Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we analyzed 10 human squamous cell carcinomas (SCCs) for alterations in the p53 tumor suppressor gene in exons 4 through 9 by single-strand conformation polymorphism (SSCP) analysis. We found that 2 of 10 SCCs displayed unusual SSCP alleles at exon 7 of the p53 gene. Subsequent cloning and sequencing of PCR-amplified exon 7 DNA from these two tumors revealed that one had a G----A transition at the first position of codon 244, predicting a glycine-to-serine amino acid change, while the other tumor exhibited a G----T base change at the second nucleotide of codon 248, predicting an arginine-to-leucine substitution. Because the mutations in the p53 tumor suppressor gene in both tumors were located opposite potential pyrimidine dimer sites (C-C), it is consistent with these mutations having been induced by the ultraviolet radiation present in sunlight. These studies demonstrate that inactivation of the p53 tumor suppressor gene, as well as activation of ras oncogenes, may be involved in the pathogenesis of some human skin cancers.
Mol Carcinog 1991
PMID:Mutations in the p53 tumor suppressor gene in human cutaneous squamous cell carcinomas. 179 82

Using the thyroid follicular cell as a model for multi-stage carcinogenesis, we have investigated the role of two potential negative growth regulators ('anti-oncogenes') in epithelial tumour progression--transforming growth factor-beta 1 (TGF beta 1) and p53. Normal follicular cells, as expected, showed marked growth inhibition in response to TGF beta 1. Adenoma cells were equally inhibited. In contrast, spontaneously and SV40-immortalised follicular cell lines showing features of malignant transformation (notably loss of growth factor dependence) had lost all responsiveness to TGF beta 1, accompanied by a partial loss of its receptors. p53 protein was below detectable limits in normal and in adenoma cells but in contrast very high levels were observed in all three transformed lines. In the SV40-immortalised cells, this was expected in view of the known stabilising effect of the viral large T protein. In the spontaneous line we found strong evidence for point mutation of p53, which is known to have the same effect. Both mechanisms result in loss of p53 tumour suppressor function despite increased protein content. We conclude that loss of inhibition by TGF beta and inactivation of p53 are important steps in in vitro immortalisation and/or in vivo tumour progression in human thyroid follicular cells, and speculate that p53 may mediate or be required for the inhibitory signal normally induced by TGF beta 1.
Mol Cell Endocrinol 1991 Apr
PMID:Correlated abnormalities of transforming growth factor-beta 1 response and p53 expression in thyroid epithelial cell transformation. 182 Sep 69

Simian virus 40 (SV40) large-T antigen and the cellular protein p53 were phosphorylated in vivo by growing cells in the presence of 32Pi. The large-T/p53 complex was isolated by immunoprecipitation and used as a substrate for protein phosphatase 2A (PP2A) consisting of the catalytic subunit (C) and the two regulatory subunits, A and B. Three different purified forms of PP2A, including free C, the AC form, and the ABC form, could readily dephosphorylate both proteins. With both large-T and p53, the C subunit was most active, followed by the AC form, which was more active than the ABC form. The activity of all three forms of PP2A toward these proteins was strongly stimulated by manganese ions and to a lesser extent by magnesium ions. The presence of complexed p53 did not affect the dephosphorylation of large-T antigen by PP2A. The dephosphorylation of individual phosphorylation sites of large-T and p53 were determined by two-dimensional peptide mapping. Individual sites within large-T and p53 were dephosphorylated at different rates by all three forms of PP2A. The phosphates at Ser-120 and Ser-123 of large-T, which affect binding to the origin of SV40 DNA, were removed most rapidly. Three of the six major phosphopeptides of p53 were readily dephosphorylated, while the remaining three were relatively resistant to PP2A. Dephosphorylation of most of the sites in large-T and p53 by the AC form was inhibited by SV40 small-t antigen. The inhibition was most apparent for those sites which were preferentially dephosphorylated. Inhibition was specific for the AC form; no effect was observed on the dephosphorylation of either protein by the free C subunit or the ABC form. The inhibitory effect of small-t on dephosphorylation by PP2A could explain its role in transformation.
Mol Cell Biol 1991 Apr
PMID:Dephosphorylation of simian virus 40 large-T antigen and p53 protein by protein phosphatase 2A: inhibition by small-t antigen. 184 68

In this report we present evidence that simian virus 40 T antigen encodes a biological activity that is functionally equivalent to the transforming activity lost by deletion of the E1A p300-binding region. T-antigen constructs from which the pRb-binding region has been deleted are virtually unable to induce foci of transformed cells in a ras cooperation assay in primary baby rat kidney cells. Nevertheless, such a construct can cooperate with an E1A N-terminal deletion mutant, itself devoid of transforming activity, to induce foci in this assay. The heterologous trans-cooperating activity observed between E1A and T-antigen deletion products is as efficient as trans cooperation between mutants expressing individual E1A domains. The cooperating function can be impaired by a deletion near the N terminus of T antigen. Such a deletion impairs neither the p53-binding function nor the activity of the pRb-binding region.
Mol Cell Biol 1991 Apr
PMID:Simian virus 40 large-T antigen expresses a biological activity complementary to the p300-associated transforming function of the adenovirus E1A gene products. 184 72

