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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Frazier DP,Kendig RD,Kai F,Maglic D,Sugiyama T,Morgan RL,Fry EA,Lagedrost SJ,Sui G,Inoue Kdoi
10.1158/0008-5472.CAN-11-2410subject
Has Abstractpub_date
2012-04-01 00:00:00pages
1740-50issue
7eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-11-2410journal_volume
72pub_type
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