Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p51 gene encodes a protein with significant homology to p53. To investigate the involvement of the p51 gene in human hepatocarcinogenesis, mutation analysis of the p51 gene was performed in 54 cases of hepatocellular carcinoma (HCC). No mutations causing amino acid substitutions or frameshifts were found by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis of the entire coding region. The result indicated that mutation of the p51 gene does not play a major role in the development of HCC in Japanese patients. Further studies on p51 expression and its functions, including the interaction with p53, are necessary to elucidate the role of the p51 gene in human hepatocarcinogenesis.
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PMID:Absence of p51 mutation in human hepatocellular carcinoma. 1069 92

We have previously demonstrated that the human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein represses the trans-activation function of p53 tumor suppressor protein. Recently, several proteins with sequence homology to p53 have been identified. In this study, we demonstrated that Tax represses the trans-activation functions of p73alpha, p73beta, and p51A, the p53-related proteins, as well as p53. Moreover, a mutant Tax of coactivator CBP-binding site (K88A), which activated NF-kappaB but not CREB pathway, could not repress the p73 nor p51 trans-activation functions, indicating that CBP-binding domain of Tax is essential for the suppression of their functions. Using proteins of Gal4-fused N-terminal region of p73 and p51, we showed that Tax-mediated inactivation of p73 or p51 requires for their N-terminal trans-activation domains. Furthermore, only the putative N-terminal trans-activation domains of them did not have enough transcriptional activities and their adjacent regions are essential for their full trans-activation, suggesting the existence of their second trans-activation subdomains. Thus, HTLV-1 Tax inactivated the p53-related proteins through their N-terminal trans-activation domains.
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PMID:Functional impairment of p73 and p51, the p53-related proteins, by the human T-cell leukemia virus type 1 Tax oncoprotein. 1069 1

The WT1 gene, which is heterozygously mutated or deleted in congenital anomaly syndromes and homozygously mutated in about 15% of all Wilms tumors, encodes tissue-specific developmental regulators. Through alternative mRNA splicing, four main WT1 protein isoforms are synthesized. All isoforms can bind to DNA via their zinc fingers, albeit with different affinities and specificities, and thereby modulate the transcriptional activity of their target genes. Several proteins bind to and alter the transcription regulatory properties of the WT1 proteins, including the product of the tumor suppressor gene p53. Interaction between WT1 and p53 was shown to modulate their ability to regulate the transcription of their respective target genes. Here, we report that all four isoforms of WT1 bind to p73, a recently cloned homologue of p53. p73 binds to the zinc finger region of WT1 and thereby inhibits DNA binding and transcription activation by WT1. Similarly, WT1 inhibits p73-induced transcription activation in reporter assays and counteracts p73-induced expression of endogenous Mdm2. This, taken together with our finding that WT1 also interacts with p63/KET, another p53 homologue, suggests that association between WT1 and the members of the p53 family of proteins may be an important determinant of their functions in cell growth and differentiation.
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PMID:Physical interaction between Wilms tumor 1 and p73 proteins modulates their functions. 1074 5

Two p53-related genes, p73 and p51, were recently identified as structural homologues of the p53 tumor suppressor gene, suggesting that the roles of these two genes may be similar to those of p53, including growth suppression and induction of apoptosis. Here we show that introduction of p73 or p51 cDNAs into cultured human cancer cells suppressed colony formation in the presence of G418. We then examined the ability of various isoforms of p73 and p51 to activate transcription of a reporter gene. This assay showed that p73beta and p51A activated transcription through a consensus p53 binding sequence, while p73alpha and p51B isoforms minimally transactivated the p53 reporter gene. To characterize further the biological functions of the p53-related genes, we constructed recombinant adenoviruses containing the p73 and p51 cDNAs. Ad-p73beta and Ad-p51A induced endogenous p21 gene expression more effectively than Ad-p73alpha and Ad-p51B, respectively. To evaluate the mode of cell death induced by p53-related genes, Ad-p73 and Ad-p51 were used to infect human cancer cells. Infection of Ad-p73beta, Ad-p51A or Ad-p51B resulted in DNA fragmentation in a subset of cancer cell lines more efficiently than did infection of Ad-p53. We then examined the combined effect of each p53-related gene and the E1A oncogene in the induction of apoptosis. The E1A oncogene cooperated with p51 as well as p53 to induce apoptosis, while p73 resulted in a weak induction of apoptosis by E1A. Overall, apoptosis induction by p51B and p73alpha isoforms may be due to mechanisms other than transcriptional activation of p53-target genes. Our results suggest that p53-related genes are both similar to and different from p53 in their pathways leading to growth suppression.
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PMID:Adenovirus-mediated transfer of p53-related genes induces apoptosis of human cancer cells. 1076 4

