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)

The 55-kDa E1B protein of adenovirus, which binds to and inactivates the tumor suppressor protein p53, is not expressed in the adenoviral mutant termed ONYX-015 (i.e., dl1520). It was reported that the mutant virus due to a deletion in E1B is able to replicate only in cells deficient for wild-type p53. Accordingly, dl1520 is currently being evaluated as a potential tool in the therapy of p53 deficient cancers. In contrast, we report here that dl1520 replicates independently of the p53 status in various tumor cell lines (U87, RKO, A549, H1299, and U373). In addition, the inhibition of p53-mediated transcriptional activation in wild-type p53 containing U2OS cells, by overexpression of a transdominant negative p53 mutant, did not render the cells permissive for dl1520 replication. Finally, we show that, depending on the multiplicity of infection, the deleted virus is able to replicate in and to kill primary human cells. Thus, the molecular basis for the growth differences of dl1520 within different cell types remains to be determined.
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PMID:Replication of ONYX-015, a potential anticancer adenovirus, is independent of p53 status in tumor cells. 981 80

The ability of the adenovirus type 5 E1B 55-kDa mutants dl1520 and dl338 to replicate efficiently and independently of the cell cycle, to synthesis viral DNA, and to lyse infected cells did not correlate with the status of p53 in seven cell lines examined. Rather, cell cycle-independent replication and virus-induced cell killing correlated with permissivity to viral replication. This correlation extended to S-phase HeLa cells, which were more susceptible to virus-induced cell killing by the E1B 55-kDa mutant virus than HeLa cells infected during G1. Wild-type p53 had only a modest effect on E1B mutant virus yields in H1299 cells expressing a temperature-sensitive p53 allele. The defect in E1B 55-kDa mutant virus replication resulting from reduced temperature was as much as 10-fold greater than the defect due to p53 function. At 39 degreesC, the E1B 55-kDa mutant viruses produced wild-type yields of virus and replicated independently of the cell cycle. In addition, the E1B 55-kDa mutant viruses directed the synthesis of late viral proteins to levels equivalent to the wild-type virus level at 39 degreesC. We have previously shown that the defect in mutant virus replication can also be overcome by infecting HeLa cells during S phase. Taken together, these results indicate that the capacity of the E1B 55-kDa mutant virus to replicate independently of the cell cycle does not correlate with the status of p53 but is determined by yet unidentified mechanisms. The cold-sensitive nature of the defect of the E1B 55-kDa mutant virus in both late gene expression and cell cycle-independent replication leads us to speculate that these functions of the E1B 55-kDa protein may be linked.
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PMID:p53 status does not determine outcome of E1B 55-kilodalton mutant adenovirus lytic infection. 981 81

Recently, several proteins have been identified that are related in their sequence to the p53 tumor-suppressor protein. One of these proteins, which is termed p73, exhibits sequence homology to the p53 transcriptional activation, DNA binding, and oligomerization domains. The adenovirus E1B 55-kDa protein, the adenovirus E4orf6 protein, and SV40 T antigen each can bind to p53 and inhibit p53 function. Here we demonstrate that the adenovirus E4orf6 protein, but not the E1B 55-kDa protein or T antigen, interacts with p73. The E4orf6 protein inhibits p73-mediated transcriptional activation and cell killing in a manner similar to its effect on p53. Thus, only a subset of viral oncoproteins that antagonize p53 function also interacts with the related p73 protein.
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PMID:Adenovirus E4orf6 oncoprotein modulates the function of the p53-related protein, p73. 986 Oct 30

