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 expression of a negative regulator of the cell cycle, p21WAF1 protein, is trans-activated by wild-type p53, but not by the mutant protein. Therefore, mutations of the p53 and WAF1 genes may be complementary. We examined DNAs from 70 human primary lung (63 of NSCLC and 7 of SCLC) and 24 pancreatic cancers (19 primary cancers and 5 cell lines) for mutations of the WAF1 gene. No mutations were detected in any samples examined, regardless of the mutational state of the p53 gene. The results suggested that aberrations of the coding sequence of the WAF1 gene are not associated with carcinogenesis in lung and pancreatic cancers.
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PMID:Absence of a mutation of the p21/WAF1 gene in human lung and pancreatic cancers. 861 30

It has been suggested that the interaction of cytomegalovirus (CMV) with the p53 tumor suppressor gene product plays a role in the development of coronary artery restenosis after angioplasty. CMV nucleic acids have been observed in the coronary arteries of allografted hearts, suggesting a possible role for the interaction of CMV with p53 in the development of accelerated graft arteriosclerosis in transplant recipients. Formalin-fixed, paraffin-embedded sections of coronary arteries from 19 transplanted hearts were immunostained for the p53 gene product using Target Unmasking Fluid (TUF)-mediated immunohistochemistry and the anti-p53 antibodies CM1 and DO7. Fresh-frozen sections of coronary arteries were also available from six of the 19 hearts, and these fresh-frozen sections were immunostained for the p53 gene product with the DO7 antibody and for WAF1 using the anti-WAF1 antibody EA10. Focal and weak staining for p53 was observed in smooth muscle and endothelial cells in two of 19 vessels, whereas the remaining 17 did not stain. CMV nucleic acids were previously shown in six of 13 of these hearts by in situ hybridization. The fresh-frozen sections of coronary arteries also did not stain for p53, but the smooth muscle cells in these vessels did stain intensely for WAF1. These results suggest three possibilities: (1) CMV-p53 interactions are not important in the development of accelerated graft arteriosclerosis; or (2) there is an interaction, but it is transient and not detectable at the time points examined in this study; or (3) there is an interaction, but binding of CMV to p53 leads to accelerated degradation of p53, as occurs with HPV-E6. The expression of WAF1 further suggests that the WAF1-mediated antiproliferative signal is intact in these vessels.
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PMID:The WAF1-mediated p53 growth-suppressor pathway is intact in the coronary arteries of heart transplant recipients. 861 73

The intracellular calcium pump sarco(endo)plasmic reticulum Ca2+ (SERCA) is responsible for the formation of the Ca2+ gradient across the endoplasmic reticulum membrane, and this gradient is used to generate the Ca2- signal during agonist-stimulated cell growth. In the present study, the role of SERCA in both cell cycle and growth control was investigated using cultured rat aortic endothelial cells (RAEC). Using a novel DNA transfection approach, cell lines were established that showed varying degree of SERCA activity through the down-regulation of the endogenous SERCA gene (B. F. Liu, X. Xu, R. Fridman, S. Muallem, and T. H. Kuo, J. Biol. Chem. 271, 1--9, 1996). Cell proliferation studies indicated that the lower SERCA expressing cells exhibited a slower growth pattern without altering the doubling time which was similar for both parental and transfected RAEC lines. G1 to S phase transition was prolonged with a smaller proportion of cells entering DNA synthesis as indicated by thymidine incorporation assay. Comparison of transfected cell lines indicated a tight coupling of SERCA activity and the length of the G1 period. Down-regulation of SERCA gene expression was accompanied by increased mRNA levels of p21 (WAF1/CIP1), a universal cell cycle inhibitor. The delay in G1 to S progression also coincided with the up-regulation of p53 mRNA and underphosphorylation of the retinoblastoma protein. This study suggests that Ca2+ metabolism in the agonist mobilizable pool controls the cell cycle through the regulation of genes operating in the critical G1 to S checkpoint.
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PMID:The exit from G(0) into the cell cycle requires and is controlled by sarco(endo)plasmic reticulum Ca2+ pump. 861 36

