한빛사논문
- 조회720
서울대학교
Dae Gyu Kim1,7, Yongseok Choi2,7, Yuno Lee3, Semi Lim1, