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Supplementary Methods from Dmp1 Physically Interacts with p53 and Positively Regulates p53′s Stability, Nuclear Localization, and Function

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posted on 2023-03-30, 21:24 authored by Donna P. Frazier, Robert D. Kendig, Fumitake Kai, Dejan Maglic, Takayuki Sugiyama, Rachel L. Morgan, Elizabeth A. Fry, Sarah J. Lagedrost, Guangchao Sui, Kazushi Inoue

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ARTICLE ABSTRACT

The transcription factor Dmp1 is a Ras/HER2-activated haplo-insufficient tumor suppressor that activates the Arf/p53 pathway of cell-cycle arrest. Recent evidence suggests that Dmp1 may activate p53 independently of Arf in certain cell types. Here, we report findings supporting this concept with the definition of an Arf-independent function for Dmp1 in tumor suppression. We found that Dmp1 and p53 can interact directly in mammalian cells via the carboxyl-terminus of p53 and the DNA-binding domain of Dmp1. Expression of Dmp1 antagonized ubiquitination of p53 by Mdm2 and promoted nuclear localization of p53. Dmp1–p53 binding significantly increased the level of p53, independent of the DNA-binding activity of Dmp1. Mechanistically, p53 target genes were activated synergistically by the coexpression of Dmp1 and p53 in p53−/−;Arf−/− cells, and genotoxic responses of these genes were hampered more dramatically in Dmp1−/− and p53−/− cells than in Arf−/− cells. Together, our findings identify a robust new mechanism of p53 activation mediated by direct physical interaction between Dmp1 and p53. Cancer Res; 72(7); 1740–50. ©2012 AACR.

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