recessive disorder with multiple clinical and biological abnormalities including sensitivity to ionising radiation. The p53 induction was significantly delayed and reduced in the 8 AT cell lines examined over the 6 h following irradiation with no dose response in p53 induction being observed compared to control cells. The increase of WAF1/CIP1(p21) and GADD45 mRNA, two genes transcriptionally activated by p53, was also reduced in the AT cell lines after such treatment. In contrast, the increase in p53 protein, WAF1/CIP1(p21) and GADD45 mRNA expression following exposure to the alkylating agent methylmethane sulphonate (25 and 100 micrograms ml-1) was similar in both cell types. No alterations in the expression of EBNA-5, an EBV-encoded nuclear antigen which has been shown to bind p53 or mutations in the p53 gene (exons 4 to 8) were found in the AT cell lines studied. The AT gene product would thus appear to be involved upstream of p53, GADD45 and WAF1/CIP1 (p21) in the signalling of the presence of strand breaks produced by ionising radiation, with this defect in response contributing to the high cancer risk and radiosensitivity observed in this disorder.
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PMID:The role of the Ataxia telangiectasia gene in the p53, WAF1/CIP1(p21)- and GADD45-mediated response to DNA damage produced by ionising radiation. 747 67

The p21WAF1/CIP1 protein was shown to be a critical downstream effector of p53 and a potent inhibitor of cyclin-dependent kinases. We investigated the effects of exogenous p21WAF1/CIP1 in two different human breast carcinoma (HBC) cell lines MCF-7 and T47D. p21WAF1/CIP1 transfected cells formed significantly reduced number of drug-resistant colonies than their mock-transfected counterparts. The majority of the p21WAF1/CIP1 transfected MCF-7 cells acquired 50-100-fold increase in their sizes and persisted as single giant cells for several days without cell division, while the remainder underwent nuclear division (multiple nuclei) but were unable to complete cytokinesis, and finally all succumbed to apoptosis. Only few p21WAF1/CIP1 transfected T47D cells displayed increase in their sizes while a number of them formed small sized drug-resistant colonies which diminished in size due to cell death. The cells in these shrinking colonies exhibited characteristic signs of apoptosis such as chromatin condensation and fragmented nuclei while their membrane integrity was preserved. Thus in HBC cell lines the growth suppression due to enforced overexpression of p21WAF1/CIP1 is associated with giant cell formation and apoptosis.
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PMID:Overexpression of p21WAF1/CIP1 induces growth arrest, giant cell formation and apoptosis in human breast carcinoma cell lines. 747 20

Incubating human cells in diethylmaleate (DEM) depletes the intracellular pool of reduced glutathione (GSH) and increases the concentration of oxidative free radicals. We found that DEM-induced oxidative stress reduced the ability of p53 to bind its consensus recognition sequence and to activate transcription of a p53-specific reporter gene. Nevertheless, DEM treatment induced expression of WAF1/CIP1 but not GADD45 mRNA. The fact that N-acetylcysteine, a precursor of GSH that blocks oxidative stress, prevented WAF1/CIP1 induction by DEM suggests that WAF1/CIP1 induction probably was a consequence of the ability of DEM to reduce intracellular GSH levels. DEM induced WAF1/CIP1 expression in Saos-2 and T98G cells, both of which lack functional p53 protein. DEM treatment did not produce an increase in membrane-associated protein kinase C, but ERK2, a mitogen-activated protein kinase, was phosphorylated in a manner consistent with ERK2 activation. DEM treatment also produced a dose-dependent delay in cell cycle progression, which at low concentrations (0.25 mM) consisted of a G2/M arrest and at higher concentrations (1 mM) also involved G1 and S phase delays. Our results indicate that oxidative stress induces WAF1/CIP1 expression and arrests cell cycle progression through a mechanism that is independent of p53. This mechanism may provide for cell cycle checkpoint control under conditions that inactivate p53.
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PMID:A p53-independent pathway for activation of WAF1/CIP1 expression following oxidative stress. 749 74

SDI1 is an inhibitor of DNA synthesis that we isolated by expression screening cDNAs prepared from senescent, terminally nondividing human cells. Other groups then cloned this gene as a cyclin-dependent kinase (cdk)-interacting protein (CIP1, p21) that inhibits cdks; the gene was also isolated by screening for genes transactivated by p53 (WAF1). p53 levels are low in senescent and quiescent contact-inhibited or serum-deprived normal human cells, which we have found express high levels of SDI1 mRNA. This indicates that alternate pathways for upregulation of message level of this gene may exist. We therefore proceeded with the study presented here, treating human cells with a variety of growth-arrest-inducing agents, including some that damaged DNA, and found that RNA levels of SDI1 were increased in all cases that resulted in growth inhibition. More important, with the exception of gamma-radiation, most of these agents were able to elevate SDI1 message levels in cells lacking wild-type p53. At least two distinct kinetic profiles for RNA induction were observed, one that implicated p53 transactivation and occurred early enough to cause arrest, and another that clearly was p53 independent and suggested a role for the SDI1 gene product in the maintenance rather than in the cause of inhibition of DNA synthesis.
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PMID:Evidence for a p53-independent pathway for upregulation of SDI1/CIP1/WAF1/p21 RNA in human cells. 752 62

