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)

The proteasome constitutes the central proteolytic component of the highly conserved ubiquitin-proteasome system, which is required for the maintenance and regulation of basic cellular processes, including differentiation, proliferation, cell cycling, gene transcription and apoptosis. Here we show that inhibition of proteasomal proteolytic activity by the proteasome inhibitors bortezomib and lactacystin suppresses essential immune functions of human CD4(+) T cells activated by allogeneic dendritic cells (DCs). In activated CD4(+) T cells, proteasome inhibition induces apoptosis accompanied by rapid accumulation and stabilization of the tumour suppressor protein p53. Activated CD4(+) T cells surviving proteasome inhibition undergo inhibition of proliferation by induction of G(1) phase cell-cycle arrest. Induction of G(1) arrest is accompanied by the accumulation of cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(KIP1) and the disappearance of cyclin A, cyclin D2 and proliferating cell nuclear antigen, proteins known to regulate G(1) to S phase cell-cycle transitions. Expression of the activation-associated cell surface receptors CD25, CD28, CD120b and CD134 as well as production of interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), interleukin-4 (IL-4) and IL-5 is suppressed in response to proteasome inhibition in CD4(+) T cells activated by DCs. Expression of CD25, IFN-gamma, TNF-alpha, IL-4 and IL-5 is known to be mediated by the transcriptional activity of nuclear factor of activated T cells (NFAT), and we show here that proteasome inhibition suppresses activation and nuclear translocation of NFATc2 in activated CD4(+) T cells. Thus, the proteasome is required for essential immune functions of activated CD4(+) T cells and can be defined as a molecular target for the suppression of deregulated and unwanted T-cell-mediated immune responses.
 ...
PMID:Proteasome inhibition suppresses essential immune functions of human CD4+ T cells. 1821 57

Treatment of exponentially growing MCF-7 human breast carcinoma cells with tamoxifen (TAM) inhibits cell growth in a dose-dependent manner. However, the molecular basis for the drug's activity and its relationship to the cell cycle have not yet been clearly established. In this study, we analyzed cell cycle-related proteins used for immunoblotting and flow cytometry in TAM-treated MCF-7 cells. In addition, the ratio of apoptosis in the cell was analyzed using labeling of DNA strand breaks (TdT assay). In flow-cytometric DNA distribution analysis, the S-phase fraction showed a marked decrease and a concomitant increase in G1- and G2-phase cells accompanying the inhibitory effect of TAM; these changes were time- and dose-dependent. Immunoblotting revealed that the levels of p53 and p21(WAF1/CIP1) in TAM-treated cells increased in a time- and dose-dependent manner, whereas those of p27(KIP1) and p16 slightly increased or remained unchanged. Furthermore, cyclin D3 and B showed sharp decreases, in contrast with p53 and p21(WAF1/CIP1) DNA-apoptosis dual analysis using flow cytometry revealed that the TAM-treated samples contained apoptotic cells, the majority of which were arrested in G1 or G2 and showed suppression of Bcl-2 protein. These results suggest that the tumorigenic effect of TAM on MCF-7 cells arises through antitumor effects that are due to the expression of cyclin-dependent kinase inhibitors, especially p21(WAF1/CIP1) and these are regulated by the decrease of wild-type p53. The proposed mechanism is similar to that underlying the cytotoxic effects of other agents and ionizing irradiation that cause DNA damage.
 ...
PMID:G1 arrest and expression of cyclin-dependent kinase inhibitors in tamoxifen-treated MCF-7 human breast cancer cells. 1839 72

