UNIPROT:P04637 - FACTA Search

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 tumour suppressor phosphoprotein associates with proteins involved in DNA replication, transcription, cell cycle machinery and regulation of its own expression. Recently it has been shown that p53 can also bind to trk A tyrosine kinase which is the receptor for nerve growth factor (NGF). This study demonstrates that p53 appears to associate with trk A via c-abl. Endogenous c-abl was detected when the trk A and p53 complex was immunoprecipitated from lysates of NGF stimulated NIH3T3 cells expressing trk A or NIH3T3 cells expressing trk A and a temperature sensitive p53 (val 135). Endogenous c-abl and trk A association was observed in NGF stimulated p53 negative fibroblasts transfected with trk A alone; suggesting that c-abl can independently bind to trk A in the absence of p53. Interestingly, association between endogenous p53 and trk A was not detected in NGF stimulated abl negative fibroblasts transfected with trk A or when these cells were exposed to gamma radiation. This result suggests that p53 preferentially binds to trk A in the presence of c-abl and that p53 and trk A do not appear to associate directly even if p53 is activated and its levels increased by gamma radiation. Overall, these data suggest that c-abl is possibly acting as an adaptor or bridge between p53 and trk A. Oncogene (2000).
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PMID:c-abl is involved in the association of p53 and trk A. 1087 55

Mutations in the p53 gene--which codifies anuclear phosphoprotein that acts as a tumor suppressor gene--is the most common genetic alteration in head and neck cancers. The aim of the present study was to investigate the prognostic significance of p53 protein over expression in squamous cell laryngeal carcinoma. To do so we analyzed 31 patients affected by precancerous lesions of the larynx who had undergone multiple biopsy between 1980 and 1995. Twenty-five of these patients later developed laryngeal carcinoma. In this group of patients, 51 biopsies were performed for precancerous lesions (17 hyperplasia, 3 light dysplasia, 23 moderate dysplasia, 8 severe dysplasia) prior to evidence of laryngeal cancer (2.04 biopsies/patient). In the group of patients who did not develop laryngeal cancer, 18 biopsy were performed (2.2 biopsies/patient) and histology revealed: 5 keratosis, 5 light dysplasia, 4 moderate dysplasia and 4 grave dysplasia. Using the immunohistopathological staining technique, 69 formalin-fixed, paraffin-embedded precancerous samples and 25 laryngeal carcinomas were examined for p53 over expression. The monoclonal antibody Pab 1801 was used with the avidinbiotin immunoperoxidase technique; p53 intensity of expression was assessed and correlated with clinical-pathological parameters. Over expression of the p53 protein was found in 56.8% of the precancerous lesions (41% of the hyperplastic lesions, 66% of light dysplastic lesions, 60% of moderate dysplastic lesions and 75% of severe dysplastic lesions) in the group patients who did develop laryngeal cancer and in 22.2% of the precancerous lesions in the group of patients that did not. The transformed lesions showed a strong correlation between intensity of positivity and grade of cellular atypia. Further in 93.3% of the patients with p53 positive precancerous lesions which later developed into laryngeal cancer, p53 over expression was present in the cancerous lesions. There was no significant correlation between p53 immuno reactivity and such clinico pathological tumor parameters as TNM staging and tumorrecurrence. On the other hand, there was a correlation between p53 overexpression and differentiation grading: p53 overexpression was found in 75% of the poorly differentiated tumors, 58.3% of moderately differentiated and 44.4% of well differentiated tumors. The fact that p53 is detected in preneoplastic lesions suggests that p53 gene alteration takes place very early in laryngeal carcinoma and moderate-to-high p53 expression constitutes a high risk of transformation into cancer; on the other hand low expression may reflect reversible changes that can be attributed to the genotoxic effects of tobacco smoking. In conclusion the present data suggest that p53 over expression could be a good prognostic marker in predicting which precancerous laryngeal lesions will progress into cancer.
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PMID:[The role of p53 tumor suppressor gene as prognostic factor in laryngeal squamous cell carcinoma]. 1087 57

Human T-cell lymphotropic virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). T-cell transformation is mainly due to the actions of the viral phosphoprotein Tax. Tax interacts with multiple transcriptional factors, aiding the transcription of many cellular genes. Here, we report that the cyclin-dependent kinase inhibitor p21/waf1 is overexpressed in all HTLV-1-infected cell lines tested as well as in ATL and HAM/TSP patient samples. Tax was found to be able to transactivate the endogenous p21/waf1 promoter, as detected by RNase protection, as well as activate a series of wild-type and 5'-deletion constructs linked to a luciferase reporter cassette. Wild-type but not a mutant form of Tax (M47) transactivated the p21/waf1 promoter in a p53-independent manner and utilized a minimal promoter that contained E2A and TATA box sequences. The p21/waf1 protein was reproducibly observed to be complexed with cyclin A/cdk2 and not with any other known G(1), S, or G(2)/M cyclins. Functionally, the association of p21/cyclin A/cdk2 decreased histone H1 phosphorylation in vitro, as observed in immunoprecipitations followed by kinase assays, and affected other substrates, such as the C terminus of Rb protein involved in c-Abl and histone deacetylase-1 (HDAC1) regulation. Interestingly, upon the use of a stress signal, such as gamma-irradiation, we found that the p21/cyclin A/cdk2 complex was able to block all known phosphorylation sites on the Rb molecule. Finally, using elutriated cell cycle fractions and a stress signal, we observed that the HTLV-1-infected T cells containing wild-type Tax, which had been in early or mid-G(1) phase prior to gamma-irradiation, arrested in G(1) and did not undergo apoptosis. This may be an important mechanism for an oncogenic virus such as HTLV-1 to stop the host at the G(1)/S boundary and to repair the damaged DNA upon injury, prior to S-phase entry.
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PMID:Overexpression of p21(waf1) in human T-cell lymphotropic virus type 1-infected cells and its association with cyclin A/cdk2. 1090 81

