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)

Exon 8 of tumour suppressor gene p53 was sequenced in domestic cats and showed remarkable similarity to the human sequence. Only four of the 13 nucleotide differences gave rise to interspecific amino acid differences. In an investigated lymphosarcoma we detected a mutation cgg --> tgg (arginine --> tryptophan) in codon no. 282.
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PMID:Sequence of an exon of the feline p53 gene--mutation in a lymphosarcoma. 822 Oct 43

An immune selection procedure was employed in order to isolate p53 binding sites from mouse genomic DNA. Two DNA clones capable of tight specific interaction with wild type p53 were subjected to further characterization. In both cases, the p53 binding regions displayed a high degree of sequence homology with the consensus binding site defined for human genomic DNA. One of the clones was found to be derived from the LTR of a retrovirus-like element (a member of the GLN family). The region encompassing the GLN LTR p53 binding site could confer p53 responsiveness upon a heterologous promoter. Furthermore, the expression of the endogenous, chromosomally integrated GLN elements was significantly induced upon activation of wild type p53 in cells harboring a temperature sensitive p53 mutant. Finally, it was demonstrated that p53 - MDM2 complexes fail to bind tightly to such a p53 binding site. This may contribute to the inhibition by MDM2 of p53-mediated transcriptional activation.
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PMID:Sequence-specific DNA binding by p53: identification of target sites and lack of binding to p53 - MDM2 complexes. 833 96

We have sequenced p53 in three colon cancer cell lines capable of autonomous proliferation. SNU-C1 and SNU-C4 cells, whose autonomous growth is dependent upon autocrine stimulation of epidermal growth factor receptor (EGFR), had wildtype p53 sequence of exons 4-9. In contrast, an EGFR ligand-independent cell line, SNU-C5, had heterozygous missense mutations affecting codons 218 (valine to leucine) and 248 (arginine to tryptophan) of p53. Bacterial cloning of p53 from SNU-C5 cells showed that the 248trp and 218leu mutants were both expressed and on separate alleles. 248trp is a common 'hot spot' mutant of p53 with variable dominant negative activity depending on the celullar context. Valine 218, in contrast, is rarely affected by mutation in cancers and is located in a region of the hydrophobic core domain away from 'hot spot' DNA contact sights. However, valine 218 is completely conserved across species, prompting us to investigate the function of 218leu in SNU-C5 cells. SNU-C5 cells exhibited complete loss of normal p53 function as evidenced by over-expression of p53 protein and by failure to show induction of p53, waf-1, mdm-2 or G1/S arrest in response to the DNA damaging agent, bleomycin. In a yeast p53 functional assay (FASAY), 50% of the clones were unable to transactivate a p53-specific promoter required for yeast colony expansion at 25, 30 or 37 degrees C. Sequencing of the p53 insert from several randomly selected wild-type and mutant yeast clones revealed that 218leu-bearing clones retained their ability to transactivate the p53-specific promoter. As expected, the 248trp-bearing clones lost this function. These data indicate that although 218leu retains normal transactivation activity on a p53 promoter in yeast at physiological temperatures, it is not capable of normal p53 function in the presence of a 248trp allele in SNU-C5 cells. It remains unclear whether the strong dominant negative activity of 248trp in SNU-C5 cells is related to the cellular context or to an unresolved abnormality of 218leu function.
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PMID:p53 functional loss in a colon cancer cell line with two missense mutations (218leu and 248trp) on separate alleles. 855 7

