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pubmed-article:12432277pubmed:abstractTextPrevious 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.lld:pubmed
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pubmed-article:12432277pubmed:authorpubmed-author:ZhangWeiWlld:pubmed
pubmed-article:12432277pubmed:authorpubmed-author:JabburJames...lld:pubmed
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pubmed-article:12432277pubmed:pagination277-83lld:pubmed
pubmed-article:12432277pubmed:dateRevised2008-11-21lld:pubmed
pubmed-article:12432277pubmed:articleTitlep53 Antiproliferative function is enhanced by aspartate substitution at threonine 18 and serine 20.lld:pubmed
pubmed-article:12432277pubmed:affiliationDepartment of Pathology, Cancer Genomics Laboratory, Graduate Program in Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.lld:pubmed
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