Dmp1 physically interacts with p53 and positively regulates p53's stability, nuclear localization, and function.

Cancer Research
Donna P FrazierKazushi Inoue

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.

References

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Citations

Nov 10, 2013·PloS One·Elizabeth A FryKazushi Inoue
Mar 16, 2016·Biochemical and Biophysical Research Communications·Ester Sara Di FilippoStefania Fulle
Aug 14, 2013·The American Journal of Pathology·Sinan ZhuKazushi Inoue
Apr 14, 2017·Cancer Investigation·Robert D KendigKazushi Inoue
Jan 1, 2015·Signal Transduction Insights·Kazushi Inoue, Elizabeth A Fry
Mar 22, 2016·Biomarkers in Cancer·Kazushi Inoue, Elizabeth A Fry
Dec 23, 2015·Genetics & Epigenetics·Kazushi Inoue, Elizabeth A Fry
Jul 12, 2013·Clinical Medicine Insights. Oncology·Kazushi InouePankaj Taneja
Jan 3, 2019·Cancer Investigation·Elizabeth A Fry, Kazushi Inoue
Jan 24, 2016·International Journal of Cancer. Journal International Du Cancer·Kazushi Inoue, Elizabeth A Fry
Jul 2, 2015·International Journal of Cancer. Journal International Du Cancer·Kazushi InoueDonna P Frazier
Aug 25, 2016·International Journal of Cancer. Journal International Du Cancer·Elizabeth A FryKazushi Inoue
Dec 10, 2016·Brain Pathology·Michael W RonellenfitschHiroko Ohgaki
Nov 7, 2018·Cancer Investigation·Kazushi Inoue, Elizabeth A Fry
Oct 31, 2020·International Journal of Molecular Sciences·Elizabeth A FryKazushi Inoue

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