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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review discusses recent insights into the roles of the p53 tumor-suppressor gene and growth factors in the development of ovarian cancer and describes the genes implicated in familial ovarian cancer syndromes related to the MSH2 (Lynch II) and BRCA1 (breast and ovarian cancer) genes. Evidence of the monoclonality of ovarian cancer, which contrasts with data supporting the polyclonal origin of primary peritoneal carcinoma, is presented. Finally, the roles of the human papillomavirus and the HIV virus in the etiology of cervical cancer are analyzed in view of the growing importance of this HIV-associated cancer and the poor outcome in these patients.
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PMID:Advances in the biology of gynecologic cancer. 782 56

The predisposition to colon cancer is multigenetically controlled in animals and probably also in humans. We have analyzed the multigenic control of susceptibility to 1,2-dimethylhydrazine-induced colon tumors in mice by using a set of 20 homozygous CcS/Dem recombinant congenic strains, each of which contains a different random subset of approximately 12.5% of genes from the susceptible strain STS/A and 87.5% of genes from the relatively resistant strain BALB/cHeA. Some CcS/Dem strains received the alleles from the susceptible strain STS/A at one or more of the multiple colon tumor susceptibility loci and are susceptible, whereas others are resistant. Linkage analysis shows that these susceptibility genes are different from the mouse homologs of the genes known to be somatically mutated in human colon cancer (KRAS2, TP53, DCC, MCC, APC, MSH2, and probably also MLH1). Different subsets of genes control tumor numbers and size. Two colon cancer susceptibility genes, Scc1 and Scc2, map to mouse chromosome 2. The Scc1 locus has been mapped to a narrow region of 2.4 centimorgans (90% confidence interval).
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PMID:Fine mapping of colon tumor susceptibility (Scc) genes in the mouse, different from the genes known to be somatically mutated in colon cancer. 857 18

A great deal of the energy and time of a cell is invested in DNA repair activities. The first step in DNA repair pathways is recognition of the lesion on the DNA. The classical lesion-recognizing proteins interact with other repair proteins to form multiprotein complexes most notable of which are those that function in Nucleotide Excision Repair (NER). Proteins involved in lesion recognition include HMG1 and 2 recognizing cisplatin adducts but also maintaining active nucleosome structures and interacting with loops in cruciforms; HMG-box nuclear proteins; XPA and XPC lacking in xeroderma pigmentosum patients and involved in lesion recognition during NER; p53 recognizing strand breaks and insertion/deletion mismatches and causing arrest in the cell cycle; MSH2 mismatch repair protein identified as the human colon cancer gene product; and others including the transcription factor YB-1 that binds to depurinated DNA with a higher affinity compared with undamaged DNA. Other type of lesion-recognizing proteins are also repair enzymes like the O(6)-methylguanine-DNA methyltransferase and DNA glycosylases. Lesion recognition is an important process and might be the rate-limiting step in the overall repair process.
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PMID:DNA lesion-recognizing proteins and the p53 connection. 861 13

Recent advances in molecular genetics have revealed that multiple genetic alterations including activation of oncogenes and inactivation of tumor suppressor genes are required for tumor development and progression. Tumorigenesis of colorectal cancer, in which most cancers are considered to arise from preceding benign adenomas, has been well documented at the molecular level. Familial adenomatous polyposis (FAP), which is characterized by the development of hundreds to thousands of adenomatous polyps in the colon and rectum, one or more of which can progress to cancer if left without surgical treatment, is a good model for elucidation of genetic alterations involved in colorectal tumorigenesis. The adenomatous polyposis coli (APC) gene responsible for FAP was isolated in 1991, and germinal and somatic mutations of the APC gene have been identified. Moreover, activation of K-ras oncogene and inactivation of several tumor suppressor genes such as MCC, p53, and DCC are supposed to play important roles at specific stages of colorectal tumorigenesis. More recently, two genes, MSH2 and MLH1, responsible for hereditary non-polyposis colorectal cancer (HNPCC) have been identified. Thus the molecular mechanism of colorectal tumorigenesis now seems to be more complicated than has been supposed.
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PMID:Multistep carcinogenesis in colorectal cancers. 862 5

