Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3.
The MDM2 homolog MDMX is an important regulator of p53 during mouse embryonic development. DNA damage promotes MDMX phosphorylation, nuclear translocation, and degradation by MDM2. Here we show that MDMX copurifies with 14-3-3, and DNA damage stimulates MDMX binding to 14-3-3. Chk2-mediated phosphorylation of MDMX on S367 is important for stimulating 14-3-3 binding, MDMX nuclear import by a cryptic nuclear import signal, and degradation by MDM2. Mutation of MDMX S367 inhibits ubiquitination and degradation by MDM2, and prevents MDMX nuclear import. Expression of 14-3-3 stimulates the degradation of phosphorylated MDMX. Chk2 and 14-3-3 cooperatively stimulate MDMX ubiquitination and overcome the inhibition of p53 by MDMX. These results suggest that MDMX-14-3-3 interaction plays a role in p53 response to DNA damage by regulating MDMX localization and stability.
LeBron
Cynthia
C
Molecular Oncology Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Chen
Lihong
L
Gilkes
Daniele M
DM
Chen
Jiandong
J
D048948:14-3-3 Proteins / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000502:physiology*; D004249:DNA Damage; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D048948:14-3-3 Proteins; D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C482984:YWHAH protein, human; D051357:Cyclin-Dependent Kinase 2