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)

Members of the INK4 protein family specifically inhibit cyclin-dependent kinase 4 (cdk4) and cdk6-mediated phosphorylation of the retinoblastoma susceptibility gene product (Rb). p16INK4A, a prototypic INK4 protein, has been identified as a tumor suppressor in many human cancers. Inactivation of p16INK4A in tumors expressing wild-type Rb is thought to be required in order for many malignant cell types to enter S phase efficiently or to escape senescence. Here, we demonstrate another mechanism of tumor suppression by implicating p16INK4A in a G1 arrest checkpoint in response to DNA damage. Calu-1 non-small cell lung cancer cells, which retain Rb and lack p53, do not arrest in G1 following DNA damage. However, engineered expression of p16INK4A at levels compatible with cell proliferation restores a G1 arrest checkpoint in response to treatment with gamma-irradiation, topoisomerase I and II inhibitors, and cisplatin. A similar checkpoint can be demonstrated in p53-/- fibroblasts that express p16INK4A. DNA damage-induced G1 arrest, which requires the expression of pocket proteins such as Rb, can be abrogated by overexpression of cdk4, kinase-inactive cdk4 variants capable of sequestering p16INK4A, or a cdk4 variant incapable of binding p16INK4A. After exposure to DNA-damaging agents, there was no change either in overall levels of p16INK4A or in amounts of p16INK4A found in complex with cdks 4 and 6. Nonetheless, p16INK4A expression is required for the reduction in cdk4- and cdk6-mediated Rb kinase activity observed in response to DNA damage. During tumor progression, loss of p16INK4A expression may be necessary for cells with wild-type Rb to bypass this G1 arrest checkpoint and attain a fully transformed phenotype.
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PMID:p16INK4A participates in a G1 arrest checkpoint in response to DNA damage. 941 85

Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor p16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer. The frequent mutations and deletions of p16 in human cancer cell lines first suggested an important role for p16 in carcinogenesis. This genetic evidence for a causal role was significantly strengthened by the observation that p16 was frequently inactivated in familial melanoma kindreds. Since then, a high frequency of p16 gene alterations were observed in many primary tumors. In human neoplasms, p16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. Additionally, the loss of p16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions. p16 is a major target in carcinogenesis, rivaled in frequency only by the p53 tumor-suppressor gene. Its mechanism of action as a CDKI has been elegantly elucidated and involves binding to and inactivating the cyclin D-cyclin-dependent kinase 4 (or 6) complex, and thus renders the retinoblastoma protein inactive. This effect blocks the transcription of important cell-cycle regulatory proteins and results in cell-cycle arrest. Although p16 may be involved in cell senescence, the physiologic role of p16 is still unclear. Future work will focus on studies of the upstream events that lead to p16 expression and its mechanism of regulation, and perhaps lead to better therapeutic strategies that can improve the clinical course of many lethal cancers.
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PMID:Role of the p16 tumor suppressor gene in cancer. 950 8

Mutations of tumor suppressor genes remove mechanisms that normally arrest proliferation of transformed cells, resulting in tumor formation. The p53 gene product functions as a tumor suppressor that induces p21/Waf-1, the 21-kDa product of the waf-1/cip-1/mda-6 gene. p21/Waf-1 is a pan-cyclin-dependent kinase inhibitor that arrests cell cycle progression under a variety of circumstances. We examined tissues from a dog with multiple primary pigmented proliferative lesions (benign, multicentric melanoma consisting of three distinct dermal lesions and a matrical cyst) for p21/Waf-1 and p53 expression by immunohistochemistry and immunoblotting. p21/Waf-1 and p-53 proteins were undetectable in the tumor cells and in the cyst but were present in adjacent normal tissues. Abundant cyclin-dependent kinase 4 (Cdk4), a protein related functionally to p21/Waf-1, also was present in the cyst. A somatic mutation of the waf-1 gene or of the p53 gene may have resulted in the loss of p21/Waf-1 expression in a common precursor of pigment-producing cells from the affected dog. Furthermore, this functional loss of p21/Waf-1 may play an important role in the genesis of canine benign melanoma.
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PMID:Functional loss of p21/Waf-1 in a case of benign canine multicentric melanoma. 953 62

