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 epidermal growth factor receptor (EGFR) gene is amplified or mutated in 30%-50% of human gliobastoma multiforme (GBM). These mutations are associated usually with deletions of the INK4a-ARF locus, which encodes two gene products (p16(INK4a) and p19(ARF)) involved in cell-cycle arrest and apoptosis. We have investigated the role of EGFR mutation in gliomagenesis, using avian retroviral vectors to transfer a mutant EGFR gene to glial precursors and astrocytes in transgenic mice expressing tv-a, a gene encoding the retrovirus receptor. TVA, under control of brain cell type-specific promoters. We demonstrate that expression of a constitutively active, mutant form of EGFR in cells in the glial lineage can induce lesions with many similarities to human gliomas. These lesions occur more frequently with gene transfer to mice expressing tv-a from the progenitor-specific nestin promoter than to mice expressing tv-a from the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter, suggesting that tumors arise more efficiently from immature cells in the glial lineage. Furthermore, EGFR-induced gliomagenesis appears to require additional mutations in genes encoding proteins involved in cell-cycle arrest pathways. We have produced these combinations by simultaneously infecting tv-a transgenic mice with vectors carrying cdk4 and EGFR or by infecting tv-a transgenic mice bearing a disrupted INK4a-ARF locus with the EGFR-carrying vector alone. Moreover, EGFR-induced gliomagenesis does not occur in conjunction with p53 deficiency, unless the mice are also infected with a vector carrying cdk4. The gliomagenic combinations of genetic lesions required in mice are similar to those found in human gliomas.
 ...
PMID:A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. 985 74

Cyclin dependent kinase inhibitor 2/multiple tumour suppressor gene 1 (CDKN2/MTS1) and retinoblastoma (Rb) tumour suppressor genes play important roles in the regulation of the cell cycle. The protein products of these genes p16INK4 (p16) and pRb, respectively, like p53 protein inhibit progression from G1 to S phase. p16 exerts its function through inhibition of CDK4-mediated phosphorylation of pRb. The pRb/p16 pathway is a critical target for molecular aberration at the G1-S checkpoint in a wide range of primary human tumours. The expression of p16 and pRb proteins was analyzed by immunohistochemistry in 35 cases of oral squamous cell carcinomas (SCCs), 22 cases of premalignant oral lesions and 30 normal oral tissues. Lack of pRb expression was observed in 23/35 (66%) oral SCCs and 14/22 (64%) premalignant lesions. Lack of p16 expression was observed in 22/35 (63%) oral SCCs and 13/22 (59%) premalignant lesions. Weak p16 and pRb immunoreactivities were observed in normal oral mucosal epithelium. The status of p16 and pRb was correlated with clinicopathological characteristics of the patients. Alteration in p16 expression showed significant correlation with tumour staging and progression (P = 0.024). Alteration in pRb/p16 expression correlated with heavy consumption of betel and tobacco. Our results suggest that alterations in the p16/pRb pathway are early events in oral tumorigenesis and may be involved in the development of betel- and tobacco-related oral malignancies.
 ...
PMID:pRb and p16 protein alterations in human oral tumorigenesis. 986 48