In a search for effectors and targets of UVB signaling in mammalian cells, we screened a keratinocyte cDNA library with differentially subtracted UVB-enriched cDNA probes. One of the UVB induced cDNA clones proved to be the rat p21Cip1/WAF1 homologue. UVB irradiation caused a rise in p53 protein levels, in association with induction of p21Cip1/WAF1 and cyclin G expression. The effects of UVB irradiation induced p21Cip1/WAF1 on the cell cycle were examined. In contrast to gamma irradiation, which caused G2 arrest, UVB treatment of asynchronous neonatal rat keratinocytes (NK) led to a marked inhibition of replicative DNA synthesis and prolonged G1 and S phase arrests, persisting to 18-24 h, with recovery of cycling by 36 h post-UVB. G1 arrest was accompanied by inhibition of cyclin D-, E- and A-associated kinases. Kinase inhibition was not due to reduction in cyclin or cdk proteins. While the association of cyclin E with Cdk2 was moderately reduced, cyclin D1/Cdk4 and cyclin A/Cdk2 complexes were not disrupted. The activating threonine 160 phosphorylation of Cdk2 in cyclin complexes was not inhibited. An incremental binding of p21 with Cdk4 paralleled the inhibition of cyclin D1/Cdk4 kinase and a similar rise in Cdk2 binding to p21 was associated with inhibition of cyclin E and cyclin A dependent kinases. Furthermore, a rise in measurable p21Cip1/WAF1-Cdk2 inhibitory activity paralleled the loss of G1 cyclin-dependent kinase activity, supporting a role for p21Cip1/WAF1 in the UVB-induced checkpoints.
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PMID:UVB radiation induces p21Cip1/WAF1 and mediates G1 and S phase checkpoints. 862 54

We previously showed that expression of the bovine papillomavirus (BPV) E2 gene results in a dramatic inhibition of the proliferation of several human cervical carcinoma cell lines, including HeLa cells which contain human papillomavirus (HPV) type 18 DNA. We have assessed the status of endogenous G1 cell cycle regulatory proteins, including the tumor suppressor proteins, p53 and p105Rb, in order to investigate growth regulatory pathways in HeLa cells following E2 expression. The p53 tumor suppressor protein is stabilized following the introduction of the E2 gene into HeLa cells. This results in the induction of the p53-responsive gene encoding the cyclin dependent kinase (cdk) inhibitor, p21/WAF1, complex formation between p21/WAF1 and cdk2 and reduction of in vitro cdk2/cyclin E kinase activity. The reduced cdk kinase activity is accompanied by the accumulation of the growth inhibitory hypophosphorylated form of the tumor suppressor protein, p105Rb. The level of the p105Rb-regulated transcription factor, E2F1, is reduced, as is transcription of a variety of E2F1-regulated genes, including B-myb. Thus, the p53 growth inhibitory pathway has evidently not accumulated mutations in HeLa cells but rather appears intact. However, this pathway remains dormant, until it is mobilized by appropriate manipulations, such as the expression of the BPV E2 protein.
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PMID:Activation of the endogenous p53 growth inhibitory pathway in HeLa cervical carcinoma cells by expression of the bovine papillomavirus E2 gene. 863 1

In this study, human and rat cancer cells were used to investigate the expression of p53 and p21/WAF1/CIP1 and their association with apoptosis after exposure to nitric oxide (NO). It was found that NO induced nuclear accumulation of p53 protein in a dose- and time-dependent manner. The level of p53 protein was elevated by about fivefold compared with that of mock-treated cells 48 h after exposure to 300 ppm NO. The induction of p53 by NO was found by pulse-chase analysis to be mainly regulated by post-translational modification. The correlation between p53 status and apoptosis induced by NO in human cancer cells was also investigated in this study. We found that apoptosis was easily induced in cells containing wild-type p53 (COLO 205 and Hep G2) after exposure to NO. The p21/WAF1/CIP1 protein was induced by NO in cells containing wild-type p53 (Hep G2) but not in cells without p53 (Hep 3B) or with mutated p53 (HT-29). Our results indicate that wild-type p53 and p21/WAF1/CIP1 expression was elevated in human cancer cells by exposure to NO and suggest that this may eventually promote apoptosis.
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PMID:Induction of p53 and p21/WAF1/CIP1 expression by nitric oxide and their association with apoptosis in human cancer cells. 863 91

