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)

Defects in cellular differentiation are a common occurrence in human cancers. The combination of recombinant human fibroblast interferon (IFN-beta) and the antileukemic compound mezerein (MEZ) results in an irreversible loss of proliferative capacity and terminal cell differentiation in H0-1 human melanoma cells. In contrast, either agent alone induces reversible growth arrest and/or specific components of the differentiation process without inducing terminal differentiation. The current study investigates changes in cell cycle, cell cycle gene expression and E2F transcription factor complex formation during the processes of reversible and irreversible (terminal) differentiation. Induction of both terminal differentiation and reversible differentiation (MEZ treatment) results in a temporal decrease in DNA synthesis and the percentage of cells in S phase and a decrease in the expression of cell cycle and growth regulated genes, including cdc2, cyclin A, cyclin B, histone H1, histone H4, nm23-H1, p53 and c-myc. Persistent gene expression changes occur in terminally differentiated cells, but not in reversibly differentiated cells. H0-1 cells contain several E2F binding activities, including uncomplexed E2F, an E2F-p107-cyclin A-cdk2 kinase complex and an Rb-E2F complex. Induction of growth arrest by MEZ results in a slow migrating gelshift band that contains E2F associated with the pRb2/p130 protein. There is also a loss of the Rb-E2F complex. Induction of terminal differentiation after treatment with IFN-beta + MEZ generates a second pRb2/p130-E2F complex that migrates considerably faster than the pRb2/p130-E2F complex resulting from growth arrest. The slower migrating complex may contribute to growth arrest, whereas the faster migrating complex may play a role in terminal differentiation. Our results demonstrate that terminal cell differentiation involves a co-ordinate and continuous suppression of a number of cell cycle and growth related genes and results in the development of a novel E2F transcription factor complex not apparent in growth arrested and reversibly differentiated human melanoma cells.
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PMID:Cell cycle gene expression and E2F transcription factor complexes in human melanoma cells induced to terminally differentiate. 756 79

The oncoprotein of simian virus-40, SV40 large T-antigen (Tag), is reported to target and to inactivate growth suppressive proteins such as the retinoblastoma family and p53 (ref. 4, 5), leading to transformation of human cell lines in vitro, tumor production in rodents, and detection of Tag in several human cancers including mesotheliomas. The retinoblastoma family contains three members, pRb, p107 and pRb2/p130 (ref. 9), that are phosphorylated in a cell cycle-dependent manner, have cell growth suppressive properties and bind to specific members of the E2F family and various cyclins. Even though mesotheliomas are among the most aggressive human cancers, alterations of important cell-cycle "controllers," such as the Rb family genes, have never been reported in these tumors. We found the presence of SV40-like sequences in 86% of 35 archival specimens of mesothelioma. We also demonstrated that SV40 Tag, isolated from frozen biopsies of human mesothelioma, binds each of the retinoblastoma family proteins, pRb, p107 and pRb2/p130, in four of four specimens. We propose that the tumorigenic potential of SV40 Tag in some human mesotheliomas may arise from its ability to interact with and thereby inactivate several tumor and/or growth suppressive proteins.
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PMID:The retinoblastoma gene family pRb/p105, p107, pRb2/p130 and simian virus-40 large T-antigen in human mesotheliomas. 925 72

The conserved region 1 and the extreme N-terminus of adenoviral oncoprotein E1A are essential for transforming activity. They also play roles in the interaction of E1A with p300/CBP and pRb and are involved in both transactivation and repression of host gene expression. It was reported recently that p53-mediated transactivation is specifically repressed by E1A and that p53-induced apoptosis can be protected by pRb. In this report, we investigated the roles of pRb and p300 in the N-terminus of E1A-mediated transcriptional regulation. We demonstrate here that p300 and pRb have no effect on DBD.1-70 transactivation and that overexpression of p300 or pRb failed to relieve the repression by E1A. Repression of p53 transactivation requires both the extreme amino terminus and CR1 but not CR2. This repressive activity of E1A specifically correlates with E1A's ability to bind p300 and TBP. On the other hand, E1A inhibited the transactivation activity of a fusion construct containing the DNA binding domain of yeast Gal4 and the transactivation domain of p53. When p53 was contransfected with E1A, similar inhibition was found in Saos-2 cells that lack endogenous pRb and p53 activity. Introduction of pRb into Saos-2 cells did not affect p53 transcription activity. E1A-mediated repression can be relieved be overexpression of either p300, hTBP, or-TFIIB but cannot be released by overexpression of pocket proteins. Our data suggest that p300/CBP and TBP but not the pocket proteins, pRb, p107, and pRb2/p130 are functional targets of E1A in transcriptional regulation and that p53 transactivation requires the function of the p300/TBP/TFIIB complex, thus delineating a new pathway by which E1A may exert its transforming activity.
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PMID:Roles of p300, pocket proteins, and hTBP in E1A-mediated transcriptional regulation and inhibition of p53 transactivation activity. 925 85

