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

p21 Is involved in the control of the mammalian cell cycle through the binding and inhibition of cyclin-dependent kinases. The cyclins are dependent on the phases of the cell cycle, and divided into two classes: mitotic cyclins (A, B1, B2) and G1 cyclins (C, D1, D2, D3, E). The product of the p21 gene is a potent downstream effector of the p53 tumor-suppressor gene function. The Hodgkin and Reed- Sternberg (H & RS) cells in Hodgkin's disease are reported to frequently express p53, p21, and nuclear proliferative activity (Ki-67). To clarify the relationship of p21, p53 and cyclins, we performed the immunohistochemistry of p53, p21, Ki-67, cyclin D1, cyclin E, cyclin A and cyclin B1, using 11 cases with Hodgkin's disease. In addition, we performed p53 gene sequencing of exon 5-8, and in situ hybridization of Epstein-Barr virus (EBV) EBER-1 region, whose products have reported to induce the expression of cyclin D. In this study, in all cases, Ki-67 was expressed in almost all H & RS cells, and p53 and p21 were expressed in H & RS cells. No p53 gene mutations were detected in any case, and p53 protein overexpression did not correlate with p53 gene mutations. The number of p21-positive H & RS cells was significantly related with that of the p53-positive cells. The cyclins E, A, B1 and D1 were also expressed in H & RS cells. Unexpectedly, the expression of the cyclins was not suppressed by p21 and p53 expression. In addition, the existence of EBV was not related to the expression of cyclins. It is considered that H & RS cells are, indeed, in cell cycle and commonly express the cell cyclins, and that the cell cycle of H & RS cells may not be specifically fixed in the G1, S, G2 or M phases.
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PMID:Expressions of cyclin E, A, and B1 in Hodgkin and Reed-Sternberg cells: not suppressed by cyclin-dependent kinase inhibitor p21 expression. 1046 93

A detailed model of the G(2) DNA damage checkpoint (G2DDC) system is presented that includes complex regulatory networks of the mitotic kinase Cdc2, phosphatase Cdc25, Wee1 kinase, and damage signal transduction pathways involving Chk1 and p53. Assumptions on the kinetic equations of the G2DDC are made, and computer simulations are carried out to demonstrate how the various subsystems operate to delay or arrest cell cycle progression. The detailed model could be used to explain various experiments relevant to G2DDC reported recently, including the nuclear export of 14-3-3-bound Cdc25, the down-regulation of cyclin B1 expression by p53, the effect of Chk1 and p53 on Cdc25 levels, and Wee1 degradation. It also is shown that, under certain conditions, p53 is necessary to sustain a G(2) arrest.
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PMID:A quantitative analysis of the kinetics of the G(2) DNA damage checkpoint system. 1050 Jan 80

14-3-3Sigma is a member of a family of proteins that regulate cellular activity by binding and sequestering phosphorylated proteins. It has been suggested that 14-3-3sigma promotes pre-mitotic cell-cycle arrest following DNA damage, and that its expression can be controlled by the p53 tumour suppressor gene. Here we describe an improved approach to the generation of human somatic-cell knockouts, which we have used to generate human colorectal cancer cells in which both 14-3-3sigma alleles are inactivated. After DNA damage, these cells initially arrested in the G2 phase of the cell cycle, but, unlike cells containing 14-3-3sigma, the 14-3-3sigma-/- cells were unable to maintain cell-cycle arrest. The 14-3-3sigma-/- cells died ('mitotic catastrophe') as they entered mitosis. This process was associated with a failure of the 14-3-3sigma-deficient cells to sequester the proteins (cyclin B1 and cdc2) that initiate mitosis and prevent them from entering the nucleus. These results may indicate a mechanism for maintaining the G2 checkpoint and preventing mitotic death.
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PMID:14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage. 1052 15

