Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 tumour suppressor gene is intensively studied because mutations in this gene are the most common genetic alteration so far identified in human cancer. Considerable emphasis has thus been placed on characterizing the biological differences between mutant and wild-type p53 protein. This has led to the realization that in cultured cells, mutant p53 behaves like an oncogene, whereas wild-type p53 is a tumor suppressor gene. The p53 protein is also a target for the tumour virus oncogene products SV40 large T, adenovirus E1B, and human papillomavirus type 16 E6, which are all capable of forming complexes to the p53 protein. Although p53 represents an extremely important cellular regulatory molecule which is well conserved, there exists two allelic variants of wild-type human p53 that differ both in primary and confirmational structure. One variant contains an arginine at amino acid 72 (p53Arg), whereas the other form contains a proline at this residue (p53Pro). The possible implications for more than one allelic variant of wild-type human p53 in the general population is unknown. The present study was undertaken to compare some of the biological features of the different wild-type p53 variants. We present data demonstrating that there was a post-transcriptional selection against accumulation of both variants of wild-type human p53 in 3T3-A31 cells, arguing that both forms are proliferation inhibitory in these cells. Both variants of human p53 were stabilized by SV40 large T, but did not displace mouse p53 from SV40 large T. Neither allelic variant of human p53 was able to reduce significantly SV40-mediated anchorage-independent growth of 3T3-A31 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular analysis of different allelic variants of wild-type human p53. 129 28

We report details of a family with classic Li-Fraumeni syndrome in which there is a mutation in codon 344 of the tumour suppressor gene TP53. Codon 344 is a key residue within the tetramerisation domain, and the amino acid substitution of a proline for a leucine is predicted to have profound implications for tetramerisation and potentially DNA binding. This is the first report of a mutation at this residue in either sporadic tumours or in the germline and the first report of a germline mutation within the tetramerisation domain. The family does not appear to be remarkable in the spectrum of tumours, and there is loss of the wild-type allele in a leiomyosarcoma from the proband. A cell line has been established from the tumour of the proband and cytogenetic and molecular studies carried out, providing an extensive analysis in this family.
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PMID:A previously undescribed mutation within the tetramerisation domain of TP53 in a family with Li-Fraumeni syndrome. 864 85

The growth suppressive activity of the retinoblastoma tumour suppressor protein is controlled by cell cycle dependent phosphorylation. However, while many in vivo phosphorylation sites have been mapped, the identities of those residues whose phosphorylation is regulated remain elusive. We have mapped the epitopes of three independent monoclonal antibodies that recognise a distinction between differentially phosphorylated pRB sub-populations. All three antibodies recognise an identical epitope which encompasses an essential serine positioned within a consensus site for proline directed kinase phosphorylation. We provide evidence that this residue, serine 608 of pRB, is an authentic phosphorylation site that can be phosphorylated in vitro by cyclin A-CDK2 and cyclin D1-CDK4 kinases but not by cyclin E-CDK2 kinase or the mitogen activated kinase ERK2. Phosphorylation at this residue seems to be cell cycle regulated, occurring prior to entry into the S phase.
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PMID:Monoclonal antibodies specific for underphosphorylated retinoblastoma protein identify a cell cycle regulated phosphorylation site targeted by CDKs. 901 Feb 27

p53 is altered in about 50 % of cancers. Most of the p53 mutants have lost the wild-type tumour suppressor activity but show oncogenic properties. The majority of the p53 alterations are missense mutations of residues located in its DNA binding domain (DBD). Only a few mutations concern residues in its tetramerisation domain (TD). However, the study of mutant proteins identified in tumors that do not form tetramers has shown that they have lost the wild-type activity like most of the p53 DBD mutants. Here, we show that two of such mutant proteins, Arg342Pro and Leu344Pro are not dominant negative and do not stimulate the expression of a reporter gene under the control of the multi-drug resistance gene-1 (MDR-1). This suggests that to be oncogenic, p53 mutants need to form tetramers. Accordingly, the dominant negative effect and the ability of a tetrameric mutant protein, Asp281Gly, to stimulate the MDR-1 promoter are abolished when its TD is rendered non-functional by the mutation of leucine 344 to a proline residue. These results suggest that mutations in the TD, are less selected in tumors than mutations in the DBD because they do not lead to oncogenic proteins.
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PMID:p53 mutants without a functional tetramerisation domain are not oncogenic. 1006 94

