TY - JOUR
T1 - SCFβ-TrCP ubiquitinates CHK1 in an AMPK-dependent manner in response to glucose deprivation
AU - Ma, Ying
AU - Cui, Danrui
AU - Xiong, Xiufang
AU - Inuzuka, Hiroyuki
AU - Wei, Wenyi
AU - Sun, Yi
AU - North, Brian J.
AU - Zhao, Yongchao
N1 - Funding Information:
The authors would like to thank Dr. Wei Liu for the AMPK-WT-MYC α2 and AMPK-DN-MYC α1 plasmids. This work was supported by the National Natural Science Foundation of China (31470753 and 81672728 to YZ), the National Key R&D Program of China (2016YFA0501800 to YZ, XX and YS), the Natural Science Foundation of Zhejiang Province (LR16C050001 to YZ), the National Institutes of Health, USA (AG052627 to BJN, GM094777 and CA229307 to WW, and CA156744 to YS), American Cancer Society Research Scholar grants to HI, and China Scholarship Council (CSC) (201706320150 to YM).
Publisher Copyright:
© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
PY - 2019/2
Y1 - 2019/2
N2 - The ATR/CHK1 pathway is a key effector of cellular response to DNA damage and therefore is a critical regulator of genomic stability. While the ATR/CHK1 pathway is often inactivated by mutations, CHK1 itself is rarely mutated in human cancers. Thus, cellular levels of CHK1 likely play a key role in the maintenance of genomic stability and preventing tumorigenesis. Glucose deprivation is observed in many solid tumors due to high glycolytic rates of cancer cells and insufficient vascularization, yet cancer cells have devised mechanisms to survive in conditions of low glucose. Although CHK1 degradation through the ubiquitin–proteasome pathway following glucose deprivation has been previously reported, the detailed molecular mechanisms remain elusive. Here, we show that CHK1 is ubiquitinated and degraded upon glucose deprivation by the Skp1-Cullin-F-box (β-TrCP) E3 ubiquitin ligase. Specifically, CHK1 contains a β-TrCP recognizable degron domain, which is phosphorylated by AMPK in response to glucose deprivation, allowing for β-TrCP to recognize CHK1 for subsequent ubiquitination and degradation. Our results provide a novel mechanism by which glucose metabolism regulates a DNA damage effector, and imply that glucose deprivation, which is often found in solid tumor microenvironments, may enhance mutagenesis, clonal expansion, and tumor progression by triggering CHK1 degradation.
AB - The ATR/CHK1 pathway is a key effector of cellular response to DNA damage and therefore is a critical regulator of genomic stability. While the ATR/CHK1 pathway is often inactivated by mutations, CHK1 itself is rarely mutated in human cancers. Thus, cellular levels of CHK1 likely play a key role in the maintenance of genomic stability and preventing tumorigenesis. Glucose deprivation is observed in many solid tumors due to high glycolytic rates of cancer cells and insufficient vascularization, yet cancer cells have devised mechanisms to survive in conditions of low glucose. Although CHK1 degradation through the ubiquitin–proteasome pathway following glucose deprivation has been previously reported, the detailed molecular mechanisms remain elusive. Here, we show that CHK1 is ubiquitinated and degraded upon glucose deprivation by the Skp1-Cullin-F-box (β-TrCP) E3 ubiquitin ligase. Specifically, CHK1 contains a β-TrCP recognizable degron domain, which is phosphorylated by AMPK in response to glucose deprivation, allowing for β-TrCP to recognize CHK1 for subsequent ubiquitination and degradation. Our results provide a novel mechanism by which glucose metabolism regulates a DNA damage effector, and imply that glucose deprivation, which is often found in solid tumor microenvironments, may enhance mutagenesis, clonal expansion, and tumor progression by triggering CHK1 degradation.
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U2 - 10.1002/1878-0261.12403
DO - 10.1002/1878-0261.12403
M3 - Article
C2 - 30428154
AN - SCOPUS:85057985646
VL - 13
SP - 307
EP - 321
JO - Molecular Oncology
JF - Molecular Oncology
SN - 1574-7891
IS - 2
ER -