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)

Expression of cell-cycle modulators at the G1-S boundary, retinoblastoma gene product (pRb), p21, p16, p27, p53, cyclin D1, and cyclin E was investigated with 104 hepatocellular carcinomas (HCC), as well as 90 of their adjacent noncancerous lesions and 9 normal liver control specimens. The labeling indices (LI) of pRb, p21, p16, and p27 were higher in HCC lesions than in the adjacent noncancerous lesions and normal controls. Especially, p27 LI in noncancerous lesions was significantly higher than that in normal livers (P =.011). Aberrant p53 expression and cyclin D1 and E overexpression were observed exclusively in HCC lesions. pRb was positive in 85.6% of the HCC cases and was not related to any clinicopathological parameters. The p21 LI was generally low (average, 5.5 +/- 9.8). Although a negative regulator, p21 LI was higher in cases with intrahepatic metastasis (P =.0359). The p16 LI was significantly decreased (P =.0121) in cases with advanced stage. p27 LI was significantly decreased in cases with portal invasion (P =.0409), poor differentiation (P <.0001), larger size (P =.0421), and intrahepatic metastasis (P =.0878, borderline significance). On the other hand, aberrant p53 expression showed positive relationships with poor differentiation (P =.0004) and Ki-67 LI (P =. 0047). Cyclin D1 overexpression was found in 32.6% of the cases and occurred more frequently in those with high Ki-67 LI (P =.0032), pRb expression (P =.0202), poor differentiation (P =.0612, borderline significance), and intrahepatic metastasis (P =.0675, borderline significance). Cyclin E was overexpressed in 35.5% and had positive relationships with Ki-67 LI (P =.0269) and stage (P =.0125). In univariate analysis, cases with p27 LI < 50 (P =.0004), cyclin D1 overexpression (P =.0041), and cyclin E overexpression (P =.0572, borderline significance) showed poorer outcomes for disease-free survival (DFS). In multivariate analysis, p27 expression could be recognized as an independent prognostic marker for DFS. These findings suggest that in HCC: 1) p27 is active against HCC progression in early phases and, possibly, hepatocarcinogenesis as a negative regulator and can be a novel prognostic marker for DFS; and 2) cyclin D1 predominantly works for cell-cycle progression at the G1-S boundary.
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PMID:Expression and prognostic roles of the G1-S modulators in hepatocellular carcinoma: p27 independently predicts the recurrence. 1038 44

In the present study we investigated the expression of the cell cycle inhibitor p27 in endometrial neoplasia using immunohistochemistry with a p27-specific antibody. Expression of p27 in endometrial carcinomas was compared with expression in the normal endometrium throughout the cycle. Normal endometrial cells showed strong nuclear expression of p27. Expression was present throughout the cycle and was stronger during the secretory phase. We found strongly reduced or abolished expression of p27 in endometrial carcinoma (85.3% of cases). The 41 tumours analysed were classified according to p27 staining intensity and percentage of positive cells into the following categories of p27 expression: negative/very low (56.0%); low (29.3%); moderate (14.7%) and high (0.0%). All the p27-positive tumours were well-differentiated endometrioid carcinomas of malignancy grade G1. Comparison with the p53 status showed that all tumours with strong p53 expression had low/negative p27 staining, while those that were positive for p27 had negative/low p53 staining. Reduced or absent p27 levels were also observed by Western blot analysis both in tumour samples and in HEC-1B endometrial adenocarcinoma cells. It thus seems that p27 expression is essential for the control of normal endometrial proliferation, and reduced or absent p27 expression may be an important step in endometrial carcinogenesis.
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PMID:Strongly reduced expression of the cell cycle inhibitor p27 in endometrial neoplasia. 1038 25

To investigate the mechanism by which presenilin (PS) overexpression induces apoptosis, we studied the effects of these proteins on cell cycle progression. Transiently transfected HeLa cells were bromodeoxyuridine (BrdU) labeled to visualize DNA synthesis by immunofluorescence and stained with propidium iodide to measure DNA content by fluorescence-activated cell sorting (FACS). BrdU labeling was decreased in cells expressing presenilin-1 (PS1), presenilin-2 (PS2), an Alzheimer's disease-associated missense mutation PS2(N141I), and the carboxyl-terminally deleted PS2 construct PS2(166aa), compared with mock and neurofilament-light (NF-L) transfected cells. Analysis of BrdU incorporation in mitotically synchronized HeLa cells suggested that cells were arresting in the G1 phase of the cell cycle, and this was confirmed by FACS analysis. Interestingly, cell cycle progression was more inhibited by the expression of PS2(N141I) compared with wild-type PS2. In addition, ATM, the gene product mutated in ataxia-telangiectasia, does not appear to be a downstream effector of PS-induced cell cycle arrest as transfection of PS constructs into an ataxia-telangiectasia cell line also resulted in cell cycle inhibition. Quantitative immunoblotting of whole-cell lysates from PS-transfected cells did not reveal increases or decreases in the steady-state levels of p21, p27, p53, pRb, or c-myc, suggesting that the presenilins mediate cell cycle arrest by mechanisms other than simple changes in the steady-state levels of these cell-cycle-related proteins.
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PMID:Presenilin overexpression arrests cells in the G1 phase of the cell cycle. Arrest potentiated by the Alzheimer's disease PS2(N141I)mutant. 1039 46