Human p21 (also known as WAF1, CIP1, or SDI1) is a dual inhibitor of cyclin dependent kinases (CDKs) and the replication factor PCNA, which plays a role as a downstream mediator of the cell-cycle arrest induced by the tumor suppressor p53. To determine whether inactivation of downstream targets of p53 might contribute to cellular transformation, we have examined the integrity of the p21 gene in 36 invasive ductal breast carcinomas. Direct sequence analysis of the polymerase chain reaction-amplified p21 gene revealed a C to T transition in codon 94 that caused the substitution of a tryptophan for an arginine in a tumor specimen. This mutation was not detected in normal DNA extracted from the same patient nor in a polymerase chain reaction-restriction fragment length polymorphism of 50 unrelated individuals, indicating that it corresponds to a tumor-specific alteration. Functional analysis of the p21(R94W) protein produced in different eukaryotic and prokaryotic expression systems revealed that this mutation impaired the ability of p21 to inhibit CDKs. By contrast, the R94W mutant was unaltered in its ability to promote cyclin-CDK association as well as in its ability to bind proliferating cell nuclear antigen, thus leaving its putative functions as kinase activator or as inhibitor of replicative DNA synthesis intact. On the basis of these functional analysis, we propose that the Arg residue at position 94 is important for the CDK inhibitory role of p21.
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PMID:Functional analysis of a p21WAF1,CIP1,SDI1 mutant (Arg94 --> Trp) identified in a human breast carcinoma. Evidence that the mutation impairs the ability of p21 to inhibit cyclin-dependent kinases. 866 32

Transgenic mice expressing wild-type murine p53 under the control of the mouse mammary tumor virus long terminal repeat (MMTV LTR) undergo progressive renal failure due to abnormal kidney development. Similar phenotypes are observed in two transgenic lines that express wild-type p53 within the ureteric bud but not in transgenic animals expressing a dominant-negative p53 mutant allele. Defective differentiation of the ureteric bud, as evidenced by altered marker expression during development, accompanies expression of the p53 transgene. At E17.5-18.5, metanephric mesenchymal cells undergo high rates of apoptosis, and fewer cells than normal are converted to tubular epithelium. As a result, p53 transgenic kidneys grow to only half of their expected size and contain about half of the normal number of nephrons, with compensatory hypertrophy of the glomeruli. In this setting, rather than arrest the cell cycle or induce apoptosis directly, abnormally high levels of wild-type p53 appear to alter cellular differentiation in embryonic ureteric buds and cause secondary effects (apoptosis and inefficient conversion to epithelium) in the adjacent undifferentiated mesenchyme.
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PMID:Wild-type p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. 884 20

We have evaluated the role of p53 in the induction of cell death by the DNA topoisomerase II inhibitor etoposide in M1 myeloid leukemia cells. Three different clones of M1 cells were used: S6, which lacks p53; Phe-132, which expresses mutant p53 constitutively; and LTR-13, which expresses mutant protein at 37 degrees C and wild-type p53 at 32 degrees C. As described previously, LTR-13 cells undergo rapid apoptosis upon induction of wild-type p53 at 32 degrees C. Multiparameter flow cytometric analysis showed that etoposide treatment (0.5 microg/ml) of all three cell lines at 37 degrees C is associated with a block in the G2 phase of the cell cycle, whereas the cells preferentially die out of the next S phase. Induction of wild-type p53 in LTR-13 cells is associated with a loss of cells in late S and G2-M phase, and the cells die out of the early S phase. Interestingly, the simultaneous induction of apoptosis by both pathways (wild-type p53 and etoposide) leads to suppression of the etoposide-induced G2 block. To determine the effect of p53 on the G2 to M transition, LTR-13 cells were incubated with etoposide for 24 h at 37 degrees C and then either maintained for an additional 12 h at 37 degrees C or shifted to 32 degrees C to activate wild-type p53. The expression of wild-type p53 resulted in an increase in mitosis-specific phosphorylation, as determined by the MPM-2 antibody as well as the formation of mitotic spindles. This was associated with an important augmentation of the cytotoxic effect of etoposide. In contrast, a similar temperature shift of Phe-132 cells, which express mutant p53, had no effect on either immunostaining with MPM-2 or the cytotoxicity. Taken together, our results indicate that wild-type p53 can override the etoposide-induced G2 block in at least some cell types. These data propose a new role for p53 in the cell death induced by chemotherapeutic agents and may have important implications for gene therapy.
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PMID:Expression of wild-type p53 increases etoposide cytotoxicity in M1 myeloid leukemia cells by facilitated G2 to M transition: implications for gene therapy. 904 Nov 78