The 34-kDa early-region 4 open reading frame 6 (E4orf6) product of human adenovirus type 5 forms complexes with both the cellular tumor suppressor p53 and the viral E1B 55-kDa protein (E1B-55kDa). E4orf6 can inhibit p53 transactivation activity, as can E1B-55kDa, and in combination these viral proteins cause the rapid turnover of p53. In addition, E4orf6-55kDa complexes play a critical role at later times in the regulation of viral mRNA transport and shutoff of host cell protein synthesis. In the present study, we have further characterized some of the biological properties of E4orf6. Analysis of extracts from infected cells by Western blotting indicated that E4orf6, like E1A and E1B products, is present at high levels until very late times, suggesting that it is available to act throughout the infectious cycle. This pattern is similar to that of E4orf4 but differs markedly from that of another E4 product, E4orf6/7, which is present only transiently. Synthesis of E4orf6 is maximal at early stages but ceases completely with the onset of shutoff of host protein synthesis; however, it was found that unlike E4orf6/7, E4orf6 is very stable, thus allowing high levels to be maintained even at late times. E4orf6 was shown to be phosphorylated at low levels. Coimmunoprecipitation studies in cells lacking p53 indicated that E4orf6 interacts with a number of other proteins. Five of these were shown to be viral or virally induced proteins ranging in size from 102 to 27 kDa, including E1B-55kDa. One such species, of 72 kDa, was shown not to represent the E2 DNA-binding protein and thus remains to be identified. Another appeared to be the L4 100-kDa nonstructural adenovirus late product, but it appeared to be present nonspecifically and not as part of an E4orf6 complex. Apart from p53, three additional cellular proteins, of 84, 19, and 14 kDa were detected by using an adenovirus vector that expresses only E4orf6. The 19-kDa species and a 16-kDa cellular protein were also shown to interact with E4orf6/7. It is possible that complex formation with these viral and cellular proteins plays a role in one or more of the biological activities associated with E4orf6 and E4orf6/7.
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PMID:Analysis of synthesis, stability, phosphorylation, and interacting polypeptides of the 34-kilodalton product of open reading frame 6 of the early region 4 protein of human adenovirus type 5. 988 28

Previous observations that the adenovirus type 5 (Ad5) E4orf6 and E4orf3 gene products have redundant effects in viral lytic infection together with the recent findings that E4orf6 possesses transforming potential prompted us to investigate the effect of E4orf3 expression on the transformation of primary rat cells in combination with adenovirus E1 oncogene products. Our results demonstrate for the first time that E4orf3 can cooperate with adenovirus E1A and E1A plus E1B proteins to transform primary baby rat kidney cells, acting synergistically with E4orf6 in the presence of E1B gene products. Transformed rat cells expressing E4orf3 exhibit morphological alterations, higher growth rates and saturation densities, and increased tumorigenicity compared with transformants expressing E1 proteins only. Consistent with previous results for adenovirus-infected cells, the E4orf3 protein is immunologically restricted to discrete nuclear structures known as PML oncogenic domains (PODs) in transformed rat cells. As opposed to E4orf6, the ability of E4orf3 to promote oncogenic cell growth is probably not linked to a modulation of p53 functions and stability. Instead, our results indicate that the transforming activities of E4orf3 are due to combinatorial effects that involve the binding to the adenovirus 55-kDa E1B protein and the colocalization with PODs independent from interactions with the PML gene product. These data fit well with a model in which the reorganization of PODs may trigger a cascade of processes that cause uncontrolled cell proliferation and neoplastic growth. In sum, our results provide strong evidence for the idea that interactions with PODs by viral proteins are linked to oncogenic transformation.
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PMID:Transforming potential of the adenovirus type 5 E4orf3 protein. 988 65

