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)

To study the mechanism by which SV40 large T antigen transforms cells under physiological conditions, we analysed several mutant forms of T antigen for their ability to induce cell proliferation and tumorigenesis in transgenic mice. These mutant proteins, which differ in their ability to form complexes with the tumor suppressors pRB and p53, were analysed under conditions in which wild-type T antigen induces choroid plexus papillomas as a result of uniform proliferation of the entire choroid plexus epithelium. The results presented here show that binding of T antigen to p53 is not required for induction of choroid plexus tumors. However, tumorigenesis does appear to require the binding of T antigen to pRB/p107. An additional activity, resident in the amino-terminal one-fifth of the protein, may also play a role. These experiments indicate the importance of whole-animal assays in determining the molecular basis of transformation, since each of these mutants possessed similar transformation phenotypes in culture but showed distinct phenotypes in the choroid plexus of the animal.
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PMID:T-antigen mutant activities in vivo: roles of p53 and pRB binding in tumorigenesis of the choroid plexus. 131 42

Inactivation of two tumor suppressor genes, RB and p53, is associated with tumor formation. To elucidate the molecular basis of the tumorigenesis of human osteosarcoma, structural and expressional alterations of these two genes were examined in five human osteosarcoma cell lines, two of which were from Japanese patients. In addition, I analyzed two adenovirus E1A-binding proteins, p107 and p300, putative "tumor suppressor gene products", which share similar properties with the RB protein in binding to the E1A oncoprotein. Detailed analyses of DNA, mRNA, and protein showed that (1) 3 lines including both Japanese lines lost the expression of the RB protein due to either the absence or the alteration of mRNA caused by DNA rearrangement, (2) abnormality of p53 gene was detected in all cell lines : 4 lines lost p53 expression due to either gene loss or the absence of mRNA, and one line expressed an abnormal form of the protein without detectable DNA and mRNA alterations and (3) no significant alteration of p107 or p300 was detected in all cell lines. These results further confirm that inactivating mutations of p53 and RB genes are deeply involved in the carcinogenesis of human osteosarcoma and suggest that p107 and p300 may not play a role in the tumorigenesis.
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PMID:[Roles of tumor suppressor genes in human osteosarcoma cells]. 182 50

The large T-antigens of SV40 and polyoma virus are nuclear, multifunctional proteins that are essential for replication of the respective viruses. They can also 'transform' cells in culture to varying extents; both can immortalise primary cells, and SV40 large T can additionally induce full transformation. Recently, p105Rb, the protein product of the anti-oncogene RB-1, has been shown to interact with both large T-antigens. SV40 large T-antigen also binds to a p105Rb related protein, p107. SV40 large T differs from that of polyoma virus in its ability to associate with another anti-oncogene product, p53. The significance of these properties to the transforming potential of both viruses is considered.
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PMID:Cell alterations induced by the large T-antigens of SV40 and polyoma virus. 196 92

The EBNA-LP protein (also known as EBNA-5) of Epstein-Barr virus (EBV) has been reported previously to colocalize in the nuclei of cells with the pRb protein and to bind in vitro to pRb and to the p53 protein, suggesting a role for EBNA-LP in modulation of the function of these proteins. Here we test in transfection assays whether EBNA-LP expression has any functional consequence for repression of E2F-1 activity by pRb or p107 or for activation of transcription by the p53 protein. No significant effect could be found, although the assay systems were sensitive to the established effects of simian virus 40 large T antigen and human papillo-mavirus type 16 E6 protein. There was very effective repression of GAL4/E2F-1 transactivation by p107, consistent with earlier reports and indicating that p107 can interact with the E2F-1 transactivation domain, even though p107 has been reported to bind specifically to E2F complexes containing E2F-4. The results indicate that, if the associations of EBNA-LP with pRB and p53 are physiologically relevant, they most likely affect other functions of these proteins or modulate their gene regulatory functions in ways that cannot be detected by transfection into cycling transformed cells.
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PMID:Epstein-Barr virus EBNA-LP and transcription regulation properties of pRB, p107 and p53 in transfection assays. 756 51

