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)

The constitutive DNA from members of four families showing predisposition to breast cancer was amplified by PCR in the region of exons 5, 6, 7 and 8 of the p53 proto-oncogene. Single-strand conformation polymorphism (SSCP) gels were used to compare patient DNA with mutant and wild-type control samples. No cases of anomalous mobility were observed in samples from the susceptible families. The lack of inherited mutations was confirmed for exons 5 and 7 by solid-phase DNA sequencing. The results lend further support to the view that inherited mutations in p53 alleles are not a significant contributor to breast cancer predisposition and it is not, therefore, clinically worthwhile to screen predisposed or potentially predisposed families for germline mutations in the p53 gene.
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PMID:Screening for germline mutations of the p53 gene in familial breast cancer patients. 773 63

The MDM2 proto-oncogene is found amplified in a variety of tumours. The oncogenic capacity of the MDM2 protein is attributed to its ability to bind the p53 tumour-suppressor protein and mask its transcriptional activation potential. Here we show that MDM2 makes a functional contact with two cooperating transcription factors, E2F1 and DP1 (refs 4,5), which are involved in S-phase progression. MDM2 contacts the activation domain of E2F1 using residues conserved in the activation domain of p53. However, in contrast to its repression of p53 activity, MDM2 stimulates the activation capacity of E2F1/DP1. These results indicate that MDM2 not only releases a proliferative block by silencing the tumour suppressor p53, it also positively augments proliferation by stimulating the S-phase inducing transcription factors E2F1/DP1.
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PMID:Stimulation of E2F1/DP1 transcriptional activity by MDM2 oncoprotein. 779 3

Apoptosis or programmed cell death represents a mechanism by which cells possessing DNA damage can be deleted. The bcl-2 proto-oncogene is a known inhibitor of apoptosis that may allow the accumulation and propagation of cells containing genetic alterations. To determine if and when the bcl-2 gene is activated during colorectal tumorigenesis and its relationship to p53, we analyzed normal mucosa, hyperplastic and dysplastic epithelial polyps, and carcinomas for the expression of these markers using immunohistochemistry. Whereas bcl-2 staining was restricted to basal epithelial cells in normal and hyperplastic mucosa, bcl-2 expression was detected in parabasal and superficial regions in dysplastic polyps and carcinomas. An inverse correlation was found between bcl-2 and p53 expression in adenomas, suggesting that these markers may regulate a common cell death pathway. Furthermore, carcinomas with a high percentage of bcl-2-positive cells were significantly more likely to have low rates of spontaneous apoptosis, as determined histologically, than those cancers with low or absent bcl-2 expression. Abnormal activation of the bcl-2 gene appears to be an early event in colorectal tumorigenesis that can inhibit apoptosis in vivo and may facilitate tumor progression.
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PMID:bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis. 781 51

The series of genetic changes leading to malignancy in colorectal cancer is well reported. This includes mutational activation of the proto-oncogene Ki-ras and mutation/deletion of the p53 tumour suppressor gene. The frequency of these mutations was investigated in a panel of 52 colorectal cancer patients using a combination of immunocytochemistry and non-radioactive, digoxigenin-labelled in situ hybridisation. Sixty two per cent (32 of 52) of the study population were positive for p53 overexpression and 36% (19 of 52) positive for Ki-ras mutation. Twenty seven per cent (14 of 52) of the patients expressed both mutations. Mutation of either the p53 or the Ki-ras gene did not correlate with Dukes's stage, tumour differentiation or 5 year survival rate of the patients. Most of the rectal carcinoma specimens (11 of 15) showed p53 over-expression but the significance of this was not supported statistically. Thus detection of molecular changes is becoming more amenable to incorporation into routine histological carcinoma assessment because of the advent of non-radioactive labelling in in situ hybridisation and antibodies suitable for paraffin wax embedded specimens. The significance of these mutations in disease prognosis, however, remains questionable.
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PMID:Mutations of Ki-ras and p53 genes in colorectal cancer and their prognostic significance. 782 87