The tumor suppressor p53 is a phosphoprotein barely detectable in the nucleus of normal cells. Upon cellular stress, particularly that induced by DNA damage, p53 can arrest cell cycle progression, thus allowing the DNA to be repaired; or it can lead to apoptosis. These functions are achieved, in part, by the transactivational properties of p53, which activate a series of genes involved in cell cycle regulation. In cancer cells bearing a mutant p53, this protein is no longer able to control cell proliferation, resulting in inefficient DNA repair and the emergence of genetically unstable cells. The most common changes of p53 in human cancers are point missense mutations within the coding sequences of the gene. Such mutations are found in all major histogenetic groups, including cancers of the colon (60%), stomach (60%), breast (20%), lung (70%), brain (40%), and esophagus (60%). It is estimated that p53 mutations are the most frequent genetic event in human cancers, accounting for more than 50% of cases. One of the most striking features of the inactive mutant p53 protein is its increased stability (half-life of several hours, compared to 20 min for wild-type p53) and its accumulation in the nucleus of neoplastic cells. Therefore, positive immunostaining is indicative of abnormalities of the p53 gene and its product. Several studies have shown that p53 mutations are associated with short survival in colorectal cancer, but the use of p53 as a tumoral marker is still a matter of debate.
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PMID:The p53 tumor suppressor gene: from molecular biology to clinical investigation. 1091 10

The adenovirus E1B-55K protein is a multifunctional phosphoprotein that regulates nuclear to cytoplasmic export of host cell and viral mRNAs during lytic viral growth. E1B-55K also blocks apoptosis by binding and functionally inactivating the human tumor suppressor protein p53. Here, we show that E1B-55K interacts with histone deacetylase 1 (HDAC1) and the transcriptional corepressor protein mSin3A, both in the adenovirus-transformed 293 cell line and during a lytic adenovirus infection. Furthermore, we show that the central amino acids 156-261 in E1B-55K are necessary for efficient HDAC1 interaction. Importantly, the E1B-55K/mSin3A/HDAC1 complex is also enzymatically active, catalyzing deacetylation of a histone substrate peptide. Collectively, our results suggest that E1B-55K interaction with mSin3A/HDAC1 containing complexes may be significant for one or several of the multiple activities ascribed to this protein.
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PMID:The adenovirus-2 E1B-55K protein interacts with a mSin3A/histone deacetylase 1 complex. 1091 22

The p53 phosphoprotein acts as a tumor-suppressor gene product through the inhibition of cell growth and induction of apoptosis in a transcription-dependent manner. These functions require p53 activation through different biochemical postranslational modifications. Given the relevance of this protein in ultraviolet light-induced carcinogenesis, whose targets are primarily skin keratinocytes, we studied the functions of p53 in epidermal cell differentiation. We selected HaCaT cells, a human keratinocyte cell line bearing point-mutated, transcriptionally inactive, but highly stable p53, which facilitates immunochemical and biochemical analysis. In addition, a reliable in vitro differentiation system has been developed with these cells (Paramio et al. Oncogene 17:949, 1998). We report that during HaCaT differentiation there is a loss of immunoreactivity of p53 against antibodies that specifically recognize epitopes located at the carboxyl terminus of the protein. Because treatment with phosphatase restores this immunoreactivity, we conclude that p53 is phosphorylated at the carboxyl terminus during keratinocyte differentiation. This biochemical modification has been associated with the transcriptional activation of the molecule, and because p53 is involved in differentiation processes in other cell types, we investigated the potential functions of p53 during epidermal differentiation. To this end, we generated HaCaT clones expressing a murine temperature-sensitive p53 (Mp53ts) by transfection because the endogenous p53 is not functional even with phosphorylation. We characterized the expression and effects of the transfected protein in different selected clones. The ultraviolet-light response of these clones was restored, demonstrating the functionality of Mp53ts in these cells. We also observed that, with induction of differentiation, Mp53ts transfected cells differentiate faster than the parental or vector-transfected control cells, demonstrating that p53 promotes epidermal differentiation. The sustained expression of p53 in differentiating cells leads to massive cell death and detachment, a phenomenon that may be similar to epidermal terminal differentiation. In addition, we observed that the expression of p53-dependent genes such as p21waf/cip1 and mdm2 (which are known to participate in epidermal differentiation) increases during HaCaT differentiation, i.e., in a p53-independent manner.
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PMID:p53 is phosphorylated at the carboxyl terminus and promotes the differentiation of human HaCaT keratinocytes. 1117 Feb 63

