MDM2 mediates ubiquitination and degradation of activating transcription factor 3.
Activating transcription factor 3 (ATF3) is a common stress sensor, and its rapid induction by cellular stresses (e.g. DNA damage) is crucial for cells to mount appropriate responses (e.g. activating the tumor suppressor p53) and maintain homeostasis. Although emerging evidence suggests that dysregulation of ATF3 contributes to occurrences of human diseases including cancer, the mechanism(s) by which ATF3 expression is regulated is largely unknown. Here, we demonstrate that mouse double minute 2 (MDM2) is a bona fide E3 ubiquitin ligase for ATF3 and regulates ATF3 expression by promoting its degradation. MDM2 via its C-terminal RING finger can bind to the Basic region of ATF3 and mediate the addition of ubiquitin moieties to the ATF3 leucine zipper domain. As a consequence, ATF3, but not a mutant deficient in MDM2 binding (Delta80-100), is degraded by MDM2-mediated proteolysis. Consistent with these results, ablation of MDM2 in cells not only increases basal ATF3 levels, but results in stabilization of ATF3 in late stages of DNA damage responses. Because ATF3 was recently identified as a p53 activator, these results suggest that MDM2 could inactivate p53 through an additional feedback mechanism involving ATF3. Therefore, we provide the first evidence demonstrating that ATF3 is regulated by a posttranslational mechanism.
Mo
Pingli
P
Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208.
Wang
Hongbo
H
Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208.
Lu
Hua
H
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and IU-Simon Cancer Center, Indianapolis, Indiana 46202.
Boyd
Douglas D
DD
Department of Cancer Biology, M. D. Anderson Cancer Center, Houston, Texas 77030.
Yan
Chunhong
C
Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208. Electronic address: yanc@mail.amc.edu.
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004249:DNA Damage / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051379:Mice; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*; D016335:Zinc Fingers
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2