Human immunodeficiency virus type 1 (HIV-1) Nef protein causes the loss of cell surface CD4 and interleukin-2 (IL-2) receptor (Tac) from peripheral blood mononuclear cells (PBMC) and CD4+ T-cell lines. As both CD4 and the IL-2 receptor play crucial roles in antigen-driven helper T-cell signalling and T-cell proliferation, respectively, the role of Nef in the viral life cycle may be to perturb signalling pathways emanating from these receptors. However, the intracellular targets for Nef that result in receptor down-regulation are unknown. Using a recombinant glutathione S-transferase-full-length 27 kDa Nef (Nef27) fusion protein, produced in Escherichia coli by translation from the first start codon of HIV-1 nef clone pNL4-3, as an affinity reagent to probe cytoplasmic extracts of MT-2 cells and PBMC, we have shown interaction with at least seven host cell protein species ranging from 24 to 75 kDa. Immunoblotting identified four of these proteins as p56lck, CD4, p53, and p44mapk/erk1, all of which are intimately involved in intracellular signalling. To assess the relevance of these interactions and further define the biochemical activity of Nef in signal transduction pathways, highly purified Nef27 protein was introduced directly into PBMC by electroporation. Nef27-treated PBMC showed reduced proliferative responsiveness to exogenous recombinant IL-2. Normally, stimulation of T-cells by IL-2 or phorbol 12-myristate 13-acetate provokes both augmentation of p56lck activity and corresponding posttranslational modification of p56lck. These changes were also inhibited by treatment of PBMC with Nef, suggesting that Nef interferes with activation of p56lck and as a consequence of signalling via the IL-2 receptor. Further evidence for Nef interfering with cell proliferation was the decreased production of the proto-oncogene c-myb, which is required for cell cycle progression, in Nef-treated MT-2 cells. In contrast to the binding characteristics and biological effects of Nef27, the alternate 25-kDa isoform of Nef (Nef25) produced by translation from the second start codon of HIV nef pNL4-3 (57 nucleotide residues downstream) was shown to interact with only three cellular proteins of approximately 26, 28, and 56 kDa from PBMC and MT-2 cells, one of which was identified as p56lck. Also, proliferation and posttranslational modification of p56lck in response to IL-2 stimulation were not profoundly affected by treatment of PBMC with Nef25 compared with Nef27.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Human immunodeficiency virus type 1 Nef protein inhibits activation pathways in peripheral blood mononuclear cells and T-cell lines. 785 25

All cancers result from the accumulation of mutations of proto-oncogenes and tumor suppressor genes. Sporadic and familial colorectal cancers result from the accumulation of the following genes, in a relatively stereotyped chronological order: the tumor suppressor gene apc whose mutations are responsible for the familial adenomatous polyposis; the proto-oncogene K-ras which is mutated in 50% of large adenomas (> 1 cm) and adenocarcinomas; the tumor suppressor gene dcc; and the tumor suppressor gene p53 whose inactivation in a factor of bad prognosis. While some of them are induced by mutagens, others result from an instability of the genome. Two types of instability are observed in both sporadic and familial colorectal cancer. The first type, which is found in 25-50% of cases, appears as cytogenetic abnormalities with aneuploidy and allelic losses. The second type of instability is induced by mutations of the hMSH2 or hMLH1 genes which code for proteins involved in the mechanism of DNA repair.
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PMID:[Genes, heredity and colorectal cancer]. 787 58

Recently, many alterations in DNA were demonstrated in human breast cancer in vivo, and their clinical and pathological implications were extensively examined. Among these gene alterations, amplification of the c-erbB-2 proto-oncogene and mutation of the p53 tumor-suppressor gene, which occur relatively frequently and are accompanied by alterations in the respective protein levels, demonstrated strong correlation to the histologic grade of atypia and were shown or suggested to be prognostic factors independent of tumor size or lymph node status. Although further analyses are necessary to clarify their prognostic significance in patients without lymph node metastasis, these are suggested to be useful in predicting patient prognosis more accurately and aiding determination of adjuvant systemic therapy.
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PMID:[Clinicopathological implications of gene alterations in breast cancer]. 790 82