Objective. We studied the molecular abnormalities involved in the pathogenesis of endocrine tumors of the uterine cervix. Methods. We obtained DNA from precisely microdissected archival tissue from 15 endocrine tumors of the uterine cervix, consisting of 5 carcinoids (1 typical, 4 atypical), 2 large cell neuroendocrine carcinomas, and 8 small cell carcinomas. We investigated the presence of high-risk (types 16 and 18) and intermediate-risk (types 31 and 33) human papilloma virus (HPV) sequences, TP53 and K-ras gene mutations, and loss of heterozygosity (LOH) at 9 genes/chromosomal regions, including 3p14.2/FHIT, 3p14-p21, 3p21, 3p22-p24, 5q21-q22/APC-MCC region, 9p21/CDKN2, 11q23/MEN1, 13q/RB, and 17p/TP53. Results. HPV sequences were detected in 8 (53%) tumors, HPV 16 in 2 cases, and HPV 18 in 2 cases. LOH at 9p21 (43%) and localized 3p deletions (47%) were the most frequent allelic losses found. Allelic losses at 5q21-q22/APC-MCC region, 11q23/MEN1, and 13q/RB were infrequent. TP53 gene mutations were detected in 7 (47%) tumors (1 atypical carcinoid and 6 carcinomas). HPV sequences were demonstrated in 4 of the 7 cases with TP53 gene mutations. No K-ras mutations were detected. Conclusion. The molecular changes present in endocrine tumors of the uterine cervix have distinct features. They incorporate those present in the neuroendocrine tumors of the lung (high frequency of TP53 gene abnormalities and 9p21 deletions) with those detected in squamous cell carcinomas of the cervix (high-risk HPV sequences and localized 3p deletions).
 ...
PMID:Molecular abnormalities associated with endocrine tumors of the uterine cervix. 988 21

Lung cancers are a heterogeneous group of tumors broadly classified as small cell or non-small cell lung cancers. In each case, numerous DNA mutations precede tumor formation, resulting in the activation of growth stimulatory genes and the loss of tumor suppressor genes. The known cellular functions of the tumor suppressor genes most commonly affected in lung cancer are reviewed herein, including the retinoblastoma (Rb) gene on chromosome 13q14, the p53 gene on 17p13, and the cyclin-dependent kinase inhibitor (CDKN2) gene on 9p21. The chromosomal locations for other potential tumor suppressor genes are on chromosomes 3p, 9p, and 11p. Candidate genes in these regions include the von Hippel-Lindau (VHL) gene at 3p25, the ubiquitin-activating enzyme homologue (UBE1L at 3p21, the genes for the dinucleoside polyphosphate hydrolase FHIT and receptor protein-tyrosine phosphatase gamma PTPRG at 3p14.2, the genes for tropomyosin beta (TM1) and a talin homologue (talin) at 9p21, and the H-ras gene at 11p15.
 ...
PMID:Hot spots for molecular genetic alterations in lung cancer. 989 Dec 28

Evidence that control of cellular proliferative potential may be linked to telomere length, along with data indicating that other factors may also be involved, will be reviewed. According to the telomere hypothesis of senescence, the sequential loss of telomeric repeat DNA that occurs during the replication of normal somatic cells eventually dictates the onset of the permanently nonreplicative state known as senescence. Many immortalized cells express telomerase, a ribonucleoprotein enzyme that replaces the telomeric DNA that would otherwise be lost due to replication. However, some immortalized human cells may avoid telomeric shortening without using telomerase. The mechanism involved is currently unknown, but other eukaryotes are able to replace telomeric DNA through (1) recombination and copy switching or (2) retrotransposition. Human fibroblasts that lose p53 function proliferate a limited number of times beyond the population-doubling level at which their normal counterparts become senescent. Lack of functional retinoblastoma (Rb) protein (or equivalent events, such as loss of p16INK4 function, resulting in abrogation of Rb regulatory activity) also permits a temporary extension of proliferative potential. The p53 and pRb effects are additive, indicating that they exert their control on proliferative potential separately. The temporary life span extension associated with loss of p53 and/or Rb pathway function is accompanied by continued telomere shortening. The proliferation arrest that eventually ensues in p53-minus cells or in p53-minus/Rb-minus cells may be regarded as terminal proliferation arrest states serving as a backup to senescence. p53-minus/Rb-minus cells cannot proliferate further unless they acquire the ability to prevent telomeric shortening. Somatic cell hybridization and microcell-mediated chromosome transfer experiments indicate that immortalization involves the loss of function of other, as yet unidentified, genes; some of these may normally repress telomerase expression in somatic cells.
 ...
PMID:Genes involved in the control of cellular proliferative potential. 992 15