MSH2 is one of the genes involved in DNA-mismatch repair. Mutations in the coding region of the human gene (hMSH2) have been shown to be directly involved in microsatellite instability in hereditary nonpolyposis colorectal tumors. Examination of the promoter region of hMHS2 revealed a site with homology to the p53 consensus binding sequence. Using gel mobility shift experiments we were able to show that purified p53 has at least in vitro the potential to specifically bind the hMSH2-p53 motif. This binding activity was even stronger than the binding activity measured with the p53-consensus site. These data identify the hMSH2 gene as a possible novel p53-regulated target gene and indicate a direct involvement of p53 in repair mechanisms via DNA binding of a mismatch repair gene.
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PMID:Specific in vitro binding of p53 to the promoter region of the human mismatch repair gene hMSH2. 863 28

The usefulness of prognostic factors in gynecological cancer was evaluated using the oncogenes, tumor suppressor genes and DNA viruses detected with the molecular biological technique. In uterine cervical cancer, HPV types 16 and 18 are considered to have a high oncogenic risk, and are commonly associated with high grade CIN and invasive cancer under persistent HPV infection. C-myc overexpression in advanced stage and p53 mutation in HPV negative case are associated with poor survival. In endometrial cancer, oncogene activation and expression are less frequent than in cervical and ovarian cancer. K-ras point mutation (codon 12) tumors are more aggressive and c-erbB-2 overexpression are associated with metastasis and poor survival. In ovarian cancer, there are numerous abnormalities of oncogenes and tumor suppressor genes. Especially, EGF-R and PDGF-R alpha expression are associated with decreased survival. p53 mutation also decreases survival and response to chemotherapy. Recently. MSH2 (Lynch II syndrome) and BRCA1 gene are known to relate with familial ovarian cancer.
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PMID:[Evaluation of prognostic factors in gynecological cancer examined by molecular biological study]. 868 14

The three known mechanisms of cellular transformation and oncogenesis include mutations in proto-oncogenes, inactivation of both copies of a tumor suppressor gene, and defects in DNA mismatch repair genes. Examples of each are included to substantiate the importance of understanding these mechanisms. RET is a proto-oncogene that is fundamental to the pathogenesis, and in the current era, molecular diagnosis of MEN 2 syndromes. TP53 is a tumor suppressor gene that is mutated in individuals with Li-Fraumeni syndrome. CDKN2 is a tumor suppressor gene that is mutated in pancreatic cancers and is associated with a poorer prognosis and the development of melanoma. MSH2 is a mismatch repair gene that is important in the pathogenesis of HNPCC and Muir-Torre syndrome. Altered gene function such as loss of DCC in colon cancers may affect cell adhesion properties and promote metastases. As we begin to better define and understand the mechanisms of neoplasia, we will be able to improve current diagnosis and treatment.
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PMID:Advances in molecular genetics. 904 82

