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)

Flavopiridol, a synthetic flavone that inhibits tumor growth in vitro and in vivo, is a potent cyclin-dependent kinase (cdk) inhibitor presently in clinical trials. In the present study, the effect of 100-500 nM flavopiridol on a panel of non-small cell lung cancer cell lines was examined. All express a wild-type retinoblastoma susceptibility protein and lack p16INK4A, and only A549 cells are known to express wild-type p53. During 72 h of treatment, flavopiridol was shown to be cytotoxic to all seven cell lines, as measured by trypan blue exclusion, regardless of whether cells were actively cycling. In most cycling cells, cytotoxicity was preceded or accompanied by cell cycle arrest. Cell death resulted in the appearance of cells with a sub-G1 DNA content, suggestive of apoptosis, which was confirmed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay and by demonstration of cleavage of caspase targets including poly(ADP-ribose) polymerase, p21Waf1, and p27Kip1. At doses at or below 500 nM, maximal cytotoxicity required 72 h of exposure. Although flavopiridol resulted in the accumulation of p53 in A549 cells, flavopiridol-mediated apoptosis was p53 independent because it occurred to the same degree in A549 cells in which p53 was targeted for degradation by HPV16E6 expression. The data indicate that flavopiridol has activity against non-small cell lung cancers in vitro and is worthy of continued clinical development in the treatment of this disease.
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PMID:Flavopiridol induces cell cycle arrest and p53-independent apoptosis in non-small cell lung cancer cell lines. 1053 62

Inactivation of the P16 (INK4A)/retinoblastoma (RB) or TP53 biochemical pathway is frequent event in most human cancers. Recent evidence has shown that P14ARF binds to MDM2 leading to an increased availability of wild type TP53 protein. Functional studies also support a putative tumor suppressor gene function for p14ARF suggesting that p14ARF or p53 inactivation may be functionally equivalent in tumorigenesis. To study the relative contribution of each pathway in tumorigenesis, we analysed and compared alterations of the p16, p14ARF and p53 genes in 38 primary non-small cell lung cancers (NSCLCs) (19 adenocarcinomas and 19 squamous carcinoma). The p16 tumor suppressor gene was inactivated in 22 of 38 (58%) tumors. Twelve of these samples (31%) had homozygous deletions by microsatellite analysis; eight of them (21%) had p16 promoter hypermethylation detected by Methylation Specific PCR (MSP) and the remaining two (5%) harbored a point mutation in exon 2 by sequence analysis. The absence of P16 protein in every case was confirmed by immunohistochemistry. Fourteen of the 22 tumors with p16 inactivation also inactivated the p14ARF gene (12 with homozygous deletions extending into INK4a/ARF and two with exon 2 mutations). Mutations of p53 were found in 18 (47%) of the tumors and nine of them (50%) harbored p14ARF inactivation. Thus, an inverse correlation was not found between p14ARF and p53 genetic alterations (P=0.18; Fisher Exact Test). Our data confirm that the p16 gene is frequently inactivated in NSCLC. Assuming that 9p deletion occurs first, the common occurrence of p53 and p14ARF alterations suggests that p14ARF inactivation is not functionally equivalent to abrogation of the TP53 pathway by p53 mutation.
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PMID:Inactivation of the INK4A/ARF locus frequently coexists with TP53 mutations in non-small cell lung cancer. 1055 71

In a recent study, it was shown that DNA damaging agent cisplatin-induced growth arrest and cell death in cancer cells by a pathway sharing some of the characteristics of replicative senescence. The aim of this study was to determine the role of p53, p21WAF1 and p16INK4A proteins in this alternative route to cancer cell death in additional human cancer cell lines. After exposure to cisplatin, all the cell lines underwent growth arrest and expressed the senescence marker senescence-associated beta-galactosidase, but showed none of the features of apoptosis. However, there was no change in p53 protein expression, and neither p21WAF1 nor p16INK4A was expressed before or up to 4 days after cisplatin exposure. These findings provide further evidence that cells carrying mutations resulting in loss of function in the p53 gene can be killed by cisplatin via a p53-independent route with some similarities to replicative senescence, but not apoptosis.
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PMID:Cisplatin-induced p53-independent growth arrest and cell death in cancer cells. 1056 14