The adenovirus type 5 (Ad5) E4orf6 protein promotes focus formation of primary baby rat kidney (BRK) cells in cooperation with Ad5 E1 proteins. This activity is most likely related to the ability of the E4orf6 protein to bind to p53 and modulate its tumor suppressor functions. In this study we report that transformed BRK cells that stably express E4orf6 in addition to E1A and E1B (ABS cells) displayed multiple additional properties commonly associated with a high grade of oncogenic transformation compared to cells expressing only E1A and E1B (AB cells). These properties included morphological alterations, markedly enhanced growth rates and growth to much higher saturation densities. Following injection into nude mice ABS-derived tumors exhibited accelerated growth and, based on histopathological criteria, proofed to be much more malignant compared to tumors generated by AB cells. Interestingly, these highly transformed properties of ABS cells correlated with a dramatic reduction of p53 steady-state levels which inversely correlated with E4orf6 expression. From these results we conclude that expression of the Ad5 E4orf6 protein (i) confers additional transformed in vitro properties to primary rat cells expressing the Ad5 E1 proteins, and (ii) increases the tumorigenic and malignant potential of these cells in vivo. Our data suggest that the Ad5 E4orf6 protein enhances the intrinsic ability of E1-transformed rat cells to grow in a neoplastic state by completely inactivating p53 tumor suppressor function in combination with the E1A and E1B proteins.
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PMID:The adenovirus E4orf6 protein contributes to malignant transformation by antagonizing E1A-induced accumulation of the tumor suppressor protein p53. 992 15

Adenovirus 12 (Ad12), but not adenovirus 2 or 5, induces metaphase chromosome fragility at four specific loci in humans: RNU1, RNU2, PSU1, and RN5S. As each of these sites corresponds to a tandemly repeated multigene family encoding a small, abundant structural RNA, we proposed that Ad12 hinders metaphase chromatin condensation, interfering either directly or indirectly with transcriptional regulation or chromatin packing of these small RNA genes. We and others subsequently found that Ad12-induced fragility of the RNU2 locus requires U2 promoter elements, viral early functions, and p53. We now show that RNU2 fragility can be induced by transfection with an expression vector encoding Ad12 E1B 55 kDa alone but not by an E1 vector encoding all E1 products (3 E1A proteins, as well as the E1B 19 kDa and 55 kDa proteins). Although Ad12 E1B 55 kDa efficiently induced fragility in transfected cells, Ad2 E1B 55 kDa did not. By swapping domains between the Ad12 and Ad2 E1B, we found that the aminoterminus of Ad12 E1B is required for induction of fragility and that the ability of the hybrid E1B proteins to induce fragility appears to correlate with nuclear localization. Furthermore, in Saos-2 cells lacking p53 function, RNU2 fragility could be induced by cotransfection with vectors encoding Ad12 E1B 55 kDa and either wild-type p53 or the R273H mutant with impaired DNA binding activity. We conclude that a functional (and probably physical) interaction between Ad12 E1B 55 kDa and p53 within the nucleus is sufficient to induce metaphase fragility of the RNU2 locus.
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PMID:Coexpression of the adenovirus 12 E1B 55 kDa oncoprotein and cellular tumor suppressor p53 is sufficient to induce metaphase fragility of the human RNU2 locus. 992 70

The E1B-55-kDa protein of adenovirus type 5 and the p53 tumor suppressor gene product form a complex that localizes to the cytoplasm, thereby downregulating p53's transcriptional activity. The E4orf6 protein binds and relocalizes E1B-55-kDa, and the proteins act synergistically to inactivate p53. We show that another adenovirus E4 gene product, E4orf3, is also sufficient to relocalize E1B-55-kDa from the cytoplasm to the nucleus. Both proteins are then found in discrete nuclear structures (tracks) that are known to contain components of the promyelocytic leukemia-associated nuclear structure. Simultaneously, p53 is dissociated from E1B-55-kDa and is found evenly distributed over the nucleoplasm. In the presence of E4orf3, p53-dependent transcriptional activity is no longer repressed by E1B-55-kDa. When E1B-55-kDa is coexpressed with E4orf3 and E4orf6, E1B-55-kDa is found to colocalize with E4orf6 rather than E4orf3. In parallel, p53 is inhibited and degraded by the combination of E1B-55-kDa and E4orf6, regardless of coexpressed E4orf3. This suggests that the effects of E4orf6 on E1B-55-kDa overrule the actions of E4orf3. When cells are infected with virus expressing E4orf3 but not E4orf6, E1B is found in the cell nucleus and p53 enters the virus replication centers. After infection with wild-type adenovirus, E4orf3 is expressed before E4orf6 and E1B temporarily colocalizes with E4orf3 in nuclear tracks before associating with E4orf6. We propose that during adenovirus infection, the E4orf3 protein transiently liberates p53 from its association with E1B-55-kDa. Subsequently, p53 is inactivated and degraded by the combination of E1B-55-kDa and E4orf6.
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PMID:Adenovirus type 5 E4orf3 protein relieves p53 inhibition by E1B-55-kilodalton protein. 997 8