A role for the Mut L homologue-1 (MLH1) protein, a necessary component of DNA mismatch repair (MMR), in G2-M cell cycle checkpoint arrest after 6-thioguanine (6-TG) exposure was suggested previously. A potential role for MLH1 in G1 arrest and/or G1-S transition after damage was, however, not discounted. We report that MLH1-deficient human colon carcinoma (HCT116) cells showed decreased survival and a concomitant deficiency in G2-M cell cycle checkpoint arrest after ionizing radiation (IR) compared with genetically matched, MMR-corrected human colon carcinoma (HCT116 3-6) cells. Similar responses were noted between murine MLH1 knockout compared to wild-type primary embryonic fibroblasts. MMR-deficient HCT116 cells or embryonic fibroblasts from MLH1 knockout mice also demonstrated classic DNA damage tolerance responses after 6-TG exposure. Interestingly, an enhanced p53 protein induction response was observed in HCT116 3-6 (MLH1+) compared with HCT116 (MLH1-) cells after IR or 6-TG. Retroviral vector-mediated expression of the E6 protein did not, however, affect the enhanced G2-M cell cycle arrest observed in HCT116 3-6 compared with MLH1-deficient HCT116 cells. A role for MLH1 in G2-M cell cycle checkpoint control, without alteration in G1, after IR was also suggested by similar S-phase progression between irradiated MLH1-deficient and MLH1-proficient human or murine cells. Introduction of a nocodazole-induced G2-M block, which corrected the MLH1-mediated G2-M arrest deficiency in HCT116 cells, clearly demonstrated that HCT116 and HCT116 3-6 cells did not differ in G1 arrest or G1-S cell cycle transition after IR. Thus, our data indicate that MLH1 does not play a major role in G1 cell cycle transition or arrest. We also show that human MLH1 and MSH2 steady-state protein levels did not vary with damage or cell cycle changes caused by IR or 6-TG. MLH1-mediated G2-M cell cycle delay (caused by either MMR proofreading of DNA lesions or by a direct function of the MLH1 protein in cell cycle arrest) may be important for DNA damage detection and repair prior to chromosome segregation to eliminate carcinogenic lesions (possibly brought on by misrepair) in daughter cells.
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PMID:Defective expression of the DNA mismatch repair protein, MLH1, alters G2-M cell cycle checkpoint arrest following ionizing radiation. 948 33

Familial juvenile polyposis (FJP) is a hamartomatouspolyposis syndrome in which affected family members develop upper and lower gastrointestinal juvenile polyps and are at increased risk for gastrointestinal cancer. A genetic locus for FJP has not yet been identified by linkage; therefore, the objective of this study was to perform a focused genome screen in a large family segregating FJP. No evidence for linkage was found with markers near MSH2, MLH1, MCC, APC, HMPS, CDKN2A, JP1, PTEN, KRAS2, TP53, or LKB1. Linkage to FJP was established with several markers from chromosome 18q21.1. The maximum LOD score was 5.00, with marker D18S1099 (recombination fraction of .001). Analysis of critical recombinants places the FJP gene in an 11.9-cM interval bounded by D18S1118 and D18S487, a region that also contains the tumor-suppressor genes DCC and DPC4. These data demonstrate localization of a gene for FJP to chromosome 18q21.1 by linkage, and they raise the possibility that either DCC or DPC4 could be responsible for FJP.
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PMID:A gene for familial juvenile polyposis maps to chromosome 18q21.1. 954 10

In order to determine the effects of mismatch repair (MMR) deficiencies in sporadic colorectal carcinomas, 45 such cancers were examined using a sensitive method called crypt isolation technique. Loss of heterozygosity (LOH) in the MSH2 or MLH1 gene was more frequently observed in replication error (RER) (+) carcinomas than in RER (-) carcinomas, which implied that loss of one normal allele could partly affect repair capacity. MSH2 gene defects at both alleles were observed in two carcinomas, which showed severe repair deficiencies. Interestingly, unlike the situation observed in the p53 gene, the MSH2 and MLH1 genes did not show complete LOH. Novel crypt isolation-based subpopulation (CISP) analysis demonstrated that at least two distinct carcinoma subpopulations existed in most carcinomas that showed incomplete LOH; one with and one without LOH. In one carcinoma that had germline mutation and somatic incomplete LOH of the MSH2 gene, the mutator phenotype was only observed in populations affected in both alleles. Thus, the MSH2 gene appears to possess the two hits mechanism of tumor suppressor genes. However, unlike the tumor suppressor genes, MMR gene defects lead to a unique mode of colorectal tumorigenesis characterized by intratumoral heterogeneity.
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PMID:Mismatch repair deficiency leads to a unique mode of colorectal tumorigenesis characterized by intratumoral heterogeneity. 954 27


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