The oncoprotein of the Simian virus 40, SV40 large T-antigen (Tag), is reported to target and inactivate growth-suppressive proteins such as the retinoblastoma (Rb) family and p53 leading to transformation of human cell lines in vitro, to produce tumours in rodents, and to be detected in several human cancers including mesothelioma. In support of the potential role of SV40 Tag in the pathogenesis of certain human cancers, we have found SV40-like sequences in 8/25 bioptic specimens of mesothelioma from patients with exposure to asbestos fibres. We have also demonstrated that the SV40 Tag detected in human mesothelioma binds the retinoblastoma family protein pRb2/p130 in 5/5 specimens studied. We submit that the tumorigenic potential of SV40 Tag in some human mesotheliomas may arise from its ability to interact with and thereby inactivate several tumour and/or growth suppressive proteins in cooperation with asbestos fibres in inducing pleural mesothelioma.
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PMID:Simian virus 40-like DNA sequences and large-T antigen-retinoblastoma family protein pRb2/p130 interaction in human mesothelioma. 977 25

We evaluated 55 samples of choroidal melanoma managed by enucleation. Knowing that the immunohistochemical expression of the retinoblastoma gene family members Rb/p105, p107, and pRb2/p130 was inversely correlated with the degree of malignancy in at least some histological types, we investigated the expression of these three proteins in choroidal melanoma. We focused on the relationship between patient survival and the immunohistochemical detection of the retinoblastoma proteins. No correlation with clinical outcome was found for Rb/p105 and p107. However, we found pRb2/p130 to be an independent prognostic factor correlating positively or directly with patient survival times and indirectly or inversely with the degree of malignancy. Demonstration of the prognostic value of the immunohistochemical expression of pRb2/p130 is of significance, even if additional studies are required to confirm these data and to compare the prognostic value of pRb2/p130 immunodetection to that of other recently proposed markers, such as p53.
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PMID:Differential expression of the retinoblastoma gene family members in choroidal melanoma: prognostic significance. 1038 32

Nasopharyngeal carcinoma (NPC) is an endemic cancer in southern China and northern Africa, and its pathogenesis is not yet well defined at the molecular level. Although the involvement of p53 and of the retinoblastoma gene (RB/p105) in NPC has been well studied, there is paucity of mutational data regarding the retinoblastoma-related gene RB2/p130 in primary tumors and particularly in NPC. We have shown previously that RB2/p130 could be rearranged in a nasopharyngeal cell line. In the present study, we screened by single-strand conformation polymorphism and sequence analysis the retinoblastoma-related gene RB2/p130 for mutations within exons 19-22. Mutations in the RB2/p130 gene were detected in 3 of 10 primary human NPCs from Northern Africa (30%). These findings, along with previous data showing that genetic replacement of RB2/p130 restores a normal growth pathway in the nasopharyngeal cell line Hone-1, strengthen the hypothesis that genetic changes of RB2/p130 may be involved in the development and/or progression of nasopharyngeal cancer and suggest that RB2/p130 could be considered a tumor suppressor gene and may be a candidate for novel gene therapeutic approaches for NPC.
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PMID:Mutations in the retinoblastoma-related gene RB2/p130 in primary nasopharyngeal carcinoma. 1147 39