The mechanism by which platelet-derived growth factor (PDGF) regulates vascular smooth muscle cell (SMC) DNA synthesis is unknown, but may involve isoprenoid intermediates of the cholesterol biosynthetic pathway. Inhibition of isoprenoid synthesis with the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, simvastatin (Sim, 1-10 microM), inhibited PDGF-induced SMC DNA synthesis by >95%, retinoblastoma gene product hyperphosphorylation by 90%, and cyclin-dependent kinases (cdk)-2, -4, and -6 activity by 80 +/- 5, 50 +/- 3, and 48 +/- 3%, respectively. This correlated with a 20-fold increase in p27(Kip1) without changes in p16, p21(Waf1), or p53 levels compared with PDGF alone. Since Ras and Rho require isoprenoid modification for membrane localization and are implicated in cell cycle regulation, we investigated the effects of Sim on Ras and Rho. Up-regulation of p27(Kip1) and inhibition of Rho but not Ras membrane translocation by Sim were reversed by geranylgeranylpyrophosphate, but not farnesylpyrophosphate. Indeed, inhibition of Rho by Clostridium botulinum C3 transferase or overexpression of dominant-negative N19RhoA mutant increased p27(Kip1) and inhibited retinoblastoma hyperphosphorylation. In contrast, activation of Rho by Escherichia coli cytotoxic necrotizing factor-1 decreased p27(Kip1) and increased SMC DNA synthesis. These findings indicate that the down-regulation of p27(Kip1) by Rho GTPase mediates PDGF-induced SMC DNA synthesis and suggest a novel direct effect of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors on the vascular wall.
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PMID:3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(Kip1). 1041 14

Virus-induced immunosuppression is the major cause of the high morbidity/mortality rates associated with acute measles. It has been shown previously that mitogen-dependent proliferation of peripheral blood lymphocytes (PBL) was strongly impaired after contact with the measles virus (MV) glycoproteins F and H expressed on the surface of infected cells, cells transfected with the corresponding expression constructs or UV-inactivated MV (UV-MV). The state of unresponsiveness was not associated with the induction of apoptosis, and a significant proportion of PBL was found to be arrested in the G0/G1 phase of the cell cycle. It is now shown that cell cycle cessation, rather than complete arrest, is induced after MV glycoprotein contact. No obvious role was found for p53 in the induction of this unresponsiveness. With UV-MV as effector, downregulation of p27, an inhibitor of cyclin-dependent kinase (CDK)-cyclin complexes, was significantly delayed after mitogenic stimulation of human PBL. The activities of both CDK4/6-cyclin D and CDK2-cyclin E complexes for phosphorylation of exogenous substrates in vitro were strongly reduced. CDK4, CDK6, cyclins D3 and E and, to a minor extent, CDK2 failed to accumulate at the protein level after mitogenic stimulation in the presence of UV-MV. These data indicate that MV-induced proliferative unresponsiveness of PBL to mitogenic stimulation is associated with a drastic deregulation of the expression of cell cycle genes essential for the G1/S phase transition.
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PMID:Measles virus-induced immunosuppression in vitro is associated with deregulation of G1 cell cycle control proteins. 1042 27

The cell cycle regulatory protein p27, an inhibitor of cyclin-dependent kinases (CDK), has been attributed a role in (i) prognosis in breast and colon cancer, (ii) induction of apoptosis in cancer cells, and (iii) resistance to cancer chemotherapy. Here we report that p27 is widely expressed in human malignant gliomas in vivo and in glioma cell lines in vitro. Serum deprivation or confluency promotes p27 protein accumulation in vitro. Neither baseline p27 levels nor p27 levels induced by confluency or serum deprivation correlate with p53 status or drug sensitivity of human glioma cell lines. Expression of antisense p27 mRNA increased the doubling times in T98G glioma cells, whereas sense p27 mRNA had no such effect. There was a density-dependent and drug-specific modulation of chemosensitivity by sense or antisense mRNA expression in T98G cells. Taken together, these data define a strong p27 response to altered growth conditions and suggest a role for p27 in modulating response to chemotherapy in human malignant glioma cells.
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PMID:p27 modulates cell cycle progression and chemosensitivity in human malignant glioma. 1044 21