In the present study, the antiproliferative effects of the ethanol extract of Artemisia princeps Pampanini (EAPP) and the mechanism involved were investigated. Of the various cancer cells examined, human neuroblastoma A172 cells were most sensitive to EAPP, and their proliferation was dose- and time-dependently inhibited by EAPP. DNA flow cytometry analysis indicated that EAPP notably induced the G(1) phase arrest in A172 cells. Of the G(1) phase cycle-related proteins examined, the expressions of cyclin-dependent kinase (CDK) 2, CDK4, and CDK6 and of cyclin D(1), D(2), and D(3) were found to be markedly reduced by EAPP, whereas cyclin E was unaffected. Moreover, the protein and mRNA levels of the CDK inhibitors p16(INK4a), p21(CIP1/WAF1), and p27(KIP1) were increased, and the activities of CDK2, CDK4, and CDK6 were reduced. Furthermore, the expressions of E2F-1 and of phosphorylated pRb were also decreased, and the protein levels of p53 and pp53 (Ser15) were increased. Up-regulation of p21(CIP1/WAF1) was found to be mediated by a p53-dependent pathway in EAPP-induced G(1)-arrested A172 cells. When these data are taken together, the EAPP was found to potently inhibit the proliferation of human neuroblastoma A172 cells via G(1) phase cell cycle arrest.
 ...
PMID:The ethanol extract from Artemisia princeps Pampanini induces p53-mediated G1 phase arrest in A172 human neuroblastoma cells. 1859 64

This study was aimed to elucidate the novel structure of HY251 isolated from the roots of Aralia continentalis and to evaluate its detailed inhibition mechanisms on cell cycle progression in HeLa cells. The structure of HY251 was elucidated based on the interpretation of the NMR spectra, as 3-propyl-2-vinyl-1,2,3,3a,3b,6,7,7a,8,8a-decahydrocyclopenta[a]indene-3,3a,7a,8a-tetraol. The flow cytometric analysis revealed an appreciable G(1) phase arrest in HeLa cells treated with 100 microM of HY251. This HY251-induced G(1) phase arrest is associated with decreased expression of cyclin D3 and up-regulation of p21(CIP1) and p27(KIP1), via p53 phosphorylation at Ser-15 by transcriptional up-regulation of ATM, which resulted in increased hypophosphorylated pRb in HeLa cells.
 ...
PMID:HY251, a novel cell cycle inhibitor isolated from Aralia continentalis, induces G1 phase arrest via p53-dependent pathway in HeLa cells. 1909 50

Human papillomavirus is involved in the carcinogenesis of tonsillar squamous cell carcinomas. Here, we investigated the expression and the prognostic value of key cell cycle proteins in the pRb and p53 pathways in both human papillomavirus type 16-positive and -negative tonsillar squamous cell carcinomas. Using immunohistochemistry, 77 tonsillar squamous cell carcinomas with known human papillomavirus type 16 status and clinical outcome were analyzed for expression of Ki67, p16(INK4A,) cyclin D1, pRb, p14(ARF), MDM2, p53, p21(Cip1/WAF1), and p27(KIP1). Results were correlated with each other and with clinical and demographic patient data. A total of 35% of tonsillar carcinomas harbored integrated human papillomavirus type 16 DNA and p16(INK4A) overexpression, both being considered essential features for human papillomavirus association. These tumors also showed the overexpression of p14(ARF) (P<0.0001) and p21(Cip1/WAF1) (P=0.001), and downregulation of pRb (P<0.0001) and cyclin D1 (P=0.027) compared with the human papillomavirus-negative cases. Univariate Cox regression analyses revealed a favorable survival rate for non-smokers (P=0.006), as well as for patients with T1-2 tumors (P<0.0001) or tumors showing low expression of cyclin D1 (P=0.028), presence of human papillomavirus and overexpression of p16(INK4A) (P=0.01), p14(ARF) (P=0.02) or p21(Cip1/WAF1) (P=0.004). In multivariate regression analyses, smoking and tumor size, as well as expression of cyclin D1 and p21(Cip1/WAF1), were found to be independent prognostic markers. We conclude that human papillomavirus positivity in tonsillar squamous cell carcinomas strongly correlates with p21(Cip1/WAF1) and p14(ARF) overexpression and downregulation of pRb and cyclin D1. In particular p21(Cip1/WAF1) overexpression is an excellent favorable prognosticator in tonsillar squamous cell carcinomas.
 ...
PMID:P21 Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis. 1930 81

HTLV-1 Tax can induce senescence by up-regulating the levels of cyclin-dependent kinase inhibitors p21(CIP1/WAF1) and p27(KIP1). Tax increases p27(KIP1) protein stability by activating the anaphase promoting complex/cyclosome (APC/C) precociously, causing degradation of Skp2 and inactivation of SCF(Skp2), the E3 ligase that targets p27(KIP1). The rate of p21(CIP1/WAF1) protein turnover, however, is unaffected by Tax. Rather, the mRNA of p21(CIP1/WAF1) is greatly up-regulated. Here we show that Tax increases p21 mRNA expression by transcriptional activation and mRNA stabilization. Transcriptional activation of p21(CIP1/WAF1) by Tax occurs in a p53-independent manner and requires two tumor growth factor-beta-inducible Sp1 binding sites in the -84 to -60 region of the p21(CIP1/WAF1) promoter. Tax binds Sp1 directly, and the CBP/p300-binding activity of Tax is required for p21(CIP1/WAF1) trans-activation. Tax also increases the stability of p21(CIP1/WAF1) transcript. Several Tax mutants trans-activated the p21 promoter, but were attenuated in stabilizing p21(CIP1/WAF1) mRNA, and were less proficient in increasing p21(CIP1/WAF1) expression. The possible involvement of Tax-mediated APC/C activation in p21(CIP1/WAF1) mRNA stabilization is discussed.
 ...
PMID:Induction of p21(CIP1/WAF1) expression by human T-lymphotropic virus type 1 Tax requires transcriptional activation and mRNA stabilization. 1935 50

The ability of oncolytic adenoviruses to replicate in and lyse cancer cells offers a potential therapeutic approach. However, selectivity and efficacy of adenovirus replication need to be improved. In this study, we present that loss of p21(WAF1) promotes adenovirus replication and more effective cell killing. To test our hypothesis, we took HCT116 colon cancer cell lines carrying deletions of either p21(WAF1) or p53, and infected these cell lines with wild-type adenovirus (WtD) or the oncolytic adenoviruses, ONYX-015 and Delta-24. We found that WtD, ONYX-015 and Delta-24 induced stronger cytopathic effects in HCT116 p21-/- cells compared with HCT116-WT cells. This was accompanied by increased virus production. siRNA-mediated knockdown of p21(WAF1), and similarly of p27(KIP1), in HCT116-WT cells also enhanced replication of and cell killing by these viruses. Furthermore, we found that TE7, an esophageal carcinoma cell line, also showed a strong cell-killing effect and virus production when p21(WAF1) expression was suppressed by RNA interference before adenoviruses infection. Also, H1299 and DU-145 cells transfected with p21(WAF1) siRNA showed higher virus production after ONYX-015 and Delta-24 infections. These observations suggest that p21(WAF1) plays a role in mediating replication of oncolytic viruses with potential implications for adenoviral therapy of cancer.
 ...
PMID:RNA interference-mediated knockdown of p21(WAF1) enhances anti-tumor cell activity of oncolytic adenoviruses. 1940 49

Cholangiocarcinoma is the second most common primary hepatic neoplasia and the only curative therapy is surgical resection or liver transplantation. Biphosphonates (BPs) are an emerging class of drugs widely used to treat bone diseases and also appear to possess direct antitumor activity. In two human cholangiocarcinoma cell lines (TFK-1 and EGI-1) we investigated, for the first time, the activity of zoledronic acid by determining proliferation, cell cycle analysis and apoptosis. The results obtained indicate that zoledronic acid induces cell-narrowing and growth inhibition, both reversed by 25 microM GGOH, and significantly affects the colony-forming ability of these cells. The inhibition by zoledronic acid of Rap1A prenylation was reversed in cell co-treated with GGOH. At 10-50 microM zoledronic acid exerted an S-phase cell cycle arrest which was confirmed by changes in the level of cyclins and of regulators p27(KIP1) and pRb. Interestingly, the expression level of cyclin A (putative S-phase marker) shows a dose-dependent increment in contrast to the decrement of cyclin D1 (putative G1 phase marker). However, neither hypodiploid cells nor cleaved PARP or caspase-3 was detected. The lack of TP53 or loss of its function, the large constitutive expressions of anti-apoptotic proteins Bcl-xL and HSP27 together with the low level of the pro-apoptotic Bax are the likely factors which protect cells from apoptosis. In conclusion, our study indicates that zoledronic acid induces S-phase arrest and cell-narrowing, both reversed by GGOH and, by changing the delicate balance between pro- and anti-apoptotic proteins, allows survival of cholangiocarcinoma cells.
 ...
PMID:Zoledronic acid determines S-phase arrest but fails to induce apoptosis in cholangiocarcinoma cells. 1946 30