Angiogenesis is an essential step in the progression of tumor formation and development. The switch to an angiogenetic phenotype can occur as a distinct step before progression to a neoplastic phenotype and is linked to genetic changes such as mutations in key cell cycle regulatory genes. The pathogenesis of the angiogenetic phenotype may involve the inactivation of tumor suppressor genes such as the "guardian of the genome," p53, and the cyclin-dependent kinase inhibitor p16. Retinoblastoma family member RB2/p130 encodes a cell cycle regulatory protein and has been found mutated in different tumor types. Overexpression of RB2/p130 not only suppresses tumor formation in nude mice but also causes regression of established tumor grafts, suggesting that RB2/p130 may modulate the angiogenetic balance. We found that induction of RB2/p130 expression using a tetracycline-regulated gene expression system as well as retroviral and adenoviral-mediated gene delivery inhibited angiogenesis in vivo. This correlated with pRb2/p130-mediated down-regulation of vascular endothelial growth factor protein expression both in vitro and in vivo.
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PMID:RB2/p130 gene-enhanced expression down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in vivo. 1121 32

There are many data on the activity of the RB gene in neural differentiation and apoptosis, but the role of pRb2/p130 in neuronal and glial maturation has been far less investigated. To elucidate the role of pRb2/p130 in astrocyte development we overexpressed this protein in astrocytoma and normal astrocyte cultures by adenoviral-mediated gene transfer. In astrocytoma cells, p130/RB2 overexpression resulted in a significant reduction of cell growth and in an increased G(0)/G(1) cell population. We did not observe any induction of programmed cell death as determined by TUNEL reaction. Interestingly, pRb2/p130 overexpression induced astrocyte differentiation. Astrocyte cell cycle arrest and differentiation seemed to proceed through a way distinct from the p53 pathway.
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PMID:pRb2/p130 gene overexpression induces astrocyte differentiation. 1127 39

We previously reported that pRb2/p130 gene, one of the Rb family members, was immunohistochemically abundantly expressed in well-differentiated oral squamous cell carcinomas, whereas in undifferentiated ones the expression was low. Oral malignant melanoma is extremely rare, however the prognosis is poor because it tends to locally invade tissue or metastasize and its biological behavior appears to be different from cutaneous malignant melanoma. The present study dealt with the expression of pRb2/p130, Rb, p53, and p16 in 13 cases of malignant melanoma of oral mucosa as revealed by immunohistochemical staining. The stage classification of the 13 patients was as follows; stage II: eight patients, stage III: three patients, and stage IV: two patients. pRb2/p130 was expressed in only two stage II-cases, neither of which have shown any evidence of recurrence or metastasis for over 14 years. Positive staining for Rb was found in three cases consisting of one stage II-case, one stage III-case, and one stage IV-case. p53 was expressed in two cases, one a stage II and the other a stage IV. Positive staining for p16 was found in seven cases consisting of four stage II-cases, two stage III-cases, and one stage IV-case. pRb2/p130 may be inversely correlated with the malignancy of oral malignant melanoma, but further study is needed.
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PMID:Expression of Rb, pRb2/p130, p53, and p16 proteins in malignant melanoma of oral mucosa. 1128 87

We examined cell cycle-related effects of the phosphatase inhibitor okadaic acid (OA) in T51B rat liver epithelial cells under conditions chosen to mimic early stages of tumor promotion by this compound. Optimal transformation (colony formation in soft agar) was seen after prolonged culture of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-initiated T51B cells in 7 nM OA. Paradoxically, T51B cells treated with 2-10 nM OA showed decreased, rather than increased, proliferation in response to epidermal growth factor (EGF), as measured by [3H]thymidine incorporation. Complete inhibition was observed within 24 h at 10 nM OA. This response paralleled a loss of EGF-stimulated cdk2 kinase activity and an increase in association of the inhibitors p21 (cip-1) and p27 (kip-1) with cdk2. An increase in p53 phosphorylated on serine 15 accompanied the rise in p21 (cip-1). Both phosphorylation of the retinoblastoma protein and induction of cyclin A by EGF were blocked in cells treated with OA, but there was an increase in cyclin E. Resting cells treated with OA alone also showed elevated cyclin E levels, together with reduced levels of the E2F regulator pRb2/p130. Taken together, these observations indicate transforming levels of okadaic acid elicit a G(1)-trapping effect by facilitating cell cycle progression to the G(1)/S checkpoint, where cells are trapped by mechanisms that include p21 (cip-1)-mediated inhibition of cdk2. They support the premise that disruption of cellular processes regulating the transitions from G(0) to G(1) to S-phase is an important early step in tumor promotion by low levels of okadaic acid.
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PMID:Abbreviated cell cycle progression induced by the serine/threonine protein phosphatase inhibitor okadaic acid at concentrations that promote neoplastic transformation. 1147 Jul 44


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