Transforming Growth Factor-beta1 (TGF-beta1) inhibits the proliferation of most cells, but stimulates some mesenchymal cell types, including murine NIH3T3 fibroblasts. We show here that TGF-beta1 growth stimulation of NIH3T3 fibroblasts is reversed when these cells are transformed by SV40 or are transfected with a plasmid encoding the SV40 Large T antigen. Inversion of the TGF-beta1 growth stimulation of NIH3T3 cells is not observed when these cells are transfected with plasmids expressing either a mutant Large T, unable to bind P53, or the E1A adenovirus oncoprotein which binds the retinoblastoma protein pRB but not P53. But when the TGF-beta1-growth stimulated cells are transfected with a plasmid expressing a mutant form of Large T capable of binding to P53, but not to pRB, or with one expressing the E1B-55 kD adenovirus oncoprotein, which also binds to P53 but not to pRB, the cells are growth-inhibited by TGF-beta1. The cdk inhibitor p21Waf is decreased in TGF-beta1-stimulated NIH3T3 fibroblasts and increased in TGF-beta1-inhibited SV40-transformed cells. Finally, we show that T12 fibroblasts, from a P53 knockout mouse, are growth inhibited by TGF-beta1 and that they remain so upon transfection with a P53 which is mutant at restrictive temperature, but become growth-stimulated by this factor at permissive temperature when P53 is functional. These data strongly suggest that growth-stimulation of fibroblasts by TGF-beta1 depends on the presence of a functional P53 protein and that inversion of this response occurs if P53 is absent or inactivated.
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PMID:Growth stimulation of murine fibroblasts by TGF-beta1 depends on the expression of a functional p53 protein. 998 20

Reactive oxygen species (ROS) play an important role in cell death induced by many different stimuli. This study shows that hydrogen peroxide-induced apoptosis in T-cells did not require tyrosine kinase p561ck, phosphatase CD45, the CD95 receptor and its associated Caspase-8. H2O2-triggered cell death led to the induced cleavage and activation of Caspase-3. Hydrogen peroxide-treatment of T-cells resulted in the formation of mitochondrial permeability transition pores, a rapid decrease of the mitochondrial transmembrane potential delta psi(m) and the release of Cytochrome C. Inhibition of the mitochondrial permeability transition by bongkrekic acid (BA), or interference with the mitochondrial electron transport system by rotenone or menadione prevented the cytotoxic effect of H2O2. Antimycin A, a mitochondrial inhibitor that increases the release of mitochondrial ROS (MiROS), enhanced apoptosis. Overexpression of Bcl-2 and the viral anti-apoptotic proteins BHRF-1 and E1B 19K counteracted H2O2-induced apoptosis. Pharmacological and genetic inhibition of transcription factor NF-kappaB protected cells from hydrogen peroxide-elicited cell death. This detrimental effect of NF-kappaB mediating hydrogen peroxide-induced cell death presumably relies on the induced expression of death effector genes such as p53, which was NF-kappaB-dependently upregulated in the presence of H2O2.
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PMID:Hydrogen peroxide-induced apoptosis is CD95-independent, requires the release of mitochondria-derived reactive oxygen species and the activation of NF-kappaB. 998 25


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