(-)-Epigallocatechin-3-gallate (EGCG) potently inhibits cell proliferation and suppresses tumor growth both in vitro and vivo, but little is known regarding the cell cycle regulatory proteins mediating these effects. This study investigated the effects of EGCG and other catechins on the cell cycle progression. DNA flow cytometric analysis indicated that 30 microM of EGCG blocked cell cycle progression at G1 phase in asynchronous MCF-7 cells. In addition, cells exposed to 30 microM of EGCG remained in the G1 phase after release from aphidicolin block. Over a 24-h exposure to EGCG, the Rb protein changed from hyper- to hypophosphorylated form and G1 arrest developed. The protein expression of cyclin D1, and E reduced slightly under the same conditions. Immunocomplex kinase experiments showed that EGCG inhibited the activities of cyclin-dependent kinase 2 (Cdk2) and 4 (Cdk4) in a dose-dependent manner in the cell-free system. As the cells were exposed to EGCG (30 microM) over 24 h a gradual loss of both Cdk2 and Cdk4 kinase activities occurred. EGCG also induced the expression of the Cdk inhibitor p21 protein and this effect correlated with the increase in p53 levels. The level of p21 mRNA also increased under the same conditions. In addition, EGCG also increased the expression of the Cdk inhibitor p27 protein within 6 h after EGCG treatment. These results suggest that EGCG either exerts its growth-inhibitory effects through modulation of the activities of several key G1 regulatory proteins such as Cdk2 and Cdk4 or mediates the induction of Cdk inhibitor p21 and p27.
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PMID:Inhibition of cyclin-dependent kinases 2 and 4 activities as well as induction of Cdk inhibitors p21 and p27 during growth arrest of human breast carcinoma cells by (-)-epigallocatechin-3-gallate. 1046 99

It is impossible to predict malignant potential of thymomas by conventional histopathological examination. In order to find a malignant marker of thymoma, we immunohistochemically examined the expression of the products of p53 and p27kip1, potential tumor suppressor genes in thymic epithelial tumors. The thymic epithelial tumors examined in the present study included 13 non-invasive thymomas, 7 invasive thymomas, and 4 thymic carcinomas. The thymic epithelial cells showed abnormal accumulation of p53 protein in 2 of 13 non-invasive thymomas (15.4%), 4 of 7 invasive thymomas (50%), and 3 of 4 thymic carcinomas (75%). The frequency of p53-expression paralleled with clinical aggressiveness. On the other hand, p27 showed no correlation with clinical aggressiveness. In conclusion, the present results suggest that the presence of p53-positive epithelial cells might be a useful indicator to predict malignant potential of thymoma.
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PMID:[Correlation between clinical aggressiveness of thymic epithelial tumors and expression of tumor suppressor gene products (p53, p27)]. 1049 46

Expression of the Epstein-Barr virus (EBV) latency-associated genes activates cell cycle progression and drives immortalization of the infected cell. In contrast, progression of the EBV replication program occurs most efficiently in growth-arrested cells. Previous studies showed that the EBV-encoded immediate-early transcription factor, Zta, can induce expression of the cyclin-dependent kinase inhibitors, p21 and p27, the tumor suppressor, p53, and cell growth arrest. Moreover, Zta-mediated induction of growth arrest occurs independently of its transcriptional transactivation function. Here we show that substitution of Zta's basic DNA binding domain with the analogous region of the Zta homologue, c-Fos, abrogates Zta's ability to induce growth arrest and to induce p21, p27, or p53 expression, suggesting that protein-protein interactions between this region of Zta and key cell cycle control proteins are involved in signaling cell cycle arrest. We also show that despite the crucial role for Zta's basic domain in eliciting cell growth arrest, its amino terminus is required for efficient induction of p27 and it modulates the level of p53 induction. Last, we provide evidence that Zta-mediated inductions of p21, p27, and p53 occur, at least in part, through distinct pathways. Therefore, Zta interacts with multiple growth arrest pathways, a property which may have evolved partly as a means to ensure that lytic replication occurs in a growth-arrested setting in multiple different tissues in various states of differentiation.
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PMID:Genetic dissection of cell growth arrest functions mediated by the Epstein-Barr virus lytic gene product, Zta. 1051 9

In this study we investigated the growth inhibitory effects of UCN-01 in several normal and tumor-derived human breast epithelial cells. We found that while normal mammary epithelial cells were very sensitive to UCN-01 with an IC50 of 10 nM, tumor cells displayed little to no inhibition of growth with any measurable IC50 at low UCN-01 concentrations (i.e. 0 - 80 nM). The UCN-01 treated normal cells arrested in G1 phase and displayed decreased expression of most key cell cycle regulators examined, resulting in inhibition of CDK2 activity due to increased binding of p27 to CDK2. Tumor cells on the other hand displayed no change in any cell cycle distribution or expression of cell cycle regulators. Examination of E6- and E7-derived strains of normal cells revealed that pRb and not p53 function is essential for UCN-01-mediated G1 arrest. Lastly, treatment of normal and tumor cells with high doses of UCN-01 (i.e. 300 nM) revealed a necessary role for a functional G1 checkpoint in mediating growth arrest. Normal cells, which have a functional G1 checkpoint, always arrest in G1 even at very high concentrations of UCN-01. Tumor cells on the other hand have a defective G1 checkpoint and only arrest in S phase with high concentrations of UCN-01. The effect of UCN-01 on the cell cycle is thus quite different from staurosporine, a structural analogue of UCN-01, which arrests normal cells in both G1 and G2, while tumor cells arrest only in the G2 phase of the cell cycle. Our results show the different sensitivity to UCN-01 of normal compared to tumor cells is dependent on a functional pRb and a regulated G1 checkpoint.
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PMID:UCN-01-mediated G1 arrest in normal but not tumor breast cells is pRb-dependent and p53-independent 1052 39


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