Hepatitis C virus nonstructural protein, NS5A, is a phosphoprotein produced from the processing of the viral polyprotein precursor. NS5A associates with several cellular proteins in mammalian cells, and the biological consequences of this interaction are currently unknown. To this end, five stable NS5A-expressing murine and human cell lines were established. Tetracycline-regulated NIH3T3 cells and rat liver epithelial cells as well as the constitutive, NS5A-expressing, human Chang liver, HeLa, and NIH3T3 cells all exhibited cell growth retardation compared with the control cells. Cell cycle analysis by flow cytometry indicated that the NS5A-expressing human epitheloid tumor cells had a reduced S phase and an increase in the G(2)/M phase, which could be explained by a p53-dependent induction of p21(Waf1/Cip1) protein and mRNA levels. NS5A interacts with Cdk1 in vivo and in vitro, and a significant portion of the p21(Waf1/Cip1) was found to be in a complex with Cdk2 in the NS5A-expressing human hepatic cell line. Cdk1 and cyclin B1 proteins were also reduced in human Chang liver cells consistent with the increase in G(2)/M phase. Our results suggest that the NS5A protein causes growth inhibition and cell cycle perturbations by targeting the Cdk1/2-cyclin complexes.
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PMID:Modulation of cell growth by the hepatitis C virus nonstructural protein NS5A. 1127 2

Utilizing the experimental model in Syrian golden hamsters, we explored the role of immunization in carcinogenesis. The animals, which were infected with liver flukes (Opisthorchis viverrini), and administered a subcarcinogenic dose of dimethylnitrosamine, developed cancer. Pre-immunizing with a crude somatic antigen did not reduce cancer development, but accelerated carcinogenesis. Histopathological analysis of the cancer tissues was done once at week 30 and again at week 39 using H and E staining, immunostaining for the p53 tumor suppressor phosphoprotein, and electron microscopy. Thirty weeks after immunization, the immunized hamsters developed tubular adenocarcinoma at a higher rate (71.43%) than the non-immunized group (20.00%). This rate (20.00%) increased to 63.64% by week 39. The small foci cancer in the non-immunized group decreased in frequency from 80.00% (at week 30) to 36.36% (by week 39), suggesting the small foci cancer progressed to tubular adenocarcinoma during the 9-week interval. Most of the observed tubular adenocarcinoma was well differentiated. Nearly all hamsters that tested positive for cancer also tested positive for p53 immunostaining in the epithelia of the small bile ducts. The positive reaction for p53-immunostaining was localized in the rough endoplasmic reticulum, Golgi apparatus and perinuclear membranes. The electron micrographs of these positive p53-immunostained cells showed characteristics of early cancer. The detection of p53 in early cancer development makes it a candidate as a tumor marker.
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PMID:Ultrastructural and immunohistochemical analysis of cholangiocarcinoma in immunized Syrian golden hamsters infected with Opisthorchis viverrini and administered with dimethylnitrosamine. 1142 79

p53 is a tumor suppressor gene and mutation of p53 is a frequent event in skin cancer. The wild-type p53 encodes for a 53-kD phosphoprotein that plays a pivotal role in regulating cell growth and cell death. The wt-p53 gene is also called "guardian of the genome", for its role in preventing the accumulation of genetic alterations, observed in cancer cells. The wild-type p53 protein plays a central role in the response of the cell to DNA damage. UV, present in sunlight, is one of the most ubiquitously present DNA damage inducing stress conditions to which skin cells are exposed. The wt-p53 protein accumulates in human skin cells in vitro and in human skin in vivo upon UV irradiation. This upregulation mounts a protective response against permanent DNA damage through transactivation of either cell cycle arrest genes and DNA repair genes or genes that mediate the apoptotic response. The molecular events which regulate the activity of the wt-p53 protein activity are only beginning to be described.
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PMID:Acute response of human skin to solar radiation: regulation and function of the p53 protein. 1168 54

The tumor suppressor protein p53 is a phosphoprotein which shows growth and transformation suppression functions. Mutational loss of p53 function is the most frequently detected genetic event in human cancers. We examined whether 9-hydroxyellipticine (9HE), a cytotoxic agent, affected the tertiary structure of mutant p53 and DNA binding characteristics. Although several types of p53 mutants were resistant to degradation by calpain, the p53 mutants treated with 9HE were markedly sensitive to calpain as well as wild-type p53. Furthermore, mutant p53 proteins isolated from 9HE-treated cells regained the ability to bind a wild-type-specific p53 DNA consensus sequence. Wild-type p53 proteins prepared from both untreated and 9HE-treated cells bound the p53 consensus sequence and were degradaded by calpain equally well. These results suggest that 9HE affects the tertiary structure of mutated p53, which results in the restoration of DNA binding characteristics.
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PMID:9-Hydroxyellipticine alters the conformation and DNA binding characteristics of mutated p53 protein. 1172 37

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