Transgenic mice were produced harboring the p53 murine cDNA clone regulated by the SV40 enhancer-promoter region 5' to the cDNA and the small t antigen splice sites, and poly(A) addition signals 3' to the cDNA. This construction was not expressed in these mice. The presence of several murine p53 introns in the cDNA, however, permitted expression of the transgene mRNA in several tissues of transgenic mice. The insertion of intron 4 led to the preferential expression of the transgene mRNA in spleen cells, where the endogenous p53 gene is also expressed at high levels. While intron 4 promoted high levels of p53 mRNA expression in a tissue-preferred manner in transgenic mice, there was no evidence that intron 4 could act as an enhancer of transcription in cell culture or in transgenic animals. The presence of some p53 introns appears to be critical for the regulation of this gene in vivo.
Mol Carcinog 1991
PMID:Tissue-specific expression of p53 in transgenic mice is regulated by intron sequences. 184 86

We analyzed the genomic structure and mRNA of the RB and p53 genes in four mouse lymphoid leukemia cell lines (DL-1, DL-5, DL-8, and DL-12). Although no gross structural alteration of the RB gene was observed in any cell line, abnormalities of RB mRNA were detected in at least two cell lines. RB mRNA expression was greatly reduced in DL-12. In addition, cloning and sequencing analysis of the RB cDNA revealed that the RB mRNA in DL-8 had a 276-nucleotide deletion presumably consisting of exons 10, 11, and 12, suggesting that altered splicing resulted in the loss of these exons. Analysis of the p53 gene indicated that DL-5 had a deletion in both alleles and expressed a smaller mRNA. These results suggest that mutations of the RB or p53 genes, or both, are associated with lymphoid leukemogenesis in mice.
Mol Carcinog 1991
PMID:Identification of RB and p53 mutations in mouse lymphoma cell lines. 191 Apr 80

The wild-type p53 protein functions to suppress transformation, but numerous mutant p53 proteins are transformation competent. To examine the role of p53 as a transcription factor, we made fusion proteins containing human or mouse p53 sequences fused to the DNA binding domain of a known transcription factor, GAL4. Human and mouse wild-type p53/GAL4 specifically transactivated expression of a chloramphenicol acetyltransferase reporter in HeLa, CHO, and NIH 3T3 cells. Several mutant p53 proteins, including a mouse p53 mutant which is temperature sensitive for suppression, were also analyzed. A p53/GAL4 fusion protein with this mutation was also transcriptionally active only at the permissive temperature. Another mutant p53/GAL4 fusion protein analyzed mimics the mutation inherited in Li-Fraumeni patients. This fusion protein was as active as wild-type p53/GAL4 in our assay. Two human p53 mutants that arose from alterations of the p53 gene in colorectal carcinomas were 30- to 40-fold less effective at activating transcription than wild-type p53/GAL4 fusion proteins. Thus, functional wild-type p53/GAL4 fusion proteins activate transcription, while several transformation competent mutants do so poorly or not at all. Only one mutant p53/GAL4 fusion protein remained transcriptionally active.
Mol Cell Biol 1991 Dec
PMID:Analysis of p53 mutants for transcriptional activity. 194 76

An understanding of the molecular pathogenesis of lung cancer has evolved from classic cytogenetic studies and the use of restriction fragment length polymorphisms to encompass the definition of specific genetic abnormalities associated with this disease. Activation of the dominant class of oncogenes is frequent, with involvement of the ras and myc families of genes being the best defined. Several examples of inactivation at specific loci exist and have been related to the presence of tumor suppressor genes, most notably the retinoblastoma gene, p53, and a putative gene located on the short arm of chromosome 3. As our understanding of the nature and interactions between these numerous genetic events evolves, new opportunities for early diagnosis, prevention, and treatment will arise.
Am J Respir Cell Mol Biol 1990 Mar
PMID:Dominant oncogenes and tumor suppressor genes in the pathogenesis of lung cancer. 196 50

EcoRI fragments of DNA isolated from the different mouse organs were hybridized to radioactivity labelled probe specific for the gene of oncoprotein p53. The analysis of the blot-hybridization points to the existence of the specific blockage of an EcoRI site flanking a 3.3 kb fragment of DNA including the pseudogene p53, isolated from the skin tissue. The existence of a polymorphous EcoRI site localized distally to the pseudogene p53 has been demonstrated in the DNA of mice of different lines.
Mol Gen Mikrobiol Virusol 1990 Apr
PMID:[Tissue-specific blocking of the EcoRI site adjacent to the pseudogene for mouse oncoprotein p53]. 197 62

Inactivation of the cellular p53 gene is a common feature of Friend virus-induced murine erythroleukemia cell lines and may represent a necessary step in the progression of this disease. As well, frequent loss or mutation of p53 alleles in diverse human tumors is consistent with the view of p53 as a tumor suppressor gene. To examine the significance of p53 gene inactivation in tumorigenesis, we have attempted to express transfected wild-type p53 in three p53-negative tumor cell lines: murine DP16-1 Friend erythroleukemia cells, human K562 cells, and SKOV-3 cells. We found that aberrant p53 proteins, which differ from wild-type p53 by a single amino acid substitution, were expressed stably in these cells, whereas wild-type p53 expression was not tolerated. The inability of p53-negative tumor cell lines to support long-term expression of wild-type p53 protein is consistent with the view that p53 is a tumor suppressor gene.
Mol Cell Biol 1991 Jan
PMID:Expression of wild-type p53 is not compatible with continued growth of p53-negative tumor cells. 198 14


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