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)

In an attempt to characterize the molecular alterations of cervical adenocarcinoma, we analyzed 32 paraffin-embedded specimens for the presence of K-ras mutations, p53 overexpression, p16 and Rb protein expression, and the presence of HPV 16 and 18 DNA. Overall 25/32 (78%) of the tumors displayed an abnormality in at least one of these analyses. K-ras mutations were detected by PCR amplification and RFLP analysis in 3 tumors, including 2 at codon 12 and 1 at codon 61. p53 overexpression determined by immunohistochemistry was demonstrated with > 80% of tumor nuclei staining in 4 cases, 10-15% of nuclei staining in 3 cases, and < 1% of nuclei staining in 5 cases. The pattern of staining was diffuse in 6 cases, focal in 1 case, and scattered in 5 cases. Analysis of p16 protein expression in 23 specimens revealed 1 tumor with abnormal staining, while Rb protein expression was determined to be normal in all 25 tumors tested. HPV DNA, detected by PCR with type-specific primers, was found in 16 tumors (50%), including 7 (22%) with HPV 16 and 9 (28%) with HPV 18. There was no correlation among these abnormalities except that the presence of HPV and strong p53 overexpression (> 80% tumor nuclei staining) were mutually exclusive events. Clinical correlation demonstrated that p53 overexpression involving the majority of tumor cell nuclei is characteristic of advanced stage disease, while HPV positivity and activated ras genes are associated with early stage disease.
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PMID:Molecular characterization of adenocarcinoma of the cervix. 903 70

Alterations, especially homozygous deletions, of the putative tumor suppressor gene, p16 (p16INK4A, MTS1, CDKN2) have been found in tumor cell lines from a variety of neoplasms. Recent studies have reported frequent p16 gene deletions in cell lines from squamous cell carcinomas of the head and neck (SCCHN), although the prevalence of alterations was variable in primary tumors. This study determined the prevalence of point mutations and deletions of the p16 gene in 33 SCCHN. In addition, the association of p16 gene alterations and abnormalities of p53, PRAD-1 (cyclin D1), and the presence of human papillomavirus (HPV) was examined. We found an overall prevalence of p16 alterations of 36% (nine deletions, three single base substitutions, including one polymorphism). Seven tumors (of 29, 24%) had an alteration of p16 and p53; five (of 33, 15%) had alterations of p16 and PRAD-1; three (of 29, 10%) had alterations of all three genes. In addition, of the five tumors with human papillomavirus detected, only one also had a p16 gene alteration. The results indicate a potentially important role for the p16 gene in head and neck tumorigenesis. In addition, the presence of tumors with multiple somatic gene alterations suggest a possible interaction in the dysregulation of the cell cycle.
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PMID:Alterations of the p16 gene in head and neck cancer: frequency and association with p53, PRAD-1 and HPV. 904 88

One prominent effect of IFNs is their cell growth inhibitory activity. The exact molecular mechanism behind this inhibition of proliferation remains to be elucidated. Possible effectors for IFN-induced growth inhibition are the recently discovered cyclin-dependent kinase inhibitors. The effect of IFN-alpha treatment on the members of the Ink4 and Cip/Kip families of Cdk inhibitors was investigated in three hematopoietic cell lines Daudi, U-266 and H9. Two of these cell lines, Daudi and U-266, respond to IFN-alpha by G1 arrest, whereas the H9 cell line is not growth arrested by IFN-alpha. We show that a p53-independent upregulation of p21 mRNA occurs following IFN-alpha treatment in all three cell lines. In Daudi and U-266 cells, the mRNA induction is accompanied by an increase in p21 protein, followed by an increased binding of p21 to Cdk2 and a subsequent decrease in Cdk2 activity, temporally coinciding with G1 arrest. In both these cell lines, there was also an increased binding of p21 to Cdk4. In contrast, p21 protein was not expressed in H9 cells, despite high levels of p21 mRNA following IFN-alpha treatment. In U-266 cells, IFN-alpha increased not only p21 but also p15 mRNA and protein levels, followed by an increased association of p15 with Cdk4. Furthermore, IFN-alpha treatment caused a four- to sixfold induction of the p16 E1beta transcript in U-266 cells. Expression levels of the other Ink4 and Cip/Kip Cdk inhibitors were not induced by IFN treatment in any of the cell lines. We conclude that IFN-alpha can act as a potent regulator of Cdk-inhibitor expression, correlating with decreased Cdk activity and cell growth inhibition. One mechanism for resistance to IFN may be loss of the ability of cells to upregulate these proteins.
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PMID:Induction of Cip/Kip and Ink4 cyclin dependent kinase inhibitors by interferon-alpha in hematopoietic cell lines. 905 38

