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)

SUMO, a small ubiquitin-related modifier, is known to covalently attach to a number of nuclear regulatory proteins such as p53, IkappaB, promyelocytic leukemia protein and c-Jun. The sumoylation reaction is catalyzed by the SUMO protease, which exposes the C-terminal active glycine residue of the nascent SUMO, the heterodimeric SUMO activating enzyme, the SUMO conjugating enzyme, Ubc9, and SUMO protein ligases, in a manner similar to ubiquitinylation. Identification of SUMO-regulated proteins is hampered by the fact that many sumoylated proteins are present at a level below normal detection limit. This limitation was overcome by either in vivo overexpression of Myc-SUMO or in vitro sumoylation with excess biotin-SUMO and Ubc9. Sumoylated proteins so obtained were affinity purified or isolated by immunoprecipitation. The isolated sumoylated proteins were identified by sequence analysis using mass spectrometric methods. Results reveal that several heterogeneous nuclear ribonucleoproteins (hnRNPs), zinc finger proteins, and nuclear pore complex proteins were sumoylated. The sumoylation of hnRNP A1, hnRNP F, and hnRNP K were confirmed in vivo by coimmunoprecipitation. In view of the facts that hnRNPs have been implicated in RNA splicing, transport, stability, and translation, our findings suggest that sumoylation could play an important role in regulating mRNA metabolism.
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PMID:Sumoylation of heterogeneous nuclear ribonucleoproteins, zinc finger proteins, and nuclear pore complex proteins: a proteomic analysis. 1516 80

5-lipoxygenase (5-LO) promotes cancer cell proliferation and survival by unclear mechanisms. Here, we show that 5-LO expression and activity were induced by genotoxic agents in a p53-independent manner and antagonized p53- or genotoxic drug-induced apoptosis in a variety of cancer cells. 5-LO inhibited p53-governed transactivation of the pro-apoptotic genes bax and pig3 but not of p21(WAF1/CIP1) or mdm2. This may be explained by 5-LO capability to inhibit the binding of p53 to promyelocytic leukemia protein (PML) and p53 subnuclear relocalization into PML-nuclear bodies in response to genotoxic stress. Interestingly, 5-LO activity appears to be involved in nuclear retention and inactivation of wild-type p53 in malignant mesothelioma cells. In these cells, genetic or pharmacological inhibition of 5-LO enabled suppression of in vitro tumorigenicity by low doses of chemotherapeutic drugs. Together, these results uncover novel functions of 5-LO and contribute to the understanding of 5-LO involvement in tumor progression. Moreover, they provide a rationale to the therapeutic use of 5-LO inhibitors to enhance cancer chemosensitivity in selected tumors.
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PMID:5-lipoxygenase antagonizes genotoxic stress-induced apoptosis by altering p53 nuclear trafficking. 1537 79

The 55-kDa gene product from subgroup C adenovirus type 5 (Ad5) early region 1 (E1B-55kDa) plays a central role in the oncogenic transformation of primary rodent cells primarily by inactivating transcriptional and presumably other functional properties of the tumor suppressor protein p53. We have previously shown that Ad5 E1B-55kDa possesses a leucine-rich nuclear export signal (NES), which confers rapid nucleocytoplasmic shuttling via the CRM1-dependent export pathway. In this study we report that an export-deficient mutant of the viral protein (E1B-NES) substantially enhances focus formation of primary baby rat kidney cells in combination with Ad E1A. Transformed rat cells stably expressing the E1B-NES protein exhibited increased tumorigenicity and accelerated tumor growth in nude mice compared to transformants containing the wild-type E1B product. This 'gain of function' correlated with enhanced inhibition of p53 transactivation in transient reporter assays and the accumulation of the mutant protein and p53 in several dot-like subnuclear aggregates. Interestingly, these structures also contained a large fraction of cellular promyelocytic leukemia protein (PML), a known regulator of p53. These data indicate that E1B-NES promotes oncogenic transformation by combinatorial mechanisms that involve modulation of p53 in the context of PML nuclear bodies. In sum, these results extend our previous observation that inhibition of PML activities by E1B-55kDa is required for efficient focus formation and provide further support for the view that blocking p53 transcriptional functions is the principal mechanism by which the Ad protein contributes to complete cell transformation in conjunction with Ad E1A.
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PMID:Blockage of CRM1-dependent nuclear export of the adenovirus type 5 early region 1B 55-kDa protein augments oncogenic transformation of primary rat cells. 1548 Apr 14