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

p53 tumor suppressor protein is required for efficient execution of apoptosis after DNA-damage in many cell systems. Since the oncogene E1a confers susceptibility to DNA-damaging agents and stabilizes p53 protein, we investigate whether the sensitivity to anticancer drugs of E1a-expressing cells was mediated by binding to a specific set of cellular proteins (p60, p105, p107 and p300) and related to the induction of apoptosis and the level of p53 protein. We studied the effect of cisplatin (CDDP), doxorubicin (DOX) and ionizing radiation (RX) on murine keratinocytes (PAM 212) transfected by the wild type E1a oncogene or several E1a mutants which bind to different subsets of cellular proteins. Keratinocytes transfected with the mutant d1787N (which binds to p60, p105, p107 and p300) showed a lethality in response to CDDP (10 micrograms ml-1) fourfold higher than controls and threefold higher in response to DOX and radiation (5 grays). The sensitivity of keratinocytes carrying the mutant NTd1598 (binding to p105, p107 and p60) to DNA-damaging agents was similar to that of control keratinocytes, while mutant d1922/947 (binding only to p300) were resistant to CDDP and RX but sensitive to DOX. Apoptosis (after 24 h) studied by DNA fragmentation and flow cytometry was only observed in cells carrying the wild type E1a or the mutant d1787N. After treatment with DNA-damaging agents, p53 protein expression increased in all the cell lines and no rE1ation to sensitivity to anticancer agents or induction of apoptosis was observed. From these results, we conclude that cell sensitivity to cisplatin and ionizing radiation induced by the E1a oncogene requires binding to p105, p107 and p300 cellular proteins, while sensitivity to Doxorubicin requires binding only to p300. Interestingly, p53 protein levels were related to the binding to the p300 protein. The high levels of p53 after CDDP and DOX in the mutant d1922/947, which are only sensitive to DOX, suggest that E1a oncogene products may induce sensitivity to DNA-damaging agents by p53-related and unrelated pathways.
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PMID:Lack of correlation between p53 protein level and sensitivity of DNA-damaging agents in keratinocytes carrying adenovirus E1a mutants. 765 31

The retinoblastoma susceptibility gene (Rb) participates in controlling the G1/S-phase transition, presumably by binding and inactivating E2F transcription activator family members. Mouse embryonic fibroblasts (MEFs) with no, one, or two inactivated Rb genes were used to determine the specific contributions of Rb protein to cell cycle progression and gene expression. MEFs lacking both Rb alleles (Rb-/-) entered S phase in the presence of the dihydrofolate reductase inhibitor methotrexate. Two E2F target genes, dihydrofolate reductase and thymidylate synthase, displayed elevated mRNA and protein levels in Rb- MEFs. Since absence of functional Rb protein in MEFs is sufficient for S-phase entry under growth-limiting conditions, these data indicate that the E2F complexes containing Rb protein, and not the Rb-related proteins p107 and p130, may be rate limiting for the G1/S transition. Antineoplastic drugs caused accumulation of p53 in the nuclei of both Rb+/+ and Rb-/- MEFs. While p53 induction led to apoptosis in Rb-/- MEFs, Rb+/- and Rb+/+ MEFs underwent cell cycle arrest without apoptosis. These results reveal that diverse growth signals work through Rb to regulate entry into S phase, and they indicate that absence of Rb protein produces a constitutive DNA replication signal capable of activating a p53-associated apoptotic response.
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PMID:Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis. 777 26

The mechanism of cell cycle withdrawal during terminal differentiation is poorly understood. We report here that the cyclin-dependent kinase (CDK) inhibitor p21Cip1/WAF1 is induced at early times of both keratinocyte and myoblast differentiation. p21Cip1/WAF1 induction is accompanied by a drastic inhibition of total Cdk2, as well as p21Cip1/WAF1-associated CDK kinase activities. p21Cip1/WAF1 has been implicated in p53-mediated G1 arrest and apoptosis. In keratinocyte differentiation, Cip1/WAF1 induction is observed even in cells derived from p53-null mice. Similarly, keratinocyte differentiation is associated with induction of Cip1/WAF1 promoter activity in both wild-type and p53-negative keratinocytes. Induction of the Cip1/WAF1 promoter upon differentiation is abolished by expression of an adenovirus E1A oncoprotein (d1922/947), which is unable to bind p105-Rb, p107, or cyclin A but which still binds the nuclear phosphoprotein p300. Overexpression of p300 can suppress the E1A effect, independent of its direct binding to E1A. Thus, terminal differentiation-induced growth arrest in both keratinocyte and myoblast systems is associated with induction of Cip1/WAF1 expression. During keratinocyte differentiation, Cip1/WAF1 induction does not require p53 but depends on the transcriptional modulator p300.
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PMID:Involvement of the cell-cycle inhibitor Cip1/WAF1 and the E1A-associated p300 protein in terminal differentiation. 777 29