Overexpression of p53 causes G2 arrest, attributable in part to the loss of CDC2 activity. Transcription of cdc2 and cyclin B1, determined using reporter constructs driven by the two promoters, was suppressed in response to the induction of p53. Suppression requires the regions -287 to -123 of the cyclin B1 promoter and -104 to -74 of the cdc2 promoter. p53 did not affect the inhibitory phosphorylations of CDC2 at threonine 14 or tyrosine 15 or the activity of the cyclin-dependent kinase that activates CDC2 by phosphorylating it at threonine 161. Overexpression of p53 may also interfere with the accumulation of CDC2/cyclin B1 in the nucleus, required for cells to enter mitosis. Constitutive expression of cyclin B1, alone or in combination with the constitutively active CDC2 protein T14A Y15F, did not reverse p53-dependent G2 arrest. However, targeting cyclin B1 to the nucleus in cells also expressing CDC2 T14A Y15F did overcome this arrest. It is likely that several distinct pathways contribute to p53-dependent G2 arrest.
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PMID:Mechanisms of G2 arrest in response to overexpression of p53. 1056 59

Olomoucine, a purine derivative, inhibits multiple cyclin-dependent kinases that play important roles in regulating the G1/S and G2/M transitions of the cell cycle. In this study we investigated the cellular effects of olomoucine in two human Burkitt's lymphoma cell lines, WMN (containing wild-type p53) and CA46 (containing mutant p53), and found that in consistency with its ability to block the activity of cyclin E/Cdk2 and cyclin B1/Cdc2 kinases, olomoucine caused cell cycle arrest at both G1/S and G2/S boundaries. Moreover, cell cycle arrest occurred equally well in these two cell lines bearing different p53 gene status, suggesting that p53 was not responsible for the cell cycle arrest by olomoucine. A similar p53-independent fashion was also observed in the cytotoxic potency and apoptosis induction of olomoucine, in contrast to ionizing radiation which caused more cytotoxic activity and apoptosis in the WMN cell line bearing wild-type p53 compared with CA46 cells bearing mutant p53. Such p53-independent cytotoxicity of olomoucine was also confirmed in other human Burkitt's lymphoma and lymphoid cell lines containing wild-type and mutant p53. Therefore, our results give an impetus to continued research into olomoucine that might be a very useful chemotherapeutic strategy in the treatment of patients with mutant p53 tumors, at least in lymphoma patients.
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PMID:Cellular effects of olomoucine in human lymphoma cells differing in p53 function. 1056 74

The breast and ovarian cancer susceptibility gene product BRCA1 has been reported to be expressed in a cell cycle-dependent manner; possess transcriptional activity; associate with several proteins, including the p53 tumor suppressor; and play an integral role in certain types of DNA repair. We show here that ectopic expression of BRCA1 using an adenovirus vector (Ad-BRCA1) leads to dephosphorylation of the retinoblastoma protein accompanied by a decrease in cyclin-dependent kinase activity. Flow cytometric analysis on Ad-BRCA1-infected cells revealed a G(1) or G(2) phase accumulation. High density cDNA array screening of colon, lung, and breast cancer cells identified several genes affected by BRCA1 expression in a p53-independent manner, including DNA damage response genes and genes involved in cell cycle control. Notable changes included induction of the GADD45 and GADD153 genes and a reduction in cyclin B1 expression. Therefore, BRCA1 has the potential to modulate the expression of genes and function of proteins involved in cell cycle control and DNA damage response pathways.
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PMID:BRCA1 effects on the cell cycle and the DNA damage response are linked to altered gene expression. 1064 42

Recently we demonstrated, using normal human fibroblasts (NHFs), that UVc radiation induces a G2/M arrest which was even more pronounced when p53 expression was inhibited. So, the aim of this study was to evaluate in NHFs the relationship between UV-induced G2/M arrest and cyclin B1 regulation and to investigate if p53 could contribute to the cyclin B1 regulation in these conditions. Following exposure of asynchronous NHFs to UV light, we showed that the induced G2/M arrest was accompanied by a dose-dependent down-regulation of cyclin B1 mRNA as evaluated by RT-PCR. Concomitantly, using flow cytometric analysis, we observed a strong accumulation of cyclin B1 protein which was correlated to the apparition of the G2/M arrest. In order to study the contribution of p53 to the cyclin B1 accumulation in response to UV exposure, we inhibited p53 induction using p53 antisense oligonucleotides. We found that the inhibition of p53 protein induction after UV exposure had no effect on the level of cyclin B1 mRNA. Moreover, although inhibition of p53 protein induction increased the number of the cells in the G2-M phase, the mean content of cyclin B1 protein was not augmented in these cells. These results indicate clearly that the induction of p53 protein following UV exposure does not regulate the level of cyclin B1 mRNA or protein in normal cells.
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PMID:p53-independent regulation of cyclin B1 in normal human fibroblasts during UV-induced G2-arrest. 1066 97

