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Stabilization of Cyclin-Dependent Kinase 4 by Methionyl-tRNA Synthetase in p16INK4a-Negative Cancer

Authors
 Nam Hoon Kwon  ;  Jin Young Lee  ;  Ye-lim Ryu  ;  Chanhee Kim  ;  Jiwon Kong  ;  Seongeun Oh  ;  Beom Sik Kang  ;  Hye Won Ahn  ;  Sung Gwe Ahn  ;  Joon Jeong  ;  Hoi Kyoung Kim  ;  Jong Hyun Kim  ;  Dae Young Han  ;  Min Chul Park  ;  Doyeun Kim  ;  Ryuichi Takase  ;  Isao Masuda  ;  Ya-Ming Hou  ;  Sung Ill Jang  ;  Yoon Soo Chang  ;  Dong Ki Lee  ;  Youngeun Kim  ;  Ming-Wei Wang  ;  Basappa  ;  Sunghoon Kim 
Citation
 ACS Pharmacology & Translational Science, Vol.1(1) : 21-31, 2018 
Journal Title
 ACS Pharmacology & Translational Science 
Issue Date
2018
Keywords
CDK4 ; cell cycle ; HSP90 ; methionyl-tRNA synthetase ; p16INK4a
Abstract
Although abnormal increases in the level or activity of cyclin-dependent kinase 4 (CDK4) occur frequently in cancer, the underlying mechanism is not fully understood. Here, we show that methionyl-tRNA synthetase (MRS) specifically stabilizes CDK4 by enhancing the formation of the complex between CDK4 and a chaperone protein. Knockdown of MRS reduced the CDK4 level, resulting in G0/G1 cell cycle arrest. The effects of MRS on CDK4 stability were more prominent in the tumor suppressor p16INK4a-negative cancer cells because of the competitive relationship of the two proteins for binding to CDK4. Suppression of MRS reduced cell transformation and the tumorigenic ability of a p16INK4a-negative breast cancer cell line in vivo. Further, the MRS levels showed a positive correlation with those of CDK4 and the downstream signals at high frequency in p16INK4a-negative human breast cancer tissues. This work revealed an unexpected functional connection between the two enzymes involving protein synthesis and the cell cycle.
Full Text
https://pubs.acs.org/doi/10.1021/acsptsci.8b00001
DOI
10.1021/acsptsci.8b00001
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Dong Ki(이동기) ORCID logo https://orcid.org/0000-0002-0048-9112
Jang, Sung Ill(장성일) ORCID logo https://orcid.org/0000-0003-4937-6167
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/165159
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