In Egypt and other regions of the Middle East where the trematode Schistosoma haematobium is endemic, bladder cancer is the most common adult cancer. Unlike bladder cancers in Western countries, which are predominantly transitional-cell carcinoma (TCC), these schistosomiasis-associated bladder cancers are predominantly squamous-cell carcinoma (SCC). Our aim was to assess a large series of schistosomiasis-associated bladder tumours for genetic alterations commonly found in TCC in the United Kingdom and the United States. We have carried out a partial allelotype of 70 tumours from patients with schistosomiasis. LOH was found on all chromosome arms studied (3p, 4p, 4q, 8p, 9p, 9q, 11p, 11q, 13q, 14q, 17p, 18q). The most frequent regions of LOH were 9p (65%), 17p (58%), 3p (40%), 9q (39%) and 8p (37%). LOH on 17p, where the TP53 gene is located, was more common in Egyptian TCC than in SCC. Similarly, 8p LOH was more common in TCC than SCC. The most striking difference between this group of tumours and TCCs from the United Kingdom and the United States was the high frequency of 9p LOH in the region of the CDKN2 gene (65%) and the relatively low frequency of 9q LOH (39%); 15 of 43 tumours with LOH of at least one marker on chromosome 9 showed LOH of 9p only. This suggests that a 9p gene, possibly CDKN2, may contribute to the development of the majority of schistosomiasis-associated bladder tumours but that genes on 9q play a much less important role.
 ...
PMID:Partial allelotype of schistosomiasis-associated bladder cancer. 1004 62

The accumulation of genetic abnormalities in a developing tumor is driven, at least in part, by the need to overcome inherent restraints on the replicative life span of human cells, two of which-senescence (M1) and crisis (M2)-have been well characterized. Here we describe additional barriers to clonal expansion (Mint) intermediate between M1 and M2, revealed by abrogation of tumor-suppressor gene (TSG) pathways by individual human papillomavirus type 16 (HPV16) proteins. In human fibroblasts, abrogation of p53 function by HPVE6 allowed escape from M1, followed up to 20 population doublings (PD) later by a second viable proliferation arrest state, MintE6, closely resembling M1. This occurred despite abrogation of p21(WAF1) induction but was associated with and potentially mediated by a further approximately 3-fold increase in p16(INK4a) expression compared to its level at M1. Expression of HPVE7, which targets pRb (and p21(WAF1)), also permitted clonal expansion, but this was limited predominantly by increasing cell death, resulting in a MintE7 phenotype similar to M2 but occurring after fewer PD. This was associated with, and at least partly due to, an increase in nuclear p53 content and activity, not seen in younger cells expressing E7. In a different cell type, thyroid epithelium, E7 also allowed clonal expansion terminating in a similar state to MintE7 in fibroblasts. In contrast, however, there was no evidence for a p53-regulated pathway; E6 was without effect, and the increases in p21(WAF1) expression at M1 and MintE7 were p53 independent. These data provide a model for clonal evolution by successive TSG inactivation and suggest that cell type diversity in life span regulation may determine the pattern of gene mutation in the corresponding tumors.
 ...
PMID:Control of replicative life span in human cells: barriers to clonal expansion intermediate between M1 senescence and M2 crisis. 1008 77

We performed molecular biological studies as well as immunohistochemical analysis of three cases of giant cell carcinoma of the pancreas. Histologically, one case was a pleomorphic giant cell carcinoma consisting of pleomorphic giant/ small cells and spindle cells, one an osteoclast-like giant cell tumor composed of osteoclastoid giant cells and pleomorphic small cells, and one a pleomorphic giant cell carcinoma with osteoclastoid giant cells. Immunohistochemically, pleomorphic giant cells and small pleomorphic cells were positive for epithelial and mesenchymal markers throughout the cases. Osteoclastoid cells were strongly positive for PG-M1 (CD68), but negative for lysozyme and epithelial markers. Pleomorphic spindle cells showed the same immunoreactivity as pleomorphic giant/small cells. Genetically, all cases contained a mutation in the K-ras (codons 12, 13) oncogene, but neither p53 (exons 5-8) nor p16INK4 (exons 1, 2) gene mutations were found in any case. Furthermore, Loss of heterozygosity (LOH) of the p53, p161NK4. APC, and DPC4 gene loci was not found in any of the cases. Immunohistochemical study demonstrated this tumor to be of epithelial origin with mesenchymal differentiation. Genetically, initiation of the tumor is similar to that of usual ductal adenocarcinoma, but progression might be rather different. The peculiar histologic and biologic features of this tumor would be the result of changes in other functional genes.
 ...
PMID:Immunohistochemical and molecular analysis of giant cell carcinoma of the pancreas: a report of three cases. 1020 90