Recent studies have suggested that p53 regulates the G2 checkpoint in the cell cycle and that this function is required for the maintenance of genomic integrity. In this study, we investigated a regulatory role of p53 specifically in G2-M transition. Human bladder carcinoma cells lacking functional p53 were synchronized at G1-S, which is preceded by p53-mediated G1 arrest. p53 expression in the synchronized cells was induced by infection with a recombinant adenovirus that encodes p53. After release from the G1-S arrest, the cells progressed to S-phase and G2 but failed to enter mitosis. Biochemical analysis showed that p53 inhibits cell cycle-dependent expression of cdc2 and cyclin B1 and consequently inhibits cdc2 kinase. The role of cyclin B1-associated cdc2 kinase in p53-mediated G2-M arrest was further investigated by expression of both cyclin B1 and cdc2AF, in which inhibitory phosphorylation sites were substituted. The cells expressing both cdc2AF and cyclin B1 showed a constitutive activation of cdc2 kinase during cell cycle progression and passed through G2-M regardless of p53 expression. Therefore, inactivation of cdc2 kinase through cdc2 and cyclin B1 repression is an essential step in p53-mediated G2-M arrest.
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PMID:Constitutive activation of cyclin B1-associated cdc2 kinase overrides p53-mediated G2-M arrest. 1067 33

Entry into mitosis is controlled by the cyclin-dependent kinase CDK1 and can be delayed in response to DNA damage. In some systems, such G(2)/M arrest has been shown to reflect the stabilization of inhibitory phosphorylation sites on CDK1. In human cells, full G(2) arrest appears to involve additional mechanisms. We describe here the prolonged (>6 day) downregulation of CDK1 protein and mRNA levels following DNA damage in human cells. This silencing of gene expression is observed in primary human fibroblasts and in two cell lines with functional p53 but not in HeLa cells, where p53 is inactive. Silencing is accompanied by the accumulation of cells in G(2), when CDK1 expression is normally maximal. The response is impaired by mutations in cis-acting elements (CDE and CHR) in the CDK1 promoter, indicating that silencing occurs at the transcriptional level. These elements have previously been implicated in the repression of transcription during G(1) that is normally lifted as cells progress into S and G(2). Interestingly, we find that other genes, including those for CDC25C, cyclin A2, cyclin B1, CENP-A, and topoisomerase IIalpha, that are normally expressed preferentially in G(2) and whose promoter regions include putative CDE and CHR elements are also downregulated in response to DNA damage. These data, together with those of other groups, support the existence of a p53-dependent, DNA damage-activated pathway leading to CHR- and CDE-mediated transcriptional repression of various G(2)-specific genes. This pathway may be required for sustained periods of G(2) arrest following DNA damage.
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PMID:Repression of CDK1 and other genes with CDE and CHR promoter elements during DNA damage-induced G(2)/M arrest in human cells. 1071 60

The transcription regulatory function of p53 was analyzed by using two inducible p53 systems in the human lung cancer cell line H1299. cDNA probes derived from RNA harvested 12 h after p53 induction were used to probe filters containing cDNA arrays. Over 20 genes were found to be significantly induced or suppressed by p53. The induced genes can be classified mainly as cell cycle inhibitors like p21waf, GADD45, apoptosis-related genes like Fas/APO1 and PIG3 or DNA repair genes like DDB2, DNA ligase and G/T mismatch DNA glycosylase. The suppressed genes include mainly cell cycle regulators like cyclin B1, cyclin H and kinases like c-abl, CLK1 and others. The most notable induced gene was MIC-1, encoding a TGF-beta-related secretory protein, suggesting a potential paracrine component for p53 growth suppression.
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PMID:Profile of gene expression regulated by induced p53: connection to the TGF-beta family. 1072 49


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