In an attempt to examine whether the inactivation of p16INK4a is an important early event in the development of sporadic melanoma in vivo, we have systematically analysed 46 uncultured primary cutaneous melanomas. Loss of heterozygosity (LOH) of chromosome region 9p21-22 (where the p16INK4a resides) was detected in 11 tumours (24%) by PCR-based LOH analyses. Direct sequencing of all three exons of the p16INK4a gene in these 11 tumours revealed no somatic mutation although germline mutations which have not been reported previously as common polymorphisms were detected in two patients. Further sequencing analyses of the p16INK4a gene exon 2 in 19 additional tumours with no evidence of LOH on 9p21-22 identified only one heterozygous C- >T mutation at codon 81 altering a proline to a leucine. A sensitive methylation-specific PCR assay did not reveal de novo methylation of the 5'CpG island in exon 1 of the p16INK4a gene in any of the tumours showing 9p21-22 allelic loss or a heterozygous p16INK4a mutation. Complete loss of p16INK4a protein, most likely due to homozygous deletion of the p16INK4a gene, was observed in 6 (15%) out of 39 evaluable cases by immunohistochemical analyses on frozen sections using two different anti-p16INK4a antibodies. The results show that inactivation of p16INK4a is not as frequent in primary melanoma as has been reported in cell lines, and warrant further search for another tumour suppressor on 9p21-22. This study also emphasizes the importance of examining uncultured primary tumours rather than cell lines to define early events in tumorigenesis.
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PMID:p16INK4a inactivation is not frequent in uncultured sporadic primary cutaneous melanoma. 1022 4

The p53 tumour suppressor gene is inactivated in various types of human cancers, and has been implicated as an early event in several cancers. A p53 Pro/Arg polymorphism at exon 4 codon 72, has been suggested to be involved in susceptibility to cancers as well. Hence, in the current study, we investigated p53 exon 4 codon 72 polymorphism using Proline or Arginine specific primers from the peripheral blood cells (PBC) representing constitutional DNA from 72 oral cancer patients. PBC from 153 normal healthy individuals were used to determine the frequency of the p53 genotypes, Pro/Pro, Arg/Arg and Pro/Arg, in the Indian population. The frequency of distribution of genotypes in the normal healthy individuals was, Pro/Pro - 0.20 (31/153), Arg/Arg -- 0.14 (22/153) and Pro/Arg -- 0.65 (100/153); and in the oral cancer patients was, Pro/Pro -- 0.19 (14/72), Arg/Arg -- 0.08 (6/72) and Pro/Arg -- 0.72 (52/72). Thus, we observed an equidistribution of the genotypes in normal control and oral cancer patients (chi(2)= 1.77, df = 2, 0.3 <P< 0.5). Further, DNA from corresponding tumours from the 72 oral cancer patients were examined for loss of heterozygosity in the p53 gene. Allelic loss was observed in 8 of 52 (15%) heterozygous informative oral cancer patients. Our data indicates an equidistribution of the genotypes and absence of over-representation of either Pro/Pro or Arg/Arg genotypes in the oral cancer patients as compared to the normal healthy controls. Hence, association of the p53 genotypes with susceptibility to oral cancer, was not observed.
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PMID:Determination of p53 genotypes in oral cancer patients from India. 1125 85

Rare inherited syndromes that to some extent explain familial glioma include Turcot's syndrome, Li-Fraumeni syndrome and neurofibromatosis types I and II. The majority of families with glioma do not meet the clinical criteria for any of these syndromes. In order to study the genetic origin of familial glioma, tumour DNA (n = 35) or blood samples (n = 8) were collected from 25 families. The glioma tumours were tested for microsatellite instability (MSI) with two markers, BAT25 and BAT26, since glioma is associated with hereditary non-polyposis colon cancer (HNPCC) in Turcot's syndrome. Furthermore, p53 was screened from blood DNA (exons 2-11) with temporal temperature gradient electrophoresis (TTGE) since germline mutations in p53 are seen in Li-Fraumeni syndrome. In gliomas, there is a wide variety of somatic mutations, such as, for instance, in p53, the epidermal growth factor receptor (EGFR) and p16. The tumour suppressor gene PTEN is also often somatically mutated in glioma, therefore it is attractive as a candidate gene for germline mutations in familial glioma. Blood DNA was directly sequenced for mutations in PTEN exons 1-9. The analysis showed that no mutations were found in either of the studied tumour suppressor genes, and no MSI-positive tumours were found. A common polymorphism in p53 at codon 72 (arginine/proline) was found in 6/8 of the patients. Apparently, mutation in the tested tumour suppressor genes or DNA mismatch repair genes does not explain the familial glioma observed in these families.
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PMID:Microsatellite instability, PTEN and p53 germline mutations in glioma families. 1166 37