The promyelocytic leukemia protein (PML), involved in the pathogenesis of acute promyelocytic leukemia, is a coactivator of p53 tumor suppressive functions. The ability of PML to inhibit growth and induce cell death in solid tumor cells, however, has not been determined. We therefore assayed the tumor suppressor activities of PML and compared them with those of p53 in four liver cancer cell lines. Following infection of cells with replication-deficient recombinant PML adenovirus, the exogenous PML localized in the nucleus and formed abnormally enlarged PML-nuclear bodies after 24 hours. In vitro growth curve analysis showed that the overexpressed PML initially induced a substantial G1 cell cycle arrest and triggered massive cell death in all tested cell lines, irrespective of their p53 status. PML-induced cell death decreased by about 30% in the presence of a broad caspase inhibitor, zVAD. The cell death effect of PML was higher than that induced by p53 over a longer period of time. As with p53, overexpression of PML was closely related to upregulation of p21 and decrease of cyclin D1 expression. Unexpectedly, retinoic acid (RA) antagonized rather than enhanced PML-triggered cell death. RA enhanced the expression of adenovirus-cytomegalovirus-promoted PML at both transcription and protein levels within 12 hours after treatment; however, the PML protein was significantly degraded in the presence of RA at days 3-5 postinfection. PML degradation was also observed in SK-BR3 breast cancer cells treated with RA. Taken together, our findings strongly support the hypothesis that PML acts as a strong independent cell death inducer and that RA conversely abolishes the therapeutic effects of the PML proteins through proteasomal degradation of the protein.
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PMID:Promyelocytic leukemia protein-induced growth suppression and cell death in liver cancer cells. 1552 77

Cellular senescence can be triggered by a variety of signals, including loss of telomeric integrity or intense oncogenic signaling, and is considered a potent, natural tumor suppressor mechanism. Previously, it was shown that the promyelocytic leukemia protein (PML) induces cellular senescence when overexpressed in primary human fibroblasts. The mechanism by which the PML IV isoform elicits this irreversible growth arrest is believed to involve activation of the tumor suppressor pathways p21/p53 and p16/Rb; however, a requirement for either pathway has not been demonstrated unequivocally. To investigate the individual contributions of p53 and Rb to PML-induced senescence, we used oncoproteins E6 and E7 from human papillomaviruses (HPVs), which predominantly target p53 and Rb. We show that E7, but not E6, circumvents PML-induced senescence. Using different E7 mutant proteins, dominant negative cyclin-dependent kinase 4, and p16 RNA interference, we demonstrate that Rb-related and Rb-independent mechanisms of E7 are necessary for subversion of PML-induced senescence and we identify PML as a novel target for E7. Interaction between E7 and a functional prosenescence complex composed of PML, p53, and CBP perturbs transcriptional activation of p53, thus highlighting a significant effect also on the p53 tumor suppressor pathway. Given the importance of HPV in the pathogenesis of cervical cancer, our results warrant a more detailed analyses of PML in HPV infections.
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PMID:Human papillomavirus oncoprotein E7 targets the promyelocytic leukemia protein and circumvents cellular senescence via the Rb and p53 tumor suppressor pathways. 3310 71

DNA damage, provoked by ultraviolet (UV) radiation, evokes a cellular damage response composed of activation of stress signaling and DNA checkpoint functions. These are translated to responses of replicative arrest, damage repair, and apoptosis aimed at cellular recovery from the damage. p53 tumor suppressor is a central stress response protein, activated by multiple endogenous and environmental insults, including UV radiation. The significance of p53 in the DNA damage responses has frequently been reviewed in the context of ionizing radiation or other double strand break (DSB)-inducing agents. Despite partly similar patterns, the molecular events following UV radiation are, however, distinct from the responses induced by DSBs and are profoundly coupled with transcriptional stress. These are illustrated, e.g., by the UV damage-specific translocations of Mdm2, promyelocytic leukemia protein, and nucleophosmin and their interactions with p53. In this review, we discuss UV damage-provoked cellular responses and the functions of p53 in damage recovery and cell death.
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PMID:Cellular UV damage responses--functions of tumor suppressor p53. 1592 59

Nuclear aggregates of polyglutamine (polyQ)-expanded proteins are associated with a number of neurodegenerative diseases including Huntington's disease (HD) and spinocerebellar ataxias (SCAs). The nuclear deposition of polyQ proteins correlates with rearrangements of nuclear matrix, transcriptional dysregulation, and cell death. To explore the requirement for polyQ tracks in educing such cellular responses, we examined whether a non-polyQ protein can deposit as nuclear aggregates and elicit similar responses. We report that a protein chimera (GFP170*) composed of the green fluorescent protein (GFP) fused to an internal fragment of the Golgi Complex Protein (GCP-170) forms nuclear aggregates analogous to those formed by polyQ proteins. Like the polyQ nuclear aggregates, GFP170* inclusions recruit molecular chaperones and proteasomal components, alter nuclear structures containing the promyelocytic leukemia protein (PML), recruit transcriptional factors such as CREB-binding protein (CBP) and p53, repress p53 transcriptional activity, and induce cell death. Our results indicate that nuclear aggregation and transcriptional effects are not unique to polyQ-containing proteins and may represent a general response to misfolded proteins in the nucleus.
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PMID:Transcriptional repression and cell death induced by nuclear aggregates of non-polyglutamine protein. 1596 98