p27Kip1 is a cyclin-dependent kinase inhibitor that regulates the decision to enter S phase or withdraw from the cell cycle. In resting cells, the level of p27Kip1 provides an inhibitory threshold above which G1 cyclin D/E/cyclin-dependent kinases accumulate before activation; however, in cycling cells, p27Kip1 protein is sequestered by high levels of active cyclin D/cyclin-dependent kinase 4 complexes. As a group, the cyclin-dependent kinase inhibitors have been proposed to act as tumor suppressor genes, and several members have been implicated in the pathogenesis of a variety of human cancers. We examined p27Kip1 expression in 116 non-Hodgkin's lymphomas including 50 cases of MCL (40 typical and 10 blastic variants), 21 follicular lymphomas, 20 diffuse large B-cell lymphomas, 16 chronic lymphocytic leukemias, 8 marginal zone B-cell lymphomas, and 1 splenic marginal zone lymphoma, and correlated its expression with that of the proliferation marker Ki67 (MiB1) and with p53. p27Kip1 gene structure was analyzed by Southern blot in the group of MCLs. In all cases of non-Hodgkin's lymphoma other than MCL, p27Kip1 expression was inversely related to the proliferation index as measured by Ki67. In contrast, in typical MCL, p27Kip1 expression was negative in 35 of 40 (88%) cases, irrespective of the proliferative rate (median 15%; range 2 to 90%). Paradoxically, in the blastic variant of MCL, 8 of 10 (80%) cases showed expression of p27Kip1, despite a high proliferation rate (median 60%; range 32 to 100%). However, the staining in most of the cases was less intense than in the reactive T lymphocytes. Deletions of p27Kip1 gene were not found in any of the 25 cases examined. p53 expression was found in 15 of 50 cases of MCL: 7 of 10 (70%) in the blastic variant and 8 of 40 (20%) in the typical MCL (70% vs. 20%, P < 0.0045). These results demonstrate that MCLs, in contrast to other non-Hodgkin's lymphomas and normal lymphoid tissue, fail to correlate p27Kip1 expression with the proliferation rate. This peculiar uncoupling of p27Kip1 protein expression from the proliferation rate may be related to the high levels of cyclin D1 expressed in MCL and is likely to have profound effects on cell cycle regulation and contribute to the pathogenesis of MCL.
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PMID:Mantle cell lymphomas lack expression of p27Kip1, a cyclin-dependent kinase inhibitor. 966 78

Germline mutations within the CDKN2A gene, coding for the cyclin-dependent kinase inhibitor p16, have been detected by screening in 8% of Swedish families with an inheritance of cutaneous melanoma (FMM) and dysplastic nevus syndrome (DNS). Contrastingly, the closely related gene CDKN2B had no disease-related mutations in these families. A majority of Swedish families with hereditary melanoma predisposition thus lack germline mutations in these cell cycle G1 checkpoint-regulating genes. Additional genes with the potential to contribute to increased melanoma risk may code for related components of the cell cycle-regulating machinery. The gene for cyclin-dependent kinase 4, CDK4, has been found in mutated form in the germline from individuals belonging to 2 melanoma kindreds in the United States. The CDKN2C gene coding for the cyclin-dependent kinase inhibitor p18 is localized on 1p32, a region frequently involved in chromosomal changes in melanomas and other tumors. The TP53 suppressor gene, involved in cell cycle regulation and maintenance of genetic stability, is found mutated in the germline of patients with hereditary Li-Fraumeni syndrome, leading to early onset of several human cancers, including melanoma. The present investigation reports the results of screening the 100 Swedish melanoma families for germline mutations in the CDK4, CDKN2C and TP53 genes. No disease-related mutations were detected in the coding regions. A direct contribution of these genes to the hereditary risk for melanoma in members of Swedish melanoma kindreds therefore appears unlikely.
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PMID:Screening of germline mutations in the CDK4, CDKN2C and TP53 genes in familial melanoma: a clinic-based population study. 972 87

