Source:http://linkedlifedata.com/resource/pubmed/id/12432277
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| rdf:type | |
| lifeskim:mentions | |
| pubmed:dateCreated |
2002-11-14
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| pubmed:abstractText |
Previous studies have demonstrated the irradiation-induced phosphorylation of p53 at Thrl8 and Ser20, residues integral within an a-helical segment of the transactivation domain. Importantly, phosphorylation at either site has been correlated with decreased binding to the inhibitory partner Mdm-2 and enhanced transactivation of p53 target genes. In this study, we investigated the impact of Asp substitution at Thrl8 and Ser20 (p53Tl8D/S20D) on the functional regulation of p53. Asp substitution is commonly accepted as a means of mimicking phosphorylation due to the introduction of negative charge within the functional group. p53T18D/S20D was refractory to in vitro digestion by calpain, a protease recognizing a-helical structure within the transactivation domain. In addition, transfected p53T18D/S20D poorly bound GST-Mdm-2 in vitro, enhanced the endogenous expression of the p53 transactivation targets p21(Waf1/Cip1) and fas/APO-1, and significantly curtailed cell proliferation relative to wild-type p53 transfected cells. Thus, Asp substitution at Thr18 and Ser20 within the a-helical segment of the transactivation domain reduced Mdm-2 interaction, upregulating transactivation of cell-cycle and apoptotic regulatory targets, curtailing cellular proliferation.
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| pubmed:grant | |
| pubmed:commentsCorrections | |
| pubmed:language |
eng
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| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD95,
http://linkedlifedata.com/resource/pubmed/chemical/Aspartic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/CDKN1A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Calpain,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase Inhibitor...,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclins,
http://linkedlifedata.com/resource/pubmed/chemical/Glutathione Transferase,
http://linkedlifedata.com/resource/pubmed/chemical/MDM2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-mdm2,
http://linkedlifedata.com/resource/pubmed/chemical/Serine,
http://linkedlifedata.com/resource/pubmed/chemical/Threonine,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Protein p53
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| pubmed:status |
MEDLINE
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| pubmed:author | |
| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
277-83
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| pubmed:dateRevised |
2008-11-21
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| pubmed:articleTitle |
p53 Antiproliferative function is enhanced by aspartate substitution at threonine 18 and serine 20.
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| pubmed:affiliation |
Department of Pathology, Cancer Genomics Laboratory, Graduate Program in Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
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