Although the cyclin-dependent kinase inhibitor p21SDI1 (WAF1/CIP1) has been proposed as the mediator of p53-induced cell cycle arrest following DNA damage, several stimuli now appear to induce SDI1 independent of p53 function. We have examined the behavior of p53 and SDI1 in an isogeneic model by manipulating p53 status in normal diploid human fibroblasts using an amphotropic retroviral vector. Following DNA strand break damage induced by bleomycin, both SDI1 induction and G1-S cell cycle arrest are p53 dependent, consistent with SDI1 being the key mediator. In contrast, in cellular senescence (and following UV irradiation), induction of SDI1 occurs independent of p53 function yet growth arrest is still p53 dependent. We conclude (a) that redundant pathways exist for induction of SDI1, but that (b) SDI1, while perhaps necessary, is not sufficient for inhibition of cell cycle progression, requiring the cooperation of an additional factor (possibly another cyclin-dependent kinase inhibitor) whose expression, at least in the case of senescence, is strictly p53 dependent.
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PMID:Mutant p53 rescues human diploid cells from senescence without inhibiting the induction of SDI1/WAF1. 753 2

The tumor suppressor gene p53 regulates G1 checkpoint prior to the initiation of DNA synthesis, which can either induce G1 arrest or signal apoptosis. The involvement of p53 in apoptosis may also be related to its ability to down-regulate transcription of the bcl-2 gene. The bcl-2 gene product prevents most types of apoptotic cell death, suggesting that bcl-2 interferes with an essential signaling molecule involved in the apoptotic cell death pathway. Although the bcl-2 protein is shown to be overexpressed in many types of human tumor including breast cancer, its biochemical or pathological consequences are poorly understood. To determine the effects of bcl-2 overexpression on apoptosis and transformation of breast epithelial cells and to investigate whether bcl-2 interferes with the p53 pathway, we introduced the bcl-2 expression vector into MCF10A cells, which were derived from diploid human breast epithelial cells containing the wild-type p53 gene. Overexpression of bcl-2 prevented free radical-induced apoptosis and induced a partially transformed phenotype in MCF10A cells. Although overexpression of bcl-2 did not affect the expression of the p53 gene, p53-dependent gene transcription such as p21WAF1/CIP1 was suppressed. These results suggest that bcl-2 may inhibit p53 functional activity and is involved in the regulation of an early commitment step either to proliferate or suicide.
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PMID:bcl-2 suppresses expression of p21WAF1/CIP1 in breast epithelial cells. 755 20

DNA-damaging agents induce accumulation of the tumor suppressor and G1 checkpoint protein p53, leading cells to either growth arrest in G1 or apoptosis (programmed cell death). The p53-dependent G1 arrest involves induction of p21 (also called WAF1/CIP1/SDI1), which prevents cyclin kinase-mediated phosphorylation of retinoblastoma protein (RB). Recent studies suggest a p53-independent G1 checkpoint as well; however, little is known about its molecular mechanisms. We report that induction of a protein-serine/threonine phosphatase activity by DNA damage signals is at least one of the mechanisms responsible for p53-independent, RB-mediated G1 arrest and consequent apoptosis. When two p53-null human leukemic cell lines (HL-60 and U-937) were treated with a variety of anticancer agents, RB became hypophosphorylated, accompanied with G1 arrest. This was followed immediately (in less than 30 min) by apoptosis, as determined by the accumulation of pre-G1 apoptotic cells and the internucleosomal fragmentation of DNA. Addition of calyculin A or okadaic acid (specific serine/threonine phosphatase inhibitors) or zinc chloride (apoptosis inhibitor) prevented the G1 arrest- and apoptosis-specific RB dephosphorylation. The levels of cyclin E- and cyclin A-associated kinase activities remained high during RB dephosphorylation, supporting the involvement of a chemotherapy-induced serine/threonine phosphatase(s) rather than p21. Furthermore, the induced phosphatase activity coimmunoprecipitated with the hyperphosphorylated RB and was active in a cell-free system that reproduced the growth arrest- and apoptosis-specific RB dephosphorylation, which was inhibitable by calyculin A but not zinc. We propose that the RB phosphatase(s) might be one of the p53-independent G1 checkpoint regulators.
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PMID:Induction of a retinoblastoma phosphatase activity by anticancer drugs accompanies p53-independent G1 arrest and apoptosis. 756 64

The p53 tumor suppressor gene is mutated in the majority of pancreatic adenocarcinomas, and several studies have suggested that loss of p53 function may contribute to the aggressive clinical behavior of pancreas cancer. Although immunocytochemical accumulation of the p53 gene product has previously been assessed as a marker for p53 mutations in cancers of the pancreas and other organ systems, the relationship between p53 mutations and p53 protein accumulation is variable. The cyclin-dependent kinase inhibitor, p21 (also known as WAF1 and CIP1), is induced by wild-type but not mutant p53, and recent work has implicated p21 as a downstream mediator of the growth-suppressing and apoptosis-promoting functions of wild-type p53. In the present work, we sought to determine whether loss of p21 expression could more precisely identify those tumors with p53 mutations and/or loss, compared with immunocytochemical assessment of p53 protein accumulation. We evaluated p53 and p21 expression immunohistochemically in a series of 21 ductal adenocarcinomas of the pancreas with known p53 mutational status. Diffuse overexpression of p53 was found in 3 of 8 cases (38%) with wild-type p53 and 7 of 13 cases (54%) with p53 mutations with or without loss of heterozygosity at 17p. Surprisingly, expression of p21 correlated neither with p53 mutational status nor with p53 protein expression. In particular, strong p21 expression was seen even in carcinomas in which molecular analysis revealed a frameshift mutation in one allele of p53 and loss of the second. These data suggest that p21 expression in pancreatic adenocarcinoma may also be induced by a p53-independent pathway and that p21 expression, as assessed immunocytochemically, does not reflect the functional status of p53 in these carcinomas.
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PMID:p53-independent expression of the cyclin-dependent kinase inhibitor p21 in pancreatic carcinoma. 757 63


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