The WAF1/Cip1 gene product is an important regulator at the G1 checkpoint in the cell cycle. WAF1/Cip1 expression can be activated through p53-dependent and p53-independent pathways. The WAF1/Cip1 protein binds to cyclin-dependent kinase complexes and inhibits the kinase activity that is required for cell cycle progression. In this preliminary study, we analyzed with Western blot assays the steady-state levels of the WAF1/Cip1 protein in the leukemia cells of 100 untreated acute myelogenous leukemia (AML) patients. Normal bone marrow cells from six donors were used as a control. The results of these analyses showed that the levels of the WAF1/Cip1 protein were very low in normal marrow cells and in the leukemia cells of 83 AML patients. High levels of WAF1/Cip1 were detected in 17 patients; these patients with high WAF1/Cip1 levels were significantly less likely to achieve complete remission (41% versus 69%, P = 0.03) and were four times as likely to be resistant to therapy (47% versus 12%, P = 0.003) as patients with very low levels of WAF1/Cip1. Median survival was 38 weeks for patients having very low expression levels versus 11 weeks for patients having high expression levels (P = 0.04). The WAF1/Cip1 level was an independent predictor for response but not survival in a stepwise multivariate regression analysis. Southern blotting analyses did not detect deletion of the WAF1/Cip1 gene in the 12 negative WAF1/Cip1 AML samples tested. Also, the level of WAF1/Cip1 protein expression was not correlated with overexpression of cyclin D1, cyclin E, proliferating cell nuclear antigen, cyclin-dependent kinase 4, or p53 in the leukemia cells. However, the levels of cyclin D1, cyclin E, and cyclin-dependent kinase 4 were elevated in most of the AML samples compared with that in normal marrow. We hypothesize that high-level constitutively expressed WAF1/Cip1 in tumor cells may result in an indolent state that is refractory to chemotherapy drugs. We conclude that the WAF1/Cip1 expression level may be an important prognostic factor for response to therapy and survival in AML patients.
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PMID:High levels of constitutive WAF1/Cip1 protein are associated with chemoresistance in acute myelogenous leukemia. 981 79

In mammalian cells, activation of certain checkpoint pathways as a result of exposure to genotoxic agents results in cell cycle arrest. The integrity of these arrest pathways is critical to the ability of the cell to repair mutations that otherwise might compromise viability or contribute to deregulation of cellular growth and proliferation. Here we examine the mechanism through which DNA damaging agents result in a G1 arrest that depends on the tumor suppressor p53 and its transcriptional target p21. By using primary cell lines lacking specific cell cycle regulators, we demonstrate that this pathway functions through the growth suppressive properties of the retinoblastoma protein (pRB) tumor suppressor. Specifically, gamma-irradiation inhibits the phosphorylation of pRB at cyclin-dependent kinase 2-specific, but not cyclin-dependent kinase 4-specific, sites in a p21-dependent manner. Most importantly, we show that pRB is a critical component of this DNA damage checkpoint. These data indicate that the p53 --> p21 checkpoint pathway uses the normal cell cycle regulatory machinery to induce the accumulation of the growth suppressive form of pRB and suggest that loss of pRB during the course of tumorigenesis disrupts the function of an important DNA damage checkpoint.
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PMID:Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after gamma-irradiation. 992 83