Oncogenic ras can transform most immortal rodent cells to a tumorigenic state. However, transformation of primary cells by ras requires either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16. Here we show that expression of oncogenic ras in primary human or rodent cells results in a permanent G1 arrest. The arrest induced by ras is accompanied by accumulation of p53 and p16, and is phenotypically indistinguishable from cellular senescence. Inactivation of either p53 or p16 prevents ras-induced arrest in rodent cells, and E1A achieves a similar effect in human cells. These observations suggest that the onset of cellular senescence does not simply reflect the accumulation of cell divisions, but can be prematurely activated in response to an oncogenic stimulus. Negation of ras-induced senescence may be relevant during multistep tumorigenesis.
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PMID:Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. 2346 17

Repression of cell cycle progression by tumor suppressors might provide a means for tumor therapy. Here we demonstrate that ectopic overexpression of the p16INK4/CDKN2 tumor suppressor from an adenovirus vector in various cell lines results in block of cell division and, subsequently, in a gradual reduction of the levels of the product of retinoblastoma susceptibility gene, pRb. Overexpression of p53 and p16INK4/CDKN2, but not p53 on its own, induces apoptotic death only in tumor cells. Simultaneous adenoviral transfer of p16 and p53 genes leads to inhibition of tumor growth in nude mice. These results suggest that combined delivery of two cooperating genes like p16 and p53 could be the basis for the development of a new strategy for cancer gene therapy.
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PMID:Adenovirally transferred p16INK4/CDKN2 and p53 genes cooperate to induce apoptotic tumor cell death. 905 59

The expression of cyclins (A, B1, D1, D3, E), cyclin-dependent kinases (CDK2(3), CDK4), and the cyclin-dependent kinase inhibitors (CDKIs) p16(INK4A) and p21(CIP1) was studied in 9 malignant human astrocytoma cell lines using northern blot analysis, immunocytochemistry, and immunoblotting to see if their altered expression contributed to astrocytoma proliferation. Steady state cell cycle mRNA expression was analyzed in unsynchronized tumor cells, and cell cycle phase-specific gene expression was analyzed in 3 synchronized cell lines. Analysis of steady state expression revealed increased levels of several different cyclin transcripts and CDKs in a number of astrocytoma cell lines compared with normal human brain tissue or cultured fibroblasts. We confirm previous reports identifying loss of p16(INK4A) in astrocytomas, as a p16(INK4A) transcript was identified in only 2 cell lines and protein in 1 cell line. However, we now show that p21(CIP1) expression was also diminished relative to normal fibroblasts in all astrocytoma cell lines studied regardless of p53 mutation status. Analysis of synchronized astrocytoma cells revealed altered timing of mRNA expression of several cyclins. Immunocytochemistry revealed a generalized increase in immunoreactivity of astrocytoma cells for most cyclins and CDKs compared with human fibroblasts. Immunoblotting also revealed increased expression of cyclin proteins in a number of astrocytoma cell lines. These data suggest that increased expression of cyclins and CDKs, and decreased expression of CDKIs by human astrocytoma cell lines may contribute to their increased proliferative state. In addition, our data show that alterations in cell cycle genes in astrocytomas are not confined to the cyclin D1-CDK4-pRb axis.
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PMID:Cyclin and cyclin-dependent kinase expression in human astrocytoma cell lines. 905 43

The tumor suppressor genes p53, retinoblastoma (RB), p16, and p15 encode proteins that regulate the cell cycle cooperatively by controlling the transition from G1 to S phase and may play an important role in cell growth and differentiation. To screen for abnormalities in these genes in cancer, we performed genetic analysis in six human pancreatic cancer and five hepatoma cell lines, by single-strand conformation polymorphism (SSCP) analysis, direct sequencing, and the reverse transcriptase-polymerase chain reaction (RT-PCR). All six pancreatic cancer cell lines had p53 mutations, with the concomitant loss of the other normal allele, encoding wild-type p53. Frequent homozygous deletions were found in p16 and p15, but the RB gene was expressed. Four of the five hepatoma cell lines had p53 mutations with loss of the normal allele and aberrant RB. There were no deletions of p16 and p15 in any of the hepatoma cell lines. These findings suggest that alterations in the p53, p16, and p15 genes are common in human pancreatic cancer cell lines, while p53 or RB mutations are common in hepatoma cell lines. Alterations of these tumor suppressor genes may thus be important features in organ-specific carcinogenesis.
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PMID:Alterations in the tumor suppressor genes p53, RB, p16/MTS1, and p15/MTS2 in human pancreatic cancer and hepatoma cell lines. 905 94