Human papillomavirus (HPV) infects the squamous epithelial cells of oral cavity and cervix leading to formation of warts that develops into the cancer. Human papillomavirus (HPV)-16 and 18 encode E6 oncoprotein, which binds to and induces degradation of the tumour suppressor protein p53. A common polymorphism of p53, encoding either proline (Pro) or arginine (Arg) at position 72, affects the susceptibility of p53 to E6 mediated degradation in vivo. Oral cancer is a pressing problem in India due to the widespread habit of chewing betel quid, which plays an important role in etiology of this disease. In the present study an attempt has been made to analyze the genetic predisposition of the Indian population to HPV infection and oral carcinogenesis. In our study a total of 110 cases of Oral Cancer highly addicted to betel quid and tobacco chewing are analyzed for HPV 16/18 infection and its association with polymorphism at p53 codon 72. Of these a total number of 37 patients (33.6%) have shown the presence of HPV, among which the presence of HPV-16, 18 and 16/18 coinfection is 22.7%, 14.5% and 10%, respectively. Our results also indicate that the p53 codon 72 genotype frequencies in Indian Oral Cancer patients are 0.55 (Arg) and 0.45 (Pro) as per Hardy-Weinberg equilibrium. In our study, striking reduction in Pro/Pro allele frequency has been found in HPV positive cases, indicating Arg/Arg genotype to be more susceptible to HPV infection and oral carcinogenesis.
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PMID:Prevalence of high-risk human papilloma virus types and its association with P53 codon 72 polymorphism in tobacco addicted oral squamous cell carcinoma (OSCC) patients of Eastern India. 1180 92

Many aspects of physiology and anatomy are precisely adjusted so that the right amount of oxygen reaches cell throughout the body. Hypoxia-inducible factor-1 (HIF-1) is activated by low oxygen tension in all mammalian cells and underpins many aspects of the impressive ability to match oxygen supply and demand. As examples, HIF-1 regulates: local capillary architecture via angiogenic signalling red cell production via erythropoietin cellular metabolism via increased expression of glucose transporters and glycolytic enzymes. HIF-1 is also important in disease, for example in cancer where it is involved in angiogenesis. This review describes how HIF-1 is regulated by oxygen and the central role played by the von Hippel-Lindau tumour suppressor protein. The underlying oxygen sensor is provided by a family of enzymes which oxidize specific proline residues in HIF alpha subunits. Inhibiting these newly discovered enzymes provides a way of activating HIF-1 in the presence of oxygen--an exciting prospect for therapeutic intervention in ischaemic diseases.
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PMID:Oxygen homeostasis and cancer: insights from a rare disease. 1219 66

Infection of high risk human papillomaviruses (HPVs) specifically the types 16 and 18 has been strongly implicated in the development of cervical cancer. The E6 oncoproteins of these high risk HPVs are known to bind and induce degradation of p53 tumour suppressor protein through the ubiquitin pathways. This degradation is controlled by a common polymorphism of the p53 gene encoding either a proline or an arginine at its codon 72 in exon 4. Recently, it has been demonstrated that the presence of homozygous arginine at codon 72 renders p53 about seven times more susceptible to E6-mediated proteolytic degradation as well as to cervical cancer than those with proline homozygotes or proline/arginine heterozygotes. In India, prevalence of HPV as well as cancers of the uterine cervix and the oral cavity are highest in the world. We have examined this allele-specific predisposition in cervical and oral cancer which is associated with HPV as well as in a non-HPV-linked cancer of the breast. We have carried out investigation in women comprising whole spectrum of cervical lesions with 128 HPV 16/18 positive and 35 HPV negative invasive cervical carcinomas and 34 cases of HPV (16/18) positive and 16 HPV negative cervical dysplasias (mild, moderate and severe) and 104 age-group-matched healthy women as controls. Additionally, we have analysed p53Arg-Pro polymorphism in 13 high risk HPV positive and 31 HPV negative oral cancers along with 20 normal controls and 77 breast cancers with 41 age-matched healthy controls. We observed more than two fold higher risk for homozygous arginine (chi2 = 6.3, df = 2, p = 0.04; OR = 2.3; 95% CI: 1.08-5.16) for HPV 16/18-positive cervical carcinomas when comparison was made only between HPV positive cervical cancers and normal controls but most interestingly, no significant association either in the frequency of homozygous arginine or proline alleles or their heterozygotes could be observed when all the three groups i.e. HPV-positive, HPV-negative cervical cancers and controls were considered simultaneously. No difference was also observed for either arginine or proline polymorphism between women with precancerous lesions of the uterine cervix carrying HPV 16/18 infection and controls. Similarly, increased risk of oral or breast cancer could not be correlated with the polymorphism of arginine/proline allele. Thus the interaction between HPV oncoproteins and the p53 gene polymorphism specifically, homozygous arginine at codon 72 appears to play no role in the development of either cervical or oral cancer and also it can not serve as a biomarker for early identification of cervical, oral or breast cancer.
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PMID:Polymorphism of the p53 codon 72 Arg/Pro and the risk of HPV type 16/18-associated cervical and oral cancer in India. 1457 84


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