Results reported here indicate that adenovirus 5 exploits the cellular aggresome response to accelerate inactivation of MRE11-RAD50-NBS1 (MRN) complexes that otherwise inhibit viral DNA replication and packaging. Aggresomes are cytoplasmic inclusion bodies, observed in many degenerative diseases, that are formed from aggregated proteins by dynein-dependent retrograde transport on microtubules to the microtubule organizing center. Viral E1B-55K protein forms aggresomes that sequester p53 and MRN in transformed cells and in cells transfected with an E1B-55K expression vector. During adenovirus infection, the viral protein E4orf3 associates with MRN in promyelocytic leukemia protein nuclear bodies before MRN is bound by E1B-55K. Either E4orf3 or E4orf6 is required in addition to E1B-55K for E1B-55K aggresome formation and MRE11 export to aggresomes in adenovirus-infected cells. Aggresome formation contributes to the protection of viral DNA from MRN activity by sequestering MRN in the cytoplasm and greatly accelerating its degradation by proteosomes following its ubiquitination by the E1B-55K/E4orf6/elongin BC/Cullin5/Rbx1 ubiquitin ligase. Our results show that aggresomes significantly accelerate protein degradation by the ubiquitin-proteosome system. The observation that a normal cellular protein is inactivated when sequestered into an aggresome through association with an aggresome-inducing protein has implications for the potential cytotoxicity of aggresome-like inclusion bodies in degenerative diseases.
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PMID:Adenovirus exploits the cellular aggresome response to accelerate inactivation of the MRN complex. 1625 36

Daxx, a death domain-associated protein, has been implicated in proapoptosis, antiapoptosis, and transcriptional regulation. Many factors known to play critically important roles in controlling apoptosis and gene transcription have been shown to associate with Daxx, including the Ser/Thr protein kinase HIPK2, promyelocytic leukemia protein, histone deacetylases, and the chromatin remodeling protein ATRX. Although it is clear that Daxx may exert multiple functions, the underlying mechanisms remain far from clear. Here, we show that Axin, originally identified for its scaffolding role to control beta-catenin levels in Wnt signaling, strongly associates with Daxx at endogenous levels. The Daxx/Axin complex formation is enhanced by UV irradiation. Axin tethers Daxx to the tumor suppressor p53, and cooperates with Daxx, but not DaxxDeltaAxin, which is unable to interact with Axin, to stimulate HIPK2-mediated Ser(46) phosphorylation and transcriptional activity of p53. Interestingly, Axin and Daxx seem to selectively activate p53 target genes, with strong activation of PUMA, but not p21 or Bax. Daxx-stimulated p53 transcriptional activity was significantly diminished by small interfering RNA against Axin; Daxx fails to inhibit colony formation in Axin(-/-) cells. Moreover, UV-induced cell death was attenuated by the knockdown of Axin and Daxx. All these results show that Daxx cooperates with Axin to stimulate p53, and implicate a direct role for Axin, HIPK2, and p53 in the proapoptotic function of Daxx. We have hence unraveled a novel aspect of p53 activation and shed new light on the ultimate understanding of the Daxx protein, perhaps most pertinently, in relation to stress-induced cell death.
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PMID:Daxx cooperates with the Axin/HIPK2/p53 complex to induce cell death. 1721 Jun 84

Cellular senescence is an important phenomenon in decreased cellular function. Recently, it was shown that cellular senescence is induced in proliferating cells within a short period of time by oxidative stresses. This phenomenon is known as premature senescence. However, it is still unknown whether premature senescence can be also induced in cardiomyocytes. The aim of the present study was to investigate whether a senescence-like phenotype can be induced in cardiomyocytes by oxidative stress. In cardiomyocytes obtained from aged rats (24 months of age), the staining for senescence-associated beta-galactosidase increased significantly and the protein or RNA levels of cyclin-dependent kinase inhibitors increased compared to those of young rats. Decreased cardiac troponin I phosphorylation and telomerase activity were also observed in aged cardiomyocytes. Treatment of cultured neonatal rat cardiomyocytes with a low concentration of doxorubicin (DOX) (10(-7) mol L(-1)) did not induce apoptosis but did induce oxidative stress, which was confirmed by 2',7'-dichlorofluorescin diacetate staining. In DOX-treated neonatal cardiomyocytes, increased positive staining for senescence-associated beta-galactosidase, cdk-I expression, decreased cardiac troponin I phosphorylation, and decreased telomerase activity were observed, as aged cardiomyocytes. Alterations in mRNA expression typically seen in aged cells were observed in DOX-treated neonatal cardiomyocytes. We also found that promyelocytic leukemia protein and acetylated p53, key proteins involved in stress-induced premature senescence in proliferating cells, were associated with cellular alterations of senescence in DOX-treated cardiomyocytes. In conclusion, cardiomyocytes treated with DOX showed characteristic changes similar to cardiomyocytes of aged rats. promyelocytic leukemia-related p53 acetylation may be an underlying mechanism of senescence-like alterations in cardiomyocytes. These findings indicate a novel mechanism of myocardial dysfunction induced by oxidative stress.
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PMID:Induction of premature senescence in cardiomyocytes by doxorubicin as a novel mechanism of myocardial damage. 1803 68


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