Epidemiological studies suggest that human papillomavirus (HPV)-infected women who smoke face an increased risk for developing cervical cancer. We have previously reported that exposure of HPV-positive organotypic cultures to benzo[a]pyrene (BaP), a major carcinogen in cigarette smoke, resulted in enhanced viral titers. Since BaP is known to deregulate multiple pathways of cellular proliferation, enhanced virion synthesis could result from carcinogen/host cell interaction. Here, we report that BaP-mediated upregulation of virus synthesis is correlated to an altered balance between cell cycle-specific cyclin-dependent kinase (CDK) activity profile compared with controls. Specifically, BaP treatment increased accumulation of hyperphosphorylated retinoblastoma protein (pRb) which coincided with increased cdc2/CDK1 kinase activity, but which further conflicted with the simultaneous upregulation of CDK inhibitors p16(INK4) and p27(KIP1), which normally mediate pRb hypophosphorylation. In contrast, p21(WAF1) and p53 levels remained unchanged. Under these conditions, CDK6 and CDK2 kinase activities were decreased, whereas CDK4 kinase activity remained unchanged. The addition of purvalanol A, a specific inhibitor of CDK1 kinase, to BaP-treated cultures, resulted in the production of noninfectious HPV type 31b (HPV31b) particles. In contrast, infectivity of control virus was unaffected by purvalanol A treatment. BaP targeting of CDK1 occurred independently of HPV status, since BaP treatment also increased CDK1 activity in tissues derived from primary keratinocytes. Our data indicate that HPV31b virions synthesized in the presence of BaP were dependent on BaP-mediated alteration in CDK1 kinase activity for maintaining their infectivity.
 ...
PMID:Downregulation of Cdc2/CDK1 kinase activity induces the synthesis of noninfectious human papillomavirus type 31b virions in organotypic tissues exposed to benzo[a]pyrene. 2018 98

The cell cycle progression is regulated by interactions of specific cyclin-dependent kinases at the G1-S and G2-M checkpoints. In addition, the cell cycle dysregulation plays a major role in carcinogenesis of human cancers. To investigate the role of cell cycle regulators in the pathogenesis and progression of human gastric cancer, the expression of cyclin D1, A, B1, p16(INK4a), p21(CPI1), p27(KIP1), p53, and pRb was investigated in 482 gastric carcinomas using immunohistochemistry in terms of histologic type, tumor invasion, size, location, and metastatic behavior. The cyclin D1, A, and B1 expression (>10%) was observed in 49%, 69%, and 49% of the cases, respectively. Negative cases for p16(INK4a), p21(CPI1), and p27(KIP1) were detected in 90%, 86%, and 50.5%. There were 30% and 68% of the gastric tumors positive for p53 and pRb, respectively. Diffuse carcinomas frequently were positive for cyclin B1 and pRb, and negative for p21. A relationship between p53 expression and intestinal type carcinomas was found. In addition, the expression of cyclin B1 was associated with regional lymph node metastasis and poor prognosis. No relationship was noticed between any other cell cycle proteins expression and age, sex, tumor size, tumor location, and lymph node involvement. These findings have shown alterations in several cell cycle regulators, and it was suggested that cyclin B1 expression is closely associated with poor behavior in gastric cancer.
 ...
PMID:Evaluation of cell cycle protein expression in gastric cancer: cyclin B1 expression and its prognostic implication. 2033 96


<< Previous 1 2 3 4 5 6 Next >>