Proliferation and differentiation of villous trophoblast during placental development, from an early stage to full-term, were investigated in routinely fixed and processed tissues, by means of the immunocytochemical localization of the cell cycle-related proto-oncogene c-myc and the p53 and retinoblastoma susceptibility (Rb) tumour-suppressor gene products. The proliferative activity of the trophoblast was determined using an antibody against proliferating cell nuclear antigen (PCNA) which stains all proliferating cells in paraffin-embedded tissues. Diffuse nuclear immunoreactivity for PCNA, c-myc and Rb gene products was a consistent finding in early cytotrophoblast; c-myc product expression was also detectable in both layers of mid-gestation trophoblast. Only scattered cytotrophoblastic nuclei of early gestational placenta displayed immunostaining for p53 gene product. In full-term placenta c-myc expression was undetectable while Rb gene product and PCNA immunoreactivity declined markedly. These results indicate that the expression of the above genes is spatio-temporally regulated during placental development. A potential involvement of the oncosuppressor gene products p53 and Rb in the control of trophoblastic proliferation and of c-myc in the control of both the proliferative and differentiation pathways of trophoblastic cells is suggested.
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PMID:C-myc and tumour suppressor gene product expression in developing and term human trophoblast. 793 96

The mdm2 proto-oncogene product binds to the p53 tumor suppressor protein and inhibits its ability to trans-activate target genes. One such target gene is mdm2 itself, which is therefore considered a component of a p53 negative feedback loop. Two tandem p53-binding motifs residing within the first intron of the murine mdm2 gene confer upon it p53-mediated activation. We now report that in murine cells p53 activates an internal mdm2 promoter (P2) located near the 3' end of intron 1, resulting in mRNA whose transcription starts within exon 2. P2 is activated by p53 within artificial constructs, as well as within the context of the chromosomal mdm2 gene. Activation follows either the introduction of overexpressed wild-type p53 into cells or the induction of endogenous wild-type p53 by ionizing radiation. The upstream, constitutive (P1) mdm2 promoter is only mildly affected by p53, if at all. The p53-derived mdm2 transcripts lack exon 1 and a few nucleotides from exon 2. As the first in-frame AUG of mdm2 is located within exon 3, the two types of mdm2 transcripts should possess similar coding potentials. Nevertheless, in vitro conditions, where each of these transcripts yields a distinct translation profile, reflect the differential usage of translation initiation codons. Initiation of translation at internal AUG codons, which occurs also in vivo, gives rise to MDM2 polypeptides incapable of binding to p53. In vitro translation profiles of the various mdm2 transcripts could be manipulated by changing the amounts of input RNA. Thus, p53 can modulate both the amount and the nature of MDM2 polypeptides through activation of the internal P2 promoter.
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PMID:Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential. 795 53

Removal of UVB-induced cyclobutane pyrimidine dimers (CPD) from each of the two strands of the transcriptionally active p53 tumor suppressor gene and the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene was determined in the epidermis of the hairless mouse using the CPD-specific enzyme T4 endonuclease V. Mice were exposed to a single dose of UVB (2 kJ/m2) and kept in darkness for up to 24 h. About 80% of the CPD were removed from the transcribed strand of the p53 and HPRT genes within 24 h. Most rapid removal was observed during the first 4 h. In contrast, very little removal of CPD from the nontranscribed strand of the p53 and the HPRT genes was observed in 24 h. The same low level of repair was observed in the inactive c-mos proto-oncogene. The efficient repair of the transcribed strand compared to the nontranscribed strand of transcriptionally active genes in the epidermis of the hairless mouse resembles the repair of CPD in cultured rodent cells. Moreover, the selective removal of CPD from the transcribed strand of the p53 gene correlates well with the known strand bias of u.v.-induced mutations at dipyrimidine sites in the p53 gene of u.v.-induced mouse skin tumors.
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PMID:Strand-specific removal of cyclobutane pyrimidine dimers from the p53 gene in the epidermis of UVB-irradiated hairless mice. 797 Jul 1


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