The predictive value of expression of p16INK4A, retinoblastoma (Rb) and p53 proteins for prognosis was evaluated in 76 patients with non-small-cell lung cancers (NSCLCs) that were potentially curatively resected between 1990 and 1995, using the results of immunostaining analyses of these proteins as reported in our previous study (Kinoshita et al, 1996). Of these NSCLCs, 22 (29%) lacked p16 protein expression and eight (11%) Rb protein, while 30 (39%) showed positive (altered) p53 protein expression. Survival of patients with p16-negative tumours was not significantly different from that of patients with p16-positive tumours (5-year survival rates 67% and 72% respectively, P = 0.8), nor was survival of patients with Rb-negative tumours significantly different from that of patients with Rb-positive tumours (5-year survival rates 42% and 69% respectively, P = 0.9). Moreover, survival of patients with p16/Rb-negative (either p16- or Rb-negative) tumours was not significantly different from that of patients with p16/Rb-positive (both p16- and Rb-positive) tumours (5-year survival rates 67% and 68% respectively, P = 0.7). In contrast, survival of patients with p53-positive (altered) tumours tended to be shorter than that of patients with p53-negative (unaltered) tumours (5-year survival rates 56% and 78% respectively, P = 0.06). In univariate analysis of potential prognostic factors, p16, Rb and p16/Rb proteins were not significant prognostic factors in the present cohort of potentially curatively resected NSCLCs. Altered p53 protein status tended to be a negative prognostic factor (P = 0.06 by the univariate analysis). These results indicate that loss of p16 protein alone, or in combination with loss of Rb protein, does not predict the clinical outcome of patients with resected NSCLCs.
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PMID:Predictive value of expression of p16INK4A, retinoblastoma and p53 proteins for the prognosis of non-small-cell lung cancers. 1057 58

In order to understand better the possible role of cell-cycle regulating molecules in the pathogenesis of Hodgkin's disease (HD), the immunohistochemical distribution pattern of p16INK4A was investigated and compared with pRb, p53, and MDM2 protein status in 44 HD cases. Our findings were correlated to the presence of Epstein-Barr virus as detected by RNA in situ hybridization and clinicopathological parameters. p16INK4A protein immunoreactivity was found in all 44 cases with a proportion of Hodgkin-Reed-Sternberg (HRS) cells ranging from 30 to 90%. In 93% of the cases studied, pRb was detected in HRS, whereas all cases showed overexpression of p53. Almost all specimens (98%) were MDM2-positive as evaluated by 1B10 and/or IF2 monoclonal antibodies. EBER 1/2-transcripts were detected in 31.8% (14 of 44) of the examined samples. A significant correlation was observed between immunoreactivity of p16INK4A and MDM2 and the number of HRS cells (P = .0012 and P = .018, respectively). In a subgroup of cases, with p16INK4A expression in more than 50% of HRS cells, the percentage of pRb-positive neoplastic cells was inversely related to that of p16-positive ones (P = .007). No clinicopathological parameters or clinical prognostic indicators, including duration of response to therapy, were statistically related to the expression levels of any of the four proteins investigated or the presence of Epstein-Barr virus. Our findings suggest that p16 and pRb are regularly expressed and that their pathway in cell-cycle machinery seems to be intact in HD. However, further investigation is needed to shed light on the involvement of cell-cycle molecules in Hodgkin's lymphomagenesis and longer patient follow-up is required for conclusive prognostic correlation.
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PMID:p16INK4A is regularly expressed in Hodgkin's disease: comparison with retinoblastoma, p53 and MDM2 protein status, and the presence of Epstein-Barr virus. 1057 4

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

The INK4A gene, a candidate tumor suppressor gene located on chromosome 9p21, encodes two protein products, p16 and p19(ARF). p16 is a negative cell cycle regulator capable of arresting cells in the G1 phase by inhibiting cyclin-dependent kinases 4 (Cdk4) and 6 (Cdk6), thus preventing pRB phosphorylation. p19(ARF) prevents Mdm2-mediated neutralization of p53. Loss of INK4A is a frequent molecular alteration involved in the genesis of several neoplasms, including tumors of neuroectodermal origin. This study investigated the frequency of INK4A gene alterations in a series of malignant peripheral nerve sheath tumors (MPNSTs) and neurofibromas (NFs). INK4A gene and the p19(ARF)-specific exon 1beta were studied in 11 MPNST samples from 8 patients and 7 neurofibromas. Presence of INK4A deletions was assessed by Southern blotting hybridization and by a multiplex polymerase chain reaction (mPCR). INK4A point mutations were examined by single-strand conformation polymorphism (SSCP) and sequencing. The p16 promoter methylation status was determined by PCR amplification of bisulfite-treated DNA. Homozygous deletions of exon 2, thus affecting both p16 and p19(ARF), were identified in MPNSTs from 4 of 8 patients. Deletions, mutations, or silencing by methylation were not identified in the neurofibromas analyzed. Based on our results, we conclude that INK4A deletions are frequent events in MPNSTs and may participate in tumor progression. Silencing of p16 by methylation, which occurs often in several tumor types, is uncommon in MPNSTs.
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PMID:Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but not in neurofibromas. 1059 15

