title: Dmp1 physically interacts with p53 and positively regulates p53's stability, nuclear localization, and function.
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.
authors.affiliation: Department of Pathology and Cancer Biology, and Graduate Program in Molecular Medicine, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
authors.forename: Donna P
authors.initials: DP
authors.lastname: Frazier
authors.forename: Robert D
authors.initials: RD
authors.lastname: Kendig
authors.forename: Fumitake
authors.initials: F
authors.lastname: Kai
authors.forename: Dejan
authors.initials: D
authors.lastname: Maglic
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Morgan
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Fry
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lagedrost
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
authors.forename: Kazushi
authors.initials: K
authors.lastname: Inoue
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000502:physiology*; D054875:Ubiquitination
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C491126:DMTF1 protein, human; C102116:Dmtf1 protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2