The expression of the WAF1/CIP1 gene product, p21, in enzyme-altered foci (EAF) induced by diethylnitrosamine (DEN) and phenobarbital (PB) was examined. p21 expression in the nucleus of hepatocytes in EAF was decreased compared to surrounding tissue. Fifty-eight percent of all GST-P-positive EAF induced by DEN and 79% of the EAF induced by PB were p21-negative. The proportion of p21-negative EAF increased with the size of the foci and more than 90% of the largest EAF were p21-negative. p21 is a mediator of p53 signals leading to block of the cell cycle. In conjunction with previous data indicating that p53 is not induced in GST-P-positive hepatocytes isolated from EAF-bearing rats, the results of this study suggest a role for altered signaling in the G1-S check point in rat hepatocarcinogenesis.
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PMID:Low expression of the WAF1/CIP1 gene product, p21, in enzyme-altered foci induced in rat liver by diethylnitrosamine or phenobarbital. 864 Jul 40

Cell cycle regulators such as cyclins, cyclin-dependent kinases (cdks) and their inhibitors control the growth of cells. SDI1/CIP1/WAF1/p21 is a potent inhibitor of G1 cdks, whose expression is induced by wild-type p53. To elucidate the mechanism of growth inhibition by transforming growth factor beta 1 (TGFbeta 1), we examined the effect of TGFbeta 1 on the expression of p21, G1 cyclins and cdks by human gastric cancer cell lines. TGFbeta 1 induced p21 expression and subsequently suppressed cdk2 kinase activity, followed by a reduction in phosphorylation of the product of the retinoblastoma tumor suppressor gene in TMK-1 cells, which are responsive to TGFbeta 1. Coimmunoprecipitation analysis demonstrated that TGFbeta 1 increased the level of p21 protein present in complexes with cdk2. In contrast, TGFbeta 1 did not induce p21 in TGFbeta 1-resistant MKN-28 cells. TGFbeta 1 did not affect the levels of p53 mRNA and protein in TMK-1 and MKN-28 cells, which contain mutated p53 genes. These mutated p53 complementary DNAs, when overexpressed, failed to activate transcription from the p21 promoter. Furthermore, TGFbeta 1 caused a reduction in the steady-state level of cyclin A protein concomitantly with inhibition of cdk2 kinase activity in TMK-1 cells. These results suggest that the growth inhibition of tumor cells by TGFbeta 1 is associated with p53-independent induction of p21, subsequent suppression of cdk activity and a decrease in cyclin A protein in TMK-1 cells.
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PMID:Inhibition of cell growth by transforming growth factor beta 1 is associated with p53-independent induction of p21 in gastric carcinoma cells. 864 69

We previously reported that introduction of the wild-type p53 gene into human cancer cells with deleted p53 enhanced apoptosis induced by chemotherapy [Fujiwara et al. (1994) Cancer Res 54:2287]. This suggests that p53 status could be a potent determinant of the therapeutic efficacy of DNA-damaging cancer therapy. We analyzed 24 patients with gastric or colorectal cancer for p53 mutations and apoptotic changes in surgical specimens. Out of 11 patients with gastric cancer, 3 were treated with chemotherapeutic drugs before resection; 5 of 13 patients with colorectal cancer had 30 Gy radiation prior to surgery. p53 mutations were detected in 4 cases of gastric cancer (36.4%) and in 6 cases of colorectal cancer (46.2%) by immunohistochemical staining. The preoperative DNA-damaging therapies increased the number of apoptotic cells in wild-type-p53-expressing tumors; tumors with mutant p53, however, significantly showed fewer apoptotic cells compared with those expressing wild-type p53. The p53-inducible WAF1/CIP1 protein was immunohistochemically observed in wild-type-p53-containing tumors, whereas mutant-p53-expressing tumors expressed no detectable WAF1/CIP1. Taken together, we conclude that p53 mutations are associated with the poor response of chemotherapy and radiotherapy.
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PMID:The p53 gene is a potent determinant of chemosensitivity and radiosensitivity in gastric and colorectal cancers. 864 47

Mutations in the WAF1/CIP1 gene were not found in 36 ovarian carcinomas, including tumours with loss of heterozygosity at the WAF1/CIP1 locus and/or lacking p53 mutations. In addition, no association was demonstrable between a polymorphism in a conserved region of the WAF1/CIP1 gene and ovarian carcinoma.
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PMID:WAF1/CIP1 structural abnormalities do not contribute to cell cycle deregulation in ovarian cancer. 864 86


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