Although SV40 oncoproteins have been detected in malignant pleural mesotheliomas (MPMs), their role in the pathogenesis and clinical behavior of these neoplasms remains controversial. In the present study, we sought to define the relevance of SV40 T/t antigen expression in established human mesothelioma cell lines deficient for p16INK4a as well as ARF expression. SV40 early region sequences were readily detected in genomic DNA isolated from pleural mesothelioma lines; however, levels of SV40 T/t antigen expression were highly variable in these cells. An adenoviral vector expressing an antisense transcript to SV40 early region inhibited T antigen expression and mediated significant growth inhibition and apoptosis in T-antigen-positive mesothelioma cells and SV40-transformed COS-7 cells. Abrogation of T/t antigen expression coincided with enhanced p21/WAF-1 expression, suggesting that restoration of p53-mediated pathways may have contributed to the growth inhibition and apoptosis induced by the antisense construct. These effects were not observed after similar treatment of mesothelioma or lung cancer cells containing no SV40 DNA sequences. Collectively, these data suggest that SV40 oncoproteins contribute to the malignant phenotype of pleural mesotheliomas and indicate that interventions designed to abrogate their expression may be efficacious in the treatment of individuals with these neoplasms.
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PMID:Antisense to SV40 early gene region induces growth arrest and apoptosis in T-antigen-positive human pleural mesothelioma cells. 1062 92

The INK4a/ARF locus encodes two cell cycle-regulatory proteins, p16INK4a andp14ARF, which share an exon using different reading frames. p14ARF antagonizes MDM2-dependent p53 degradation. However, no point mutations in p14ARF not altering p16INK4a have been described in primary tumors. We report that p14ARF is epigenetically inactivated in several colorectal cell lines, and its expression is restored by treatment with demethylating agents. In primary colorectal carcinomas, p14ARF promoter hypermethylation was found in 31 of 110 (28%) of the tumors and observed in 13 of 41 (32%) colorectal adenomas but was not present in any normal tissues. p14ARF methylation appears in the context of an adjacent unmethylated p16INK4a promoter in 16 of 31 (52%) of the carcinomas methylated at p14ARF. Although p14ARF hypermethylation was slightly overrepresented in tumors with wild-type p53 compared to tumors harboring p53 mutations [19 of 55 (34%) versus 12 of 55 (22%)], this difference did not reach statistical significance. p14ARF aberrant methylation was not related to the presence of K-ras mutations. Our results demonstrate that p14ARF promoter hypermethylation is frequent in colorectal cancer and occurs independently of the p16INK4a methylation status and only marginally in relation to the p53 mutational status.
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PMID:Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status. 1064 64

The INK4a-ARF locus encodes 2 separate proteins through differential splicing of alternative first exons to produce p16INK4a (exon 1alpha) and p14ARF (exon 1beta) products in human cells. The p16INK4a protein inhibits the cyclin D-dependent kinases (CDK) that control the phosphorylation of the Rb protein and cell proliferation. The p14ARF gene product can complex with and sequester the MDM2 protein within the nucleus, thus modulating the activity of the p53 protein. Loss of p16INK4a expression would disrupt the retinoblastoma (Rb)/p16INK4a/cyclin D-dependent kinase (CDK4) pathway, whereas loss of p14ARF expression would inactivate both the Rb and p53/ MDM2/p14ARF pathways through MDM2, which can complex with either Rb or p53. Loss of the p16INK4a gene on 9p21 has been documented in a wide range of human tumors, including one third of glioblastomas. However, in tumors showing homozygous loss of exon 2 of the p16INK4a gene, loss of exon 1beta of the p14ARF gene has not been established. In this study, we have assessed deletion of the p14ARF gene in 29 pediatric and 107 adult high-grade astrocytomas and 9 glioma cell lines, using multiplex PCR analysis for exon 1beta. We found homozygous deletions for exon 1alpha and exon 1beta in 3 of 29 (10%) of the pediatric cases (2 grade III, 1 grade IV), 25 of 107 (23%) of the adult cases (6 grade III and 19 grade IV), and 8 of 9 (89%) of the glioma cell lines. Therefore, loss of the INK4a-ARF locus in high-grade astrocytomas may contribute to the highly malignant behavior and treatment resistance of these tumors through elimination of multiple checkpoint cell cycle control proteins.
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PMID:Incidence of p14ARF gene deletion in high-grade adult and pediatric astrocytomas. 1066 22


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