We have identified a new human p53 homologue, p40 (p51/p63). This gene was mapped to the distal arm of 3q and was found to be essential for normal epithelial development. We used microsatellite and FISH analyses to search for genetic alterations of p40 in primary HNSCC. A more precise localization of p40 was completed using 6 known markers on 3q and a newly isolated microsatellite marker within the p40 gene. We also determined the genomic organization of the p40 gene using human YAC and BAC clones. Microsatellite analysis revealed that 14 of 26 (54%) primary HNSCC had allelic imbalance in at least 1 of the 7 microsatellite loci. However, FISH analysis with a p40 probe showed that a majority of HNSCC had an increased copy number of the locus regardless of allelic status. Thus, overrepresentation of the p40 locus may play an important role in the development of HNSCC.
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PMID:Frequent gain of the p40/p51/p63 gene locus in primary head and neck squamous cell carcinoma. 1079 91

We and others recently isolated a human p53 homologue (p40/p51/p63/p73L) and localized the gene to the distal long arm of chromosome 3. Here we sought to examine the role of p40/p73L, two variants lacking the N-terminal transactivation domain, in cancer. Fluorescent in situ hybridization (FISH) analysis revealed frequent amplification of this gene locus in primary squamous cell carcinoma of the lung and head and neck cancer cell lines. (We named this locus AIS for amplified in squamous cell carcinoma.) Furthermore, amplification of the AIS locus was accompanied by RNA and protein overexpression of a variant p68(AIS) lacking the terminal transactivation domain. Protein overexpression in primary lung tumors was limited to squamous cell carcinoma and tumors known to harbor a high frequency of p53 mutations. Overexpression of p40(AIS) in Rat 1a cells led to an increase in soft agar growth and tumor size in mice. Our results support the idea that AIS plays an oncogenic role in human cancer.
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PMID:AIS is an oncogene amplified in squamous cell carcinoma. 1080 2

p51A, or TAp63gamma, a translation product of gene p51, or p63, was identified as a homolog of p53 in its primary structure and transactivating function. p53 plays a decision-making role in inducing either cell cycle arrest or apoptosis in response to DNA damage, and thereby preserves genome integrity of living cells. To compare the biological activities between p51A and p53, cell lines with low-level, constitutive expression of each protein were obtained by cDNA transfection of mouse erythroleukemic cells. Production of p51A with an apparent molecular mass of 57-kilodalton (kD) accompanied induction of p21waf1 and appearance of hemoglobin-producing cells. After DNA-damaging treatment either with ultraviolet light (UV) irradiation or with actinomycin D, the p51A protein accumulated in time courses corresponding to those of wild-type p53, and caused an increase in the hemoglobin-positive cell count. In contrast, p53-accumulated cells underwent apoptosis without exhibiting the feature of erythroid differentiation. The mode of p21waf1 and Bax-alpha upregulations varied between p51A- and p53-expressing cells and between the types of DNA damage. These results suggest the possibility that p51A induces differentiation under genotoxic circumstances. There may be cellular factors that control p51A protein stability and transactivating ability.
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PMID:p51A (TAp63gamma), a p53 homolog, accumulates in response to DNA damage for cell regulation. 1087 67