Classical cytotoxic therapy has been minimally useful in the treatment of hepatocellular carcinoma. In an effort to develop a new approach to the treatment of this neoplasm, we have investigated the signal transduction pathways regulating the growth of human hepatoma cells. In the data reported here, cyclic AMP (cAMP), a negative growth regulator for many cells of epithelial origin, induced G1 synchronization and apoptosis in the HepG2 human hepatoma cell line. The effects of cAMP on the components of the G1/S transition were analyzed. There was no detectable effect of two different cAMP analogs, 8-bromo cAMP or dibutyryl cAMP on the level of the D-type cyclins, cyclin E, cyclin-dependent kinase 2, cyclin-dependent kinase 4, p53, or the cyclin-dependent kinase inhibitors p21 or p27. In contrast, the cAMP analogs induced a dramatic downregulation of cyclin A protein, cyclin A messenger RNA, and cyclin A-dependent kinase activity. Cyclin A-dependent kinase has been shown to be required for the G1-S transition. Furthermore, cyclin A deregulation has been implicated in the pathogenesis of hepatocellular carcinoma. The data reported here suggest a novel signal transduction-based approach to hepatoma therapy.
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PMID:Cyclic AMP induces inhibition of cyclin A expression and growth arrest in human hepatoma cells. 1020 5

Gene amplification and enhanced expression of the epidermal growth factor receptor (EGFR) represent the major molecular genetic alteration in glioblastomas and it may play an essential role in cell growth and in the carcinogenic process. On the other hand, the nuclear suppressor proteins PML and p53 are also known to play critical roles in cancer development and in suppressing cell growth. Here we report that, in glioblastoma cells with defective EGFR function, the expressions of both promyelocytic leukaemia (PML) and p53 were altered. Cells that were transfected with the antisense-cDNA of EGFR were found to have more cells in G1 and fewer cells in S phase. In addition, the transfected cells were found to be non-responsive to EGF-induced cell growth. Interestingly, the expression of the suppressors p53 and PML were found to be significantly increased by immunohistochemical assay in the antisense-EGFR cells. Moreover, the PML expression in many of the cells was converted from the nuclear dot pattern into fine-granulated staining pattern. In contrast, the expressions of other cell cycle regulated genes and proto-oncogene, including the cyclin-dependent kinase 4 (cdk4), retinoblastoma, p16INK4a and p21H-ras, were not altered. These data indicate that there are specific inductions of PML and p53 proteins which may account for the increase in G1 and growth arrest in antisense-EGFR treated cells. It also indicates that the EGF, p53 and PML transduction pathways were linked and they may constitute an integral part of an altered growth regulatory programme. The interactions and cross-talks of these critical molecules may be very important in regulating cell growth, differentiation and cellular response to treatment in glioblastomas.
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PMID:Altered expression of the suppressors PML and p53 in glioblastoma cells with the antisense-EGF-receptor. 1057 56

By crossing TG.AC v-Ha-ras and K6/ODC transgenic mice, we found previously that an activated ras and follicular ornithine decarboxylase (ODC) overexpression cooperate to generate spontaneous tumors in the skin. Cellular proliferation was dramatically increased in the K6/ODC transgenic skin, as evidenced by elevated proliferating cell nuclear antigen and Ki67 expression compared with nontransgenic littermates. Keratinocytes isolated from transgenic skin also displayed increased clonal growth. Paradoxically, expression of the growth inhibition-associated proteins p53, p21Waf1, p27Klp1, and Bax was increased with ODC overexpression in the skin. ODC overexpression did not affect cyclin D/cyclin-dependent kinase 4 (Cdk4)-dependent phosphorylation of retinoblastoma protein but stimulated cyclin E/Cdk2 and cyclin A/Cdk2-associated kinase activity, with minimal effect on the levels of these proteins. Thus, ODC/polyamine-induced activation of cyclin E/Cdk2 and cyclin A/Cdk2-associated kinase activity may cooperate with the ras induction of cyclin D/Cdk4/6-associated retinoblastoma protein phosphorylation to not only stimulate proliferation but ultimately contribute to tumor development.
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PMID:Effect of elevated levels of ornithine decarboxylase on cell cycle progression in skin. 1059 50


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