Loss of p16 expression can occur via homozygous deletion, point mutation, or hypermethylation of exon 1. Astrocytomas representing all World Health Organization (WHO) grades of malignancy were analyzed in a correlative study using multiplex polymerase chain reaction (PCR) analysis to detect deletions of the p16 gene together with immunohistochemistry to detect loss of the protein in archival specimens of the same tumors. Homozygous deletions of p16 were detected in 29% (15 of 52) of WHO grade 3 and 4 tumors. Immunostaining for p16 protein was present in 26 tumors retaining the p16 gene and absent in 11 tumors with deletions of the p16 gene. A close correlation was found between the two detection methods, with all tumors lacking immunostaining showing homozygous loss of the p16 gene. Astrocytomas exhibiting inactivation of the p16 gene most often contained p53 gene mutations or amplified epidermal growth factor receptor genes, genetic characteristics associated with both the progressive and de novo tumor variants. Immunohistochemical evaluation may be a useful, rapid method to screen astrocytomas for loss of p16 gene expression, regardless of the underlying mechanism leading to p16 gene inactivation.
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PMID:Correlative immunohistochemistry and molecular genetic study of the inactivation of the p16INK4A genes in astrocytomas. 909 51

Nasopharyngeal carcinoma, which is very frequent in southern China, has in previous investigations been found to be associated with a number of risk factors, including a disease susceptibility gene linked to the HLA-region, p53 alleles and deletions of the chromosome 9p21-22 region, which includes the IFNA and p16 loci. We have therefore studied 64 patients (54 males and 10 females) with nasopharyngeal carcinoma and 99 healthy controls from the Guizhou province in southern China with respect to association with the SspI polymorphism at the IFNA17 locus, and the possible interaction between IFNA17 and p53 alleles in the etiology of nasopharyngeal carcinoma. The frequency of the SspI A1 allele was much higher (P < 10(-10)) in Chinese patients and controls than in a previously reported study of Swedes. Among the patients there was a significant increase in the frequencies of the SspI A2 allele (P = 0.011) and SspI 2-2 genotype with an OR (odds ratio) of 2.76, 95% CI = 1.13-6.73 in relation to the SspI 1-1 type. When combinations of SspI and the p53 codon 72 (BstUI) genotypes were studied a highly significant risk figure was found for the SspI 2-2/BstUI 1-1 (pro/pro) combination (OR = 8.2, 95% CI = 2.2-30.0). No other combinations showed significant risk figures. There was no significant interaction between the SspI 2-2 and BstUI 1-1 types indicating that IFN-alpha and p53 genotypes behave as independent risk factors. Since IFN-alpha is located close to the tumor suppressor gene p16, and intronic p53-haplotypes show stronger association with nasopharynx cancer than the codon 72-polymorphism, both associations may be due to linkage disequilibrium with adjacent genes influencing cell-cycle control.
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PMID:Interferon-alpha and p53 alleles involved in nasopharyngeal carcinoma. 911 Nov 94

During tumorigenesis, positive selection is exerted upon those tumor cells that alter rate-limiting regulatory pathways. A corollary of this principle is that mutation of one gene abrogates the need for alteration of another gene in the same pathway and also that the coexistence in a single tumor of mutations in different genes implies their involvement in distinct tumor-suppressive pathways. We studied 42 pancreatic adenocarcinomas for genetic alterations in the K-ras oncogene and the p16, p53, and DPC4 tumor suppressor genes. All of them had the K-ras gene mutated. Thirty-eight % of the tumors had four altered genes, another 38% had three altered genes, 15% had two altered genes, and 8% of the tumors had one altered gene. Interestingly, we noted a high concordance of DPC4 and p16 inactivations (P = 0.007), suggesting that the genetic inactivation of p16 increases the selective advantage of subsequent mutation in DPC4. No statistically significant association was identified between the alteration of these cancer genes and pathological or clinical parameters. This type of multigenic analysis in human tumors may serve to substantiate experimental tumor models and thus increase our understanding of the truly physiologically relevant tumor-suppressive pathways that are abrogated during human tumorigenesis.
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PMID:Tumor-suppressive pathways in pancreatic carcinoma. 913 16


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