A newly identified gene, p51, is a functional and structural homologue of the p53 gene and thus a Candidate tumor suppressor gene. To elucidate the role of the p51 gene in lung carcinogenesis, we determined the sequences of exon-intron boundaries and the 5'- and 3'-flanking regions of all the 15 coding exons and performed a mutation analysis, as well as detailed analysis for gene expression. A frameshift mutation was detected in 1 of 44 lung cancer cell lines, whereas no mutation was detected in 45 primary lung cancers. Thus, p51 mutation occurs only in a small subset of lung cancer. Expression of the p51 gene was detected in 23 of 43 cell lines by Northern blot analysis and 34 of 44 by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Thus, p51 expression is low or absent in a subset of lung cancer. The deltaN isotype of p51 transcripts was dominantly expressed in several cell lines, particularly in cell lines with high levels of p51 expression. Because the deltaN isotype encodes a protein that transdominantly suppresses the transactivation function of the TA type of p51, it is possible that p51 protein is not functionally active, even in lung cancer cells with p51 mRNA expression, due to expression of dominant-negative p51 protein. These results suggested that the p51 gene is inactive in a considerable proportion of lung cancers. RT-PCR analysis also revealed the presence of a novel type of mRNA transcript, p51delta, which lacks exons 12 and 13 by alternative splicing. The delta isotype was expressed in 18 of 44 lung cancer cell lines and in diverse normal tissues. Further analysis on p51 expression in cancerous as well as noncancerous cells will provide us with valuable information for the understanding of multiple functions of the p53 family proteins in human carcinogenesis.
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PMID:Mutation and expression of the p51 gene in human lung cancer. 1093 72

Studies of immune recognition in cancer have defined several tumor antigens using autologous cytotoxic T lymphocytes and by detection of serum antibodies to tumor-associated products such as p53 and HER-2/neu. The AIS gene is a p53 homologue with multiple protein products (p40, p51, p63, p73L) on chromosomal arm 3q, frequently amplified and over-expressed in squamous-cell carcinoma of the respiratory tract. We analyzed the humoral response to p40(AIS) (a core domain of AIS products without the transactivation domain) by Western blot and ELISA using bacterially synthesized p40(AIS) protein. Antibodies were detected in the sera of 17/94 (18%) HNSCCs and 13/76 (17%) lung cancers, including 5/18 (26%) squamous-cell carcinomas. Anti-p40(AIS) antibodies were not associated with factors such as sex, age, histopathological grading, extent or size of primary tumor, lymph node involvement and staging. Our results indicate that amplification and over-expression of p40(AIS) may lead to antigen recognition by an autologous host with cancer. AIS may thus represent a new group of developmentally regulated genes that are recognized as tumor antigens.
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PMID:Circulating antibodies to p40(AIS) in the sera of respiratory tract cancer patients. 1110 98

A human p53 homologue, p63 (p40/p51/p73L/CUSP) that maps to the chromosomal region 3q27-29 was found to produce a variety of transcripts that encode DNA-binding proteins with and without a trans-activation domain (TA- or Delta N-, respectively). The p63 gene locus was found to be amplified in squamous cell carcinoma, and overexpression of Delta Np63 (p40) led to increased growth of transformed cells in vitro and in vivo. Moreover, p63-null mice displayed abnormal epithelial development and germ-line human mutations were found to cause ectodermal dysplasia. We now demonstrate that certain p63 isotypes form complexes with p53. p53 mutations R175H or R248W abolish the association of p53 with p63, whereas V143A or R273H has no effect. Deletion studies suggest that the DNA-binding domains of both p53 and p63 mediate the association. Overexpression of wild type but not mutant (R175H) p53 results in the caspase-dependent degradation of certain Delta Np63 proteins (p40 and Delta Np63 alpha). The association between p53 and Delta Np63 supports a previously unrecognized role for p53 in regulation of Delta Np63 stability. The ability of p53 to mediate Delta Np63 degradation may balance the capacity of Delta Np63 to accelerate tumorigenesis or to induce epithelial proliferation.
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PMID:p53 associates with and targets Delta Np63 into a protein degradation pathway. 1117 34


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