Dmp1 Physically Interacts with p53 and Positively Regulates p53%26apos;s Stability, Nuclear Localization, and Function

作者：Frazier Donna P; Kendig Robert D; Kai Fumitake; Maglic Dejan; Sugiyama Takayuki; Morgan Rachel L; Fry Elizabeth A; Lagedrost Sarah J; Sui Guangchao; Inoue Kazushi^*

来源：Cancer Research, 2012, 72(7): 1740-1750.

DOI：10.1158/0008-5472.CAN-11-2410

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 thatDmp1 may activate p53 independently of Arfin 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.

• 出版日期2012-4-1