TY - JOUR
T1 - Competitive ubiquitination activates the tumor suppressor p53
AU - Li, Xingyao
AU - Guo, Mengqi
AU - Cai, Lun
AU - Du, Tingting
AU - Liu, Ying
AU - Ding, Han Fei
AU - Wang, Hongbo
AU - Zhang, Junran
AU - Chen, Xiaoguang
AU - Yan, Chunhong
N1 - Funding Information:
Acknowledgements This work was supported by the National Institutes of Health grants (R01CA139107 and R01CA164006), and the US Department of Defense award (W81XWH1910587) to CY. We thank Dr Ami Aronheim and Dr Jiandong Chen for providing the rJDP2 constructs and the myc-MDMX plasmid, respectively.
Publisher Copyright:
© 2019, The Author(s).
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Blocking p53 ubiquitination through disrupting its interaction with MDM2 or inhibiting the MDM2 catalytic activity is the central mechanism by which the tumor suppressor p53 is activated in response to genotoxic challenges. Although MDM2 is first characterized as the major E3 ubiquitin ligase for p53, it can also catalyze the conjugation of ubiquitin moieties to other proteins (e.g., activating transcription factor 3, or ATF3). Here we report that ATF3 can act as an ubiquitin “trap” and competes with p53 for MDM2-mediated ubiquitination. While ATF3-mediated p53 stabilization required ATF3 binding to the MDM2 RING domain, we demonstrated that ATF3 ubiquitination catalyzed by MDM2 was indispensable for p53 activation in response to DNA damage. Moreover, a cancer-derived ATF3 mutant (R88G) devoid of ubiquitination failed to prevent p53 from MDM2-mediated degradation and thus was unable to activate the tumor suppressor. Therefore, we have identified a previously-unknown mechanism that can activate p53 in the genotoxic response.
AB - Blocking p53 ubiquitination through disrupting its interaction with MDM2 or inhibiting the MDM2 catalytic activity is the central mechanism by which the tumor suppressor p53 is activated in response to genotoxic challenges. Although MDM2 is first characterized as the major E3 ubiquitin ligase for p53, it can also catalyze the conjugation of ubiquitin moieties to other proteins (e.g., activating transcription factor 3, or ATF3). Here we report that ATF3 can act as an ubiquitin “trap” and competes with p53 for MDM2-mediated ubiquitination. While ATF3-mediated p53 stabilization required ATF3 binding to the MDM2 RING domain, we demonstrated that ATF3 ubiquitination catalyzed by MDM2 was indispensable for p53 activation in response to DNA damage. Moreover, a cancer-derived ATF3 mutant (R88G) devoid of ubiquitination failed to prevent p53 from MDM2-mediated degradation and thus was unable to activate the tumor suppressor. Therefore, we have identified a previously-unknown mechanism that can activate p53 in the genotoxic response.
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U2 - 10.1038/s41418-019-0463-x
DO - 10.1038/s41418-019-0463-x
M3 - Article
C2 - 31796886
AN - SCOPUS:85076010894
SN - 1350-9047
VL - 27
SP - 1807
EP - 1818
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 6
ER -
