Dmp1 physically interacts with p53 and positively regulates p53's stability, nuclear localization, and function.
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.
Mesh Terms:
Active Transport, Cell Nucleus, Animals, Binding Sites, Cell Nucleus, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16, Humans, Mice, Mice, Inbred C57BL, Proto-Oncogene Proteins c-mdm2, Transcription Factors, Transcription, Genetic, Tumor Suppressor Protein p53, Ubiquitination
Active Transport, Cell Nucleus, Animals, Binding Sites, Cell Nucleus, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16, Humans, Mice, Mice, Inbred C57BL, Proto-Oncogene Proteins c-mdm2, Transcription Factors, Transcription, Genetic, Tumor Suppressor Protein p53, Ubiquitination
Cancer Res.
Date: Apr. 01, 2012
PubMed ID: 22331460
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