Journal
CANCER BIOLOGY & THERAPY
Volume 1, Issue 3, Pages 277-283Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cbt.81
Keywords
mutagenesis; Mdm-2; p21(Waf1/Cip1); Fas/APO-1; transactivation; protein conformation; growth regulation
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Funding
- NCI NIH HHS [CA55164, CA16672, CA77339, CA67987] Funding Source: Medline
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Previous studies have demonstrated the irradiation-induced phosphorylation of p53 at Thr18 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 Thr18 and Ser20 (p53T18D/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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