Using HeLa cells stably transfected with an HIV-LTR-CAT construct, we demonstrated a peak in CAT induction that occurs in viable (but not necessarily cell-division-competent) cells 24 h following exposure to some cell-killing agents. gamma rays were the only cell-killing agent which did not induce HIV transcription; this can be attributed to the fact that gamma-ray-induced apoptotic death requires functional p53, which is not present in HeLa cells. For all other agents, HIV-LTR induction was dose-dependent and correlated with the amount of cell killing that occurred in the culture. Doses which caused over 99% cell killing induced HIV-LTR transcription maximally, demonstrating that cells that will go on to die by 14 days are the cells expressing HIV-LTR-CAT.
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PMID:HIV expression is induced in dying cells. 911 23

Highly conserved regions of the tumour suppressor gene p53, including the typical human tumour hot spots (codons 175, 245, 248, 249, 273 and 282), were investigated in various canine neoplasms. A mutation CGG-->TGG (arginine-->tryptophan) was detected in codon 249 in an adenoma of the circumanal gland.
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PMID:Canine tumour suppressor gene p53--mutation in a case of adenoma of circumanal glands. 923 81

Azelaic bishydroxamic acid (ABHA), a potent differentiating agent for lymphoid cells, was selectively toxic for 5 human tumor cell lines and transformed human melanocytes and keratinocytes (dose for 37% survival, D37, 30-100 microg/mL) compared with normal cells (melanocytes, fibroblasts; D37 > 300 microg/mL). Dendritic morphology was the only indicator found for increased differentiation, markers for the pigmentation pathway being unchanged or inhibited by ABHA. In contrast to hexamethylene bisacetamide and azelaic acid, ABHA significantly increased the HIV LTR, SV40 and c-fos promoter activities during a 24 hr treatment. Metallothionein promoter activity was enhanced by 5 hr treatment with ABHA in a sensitive melanoma cell line (MM96L) but was inhibited in a more resistant line (HeLa); c-fos promoter activity was inhibited in HeLa during this time. Transcription from a p53 binding response element was inhibited in MM96L by a 24 hr ABHA treatment but enhanced in HeLa. ABHA may represent a structural prototype for designing more potent and selective anti-melanoma agents.
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PMID:Tumor selectivity and transcriptional activation by azelaic bishydroxamic acid in human melanocytic cells. 926 25

Five cases of adenoid basal carcinoma (ABC) of the uterine cervix were examined for the presence of p53 tumor suppressor gene, K-ras-2 oncogene, and human papillomavirus (HPV). A topographic genotyping approach was used to search for point mutations in K-ras-2 (exon 1 and 2) and p53 (exons 5 to 8) in archival formalin-fixed tissue blocks. Minute target sites were selected from polymerase chain reaction (PCR) amplified and directly sequenced tissue sections. Tissue sections were additionally subjected to immunohistochemical staining for p53 and WAF-1 protein. Because wild type p53 induces WAF-1 gene expression, immunohistochemical staining for WAF-1 protein using monoclonal antibodies may serve as an indirect means to test for p53 mutational damage. Mutational genotype was compared to histopathologic features and immunohistochemical staining. To study the role of HPV, L1 region consensus primers were used to amplify topographic samples, followed by HPV genotyping by direct sequencing and comparison to known viral strains. ABC was found to contain HPV in all cases, proven by genotyping to be HPV type 16 in each case. The virus showed no evidence of genomic variation from prototype HPV type 16 in the L1 segment examined. No K-ras-2 point mutations were identified. p53 immunopositivity was present in all tumors, being weak and focal in 4 and strong and diffuse in 1. WAF-1 immunostaining was positive in two tumors showing weak focal p53 immunopositivity. The single strong and diffuse p53 immunopositive tumor was negative for WAF-1 and was shown to contain a missense p53 point mutation (exon 7-codon 248 tryptophan). In conclusion, ABC is characterized by the presence of HPV type 16. K-ras-2 point mutation appears to play no role in the development of this tumor. p53 gene alterations are common including wild type hyperexpression (weak focal p53 immunopositivity, WAF-1 positivity, no mutational change) and p53 point mutational damage.
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PMID:The origin and molecular characterization of adenoid basal carcinoma of the uterine cervix. 942 Oct 66


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