The tumor suppressor p16(INK4a) inhibits cyclin-dependent kinases 4 and 6. This activates the retinoblastoma protein (pRB) and, through incompletely understood events, arrests the cell division cycle. To permit biochemical analysis of the arrest, we generated U2-OS osteogenic sarcoma cell clones in which p16 transcription could be induced. In these clones, binding of p16 to cdk4 and cdk6 abrogated binding of cyclin D1, p27(KIP1), and p21(WAF1/CIP1). Concomitantly, the total cellular level of p21 increased severalfold via a posttranscriptional mechanism. Most cyclin E-cdk2 complexes associated with p21 and became inactive, expression of cyclin A was curtailed, and DNA synthesis was strongly inhibited. Induction of p21 alone, in a sibling clone, to the level observed during p16 induction substantially reproduced these effects. Overexpression of either cyclin E or A prevented p16 from mediating arrest. We then extended these studies to HCT 116 colorectal carcinoma cells and a p21-null clone derived by homologous recombination. In the parental cells, p16 expression also augmented total cellular and cdk2-bound p21. Moreover, p16 strongly inhibited DNA synthesis in the parental cells but not in the p21-null derivative. These findings indicate that p21-mediated inhibition of cdk2 contributes to the cell cycle arrest imposed by p16 and is a potential point of cooperation between the p16/pRB and p14(ARF)/p53 tumor suppressor pathways.
 ...
PMID:Induction of p21(WAF1/CIP1) and inhibition of Cdk2 mediated by the tumor suppressor p16(INK4a). 1020 15

Molecular genetic alterations that disturb cell cycle regulation in tumor cells can affect their response to chemotherapeutic agents and radiation. Many genes that regulate the critical cell cycle checkpoint at G1S are altered in human tumors. These genetic changes can result in uncontrolled cellular proliferation, genetic instability, and altered response to radiation and chemotherapy. The p53 tumor suppressor gene serves a critical role at the G1S transition, where it can either block entry into S phase or activate programmed cell death (apoptosis) in response to DNA damage. p53 Gene mutations are common in human tumors and interfere with the activation of apoptosis in response to most chemotherapeutic agents. Paclitaxel is a potent chemotherapeutic agent that interferes with mitotic spindle function to block cells at G2M, the most radiosensitive phase of the cell cycle. Utilization of paclitaxel as a radiation sensitizer in vivo to treat aggressive, locally advanced neoplasms has resulted in high response rates and acceptable toxicity in protocols for non-small cell lung carcinoma, upper gastrointestinal tract carcinoma, and other malignancies. Recent evidence suggests that paclitaxel is unique in its ability to activate apoptosis in tumor cells with p53 mutations in vitro and in vivo. The p16(INK4a) (MTS-1, CDKN2) gene product acts in the same pathway as p53 to inhibit cell cycle progression at G1/S. p16(INK4a) is deleted and/or mutated in a significant fraction of human tumors, including pancreatic carcinoma. The effects of p16(INK4a) alterations in response to paclitaxel/radiation and the risk of systemic relapse are currently being evaluated. Information about molecular genetic alterations in individual tumors ultimately may be a critical factor in choosing between therapeutic options.
 ...
PMID:Role of p53 and p16 gene alterations in determining response to concurrent paclitaxel and radiation in solid tumor. 1021 May 35


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>