Tumor suppressor proteins are believed to play a role in regulating cell cycle control during mammalian development. The E6 and E7 oncoproteins from human papillomavirus type 16 are known to affect cell growth control, at least in part, through their inactivation of cellular tumor suppressor gene products, p53 and Rb, respectively. Therefore, these viral proteins can serve as trans-dominant repressors of tumor suppressor gene function. To study the potential role of p53 and Rb in murine lens morphogenesis, we generated transgenic mice in which the expression of E6 or E7 was directed to the developing lens. Transgenic mice expressing E7 exhibited microphthalmia and cataracts, whereas transgenic mice expressing E6 exhibited cataracts without noticeable microphthalmia. Microscopic analysis of the lenses from neonatal and adult E7 transgenic mice revealed inhibition of lens fiber cell differentiation, induction of cell proliferation in spatially inappropriate regions of the lens, and apoptosis. Transgenic mice expressing a mutant E7 that is defective in Rb/p107 binding exhibited normal eyes, suggesting that the activity of Rb and/or Rb-like proteins is required for the perturbation of lens development and induction of apoptosis in E7 mice. Microscopic analysis of lenses from E6 neonatal and adult transgenic mice indicated the presence of nuclei in elongated fiber cells, suggesting that E6 inhibits lens fiber cell denucleation. Furthermore, expression of E6 inhibited the apoptotic-like DNA degradation observed in the lenses of nontransgenic 15.5-day embryos. In lenses from neonatal E6 x E7 double transgenic mice, the level of apoptosis was reduced compared with that seen in lenses from neonatal E7 mice. In adults E6 x E7 double transgenic mice, lens tumors developed, whereas in E6 or E7 only transgenic mice, tumors did not. Taken together, these results point to specific roles in lens morphogenesis for Rb and p53 and to the necessity of these tumor suppressor gene products in regulating exit from the normal cell division cycle in differentiating lens fiber cells.
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PMID:Altered cell cycle regulation in the lens of HPV-16 E6 or E7 transgenic mice: implications for tumor suppressor gene function in development. 792 31

The four principal gut epithelial cell lineages undergo continuous and rapid renewal during a geographically well-organized migration along the crypt-to-villus axis. The molecules that regulate their proliferation and differentiation programs are largely unknown. The large tumor antigen (TAg) of wild-type (wt) simian virus 40 (SV40) and its mutant derivatives represent tools for describing the contributions of regulators of the cell cycle to the proliferative state of each lineage. Expression of SV40 TAgwt in postmitotic, villus-associated enterocytes of transgenic mice causes them to reenter the cell cycle without an apparent effect on their state of differentiation. When human KRAS with a Val-12 substitution ([Val12]KRAS) is coexpressed with SV40 TAgwt in villus enterocytes of bitransgenic animals, the two oncoproteins cooperate to produce dedifferentiation (dysplasia). SV40 mutant d11137 expresses a TAg that is unable to complex with p53 but retains N-terminal transforming functions, including the ability to complex pRB, p107, and p300. When SV40 TAgd11137 is expressed in villus enterocytes, they reenter into the cell cycle. However, coexpression of SV40 TAgd11137 and [Val12]KRAS does not produce dysplastic changes. Thus, the N-terminal 121 residues of TAg are sufficient to perturb the proliferative state of the enterocyte but not to produce detectable changes in the state of differentiation when coexpressed with [Val12]KRAS.
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PMID:Expression of wild-type and mutant simian virus 40 large tumor antigens in villus-associated enterocytes of transgenic mice. 804 20


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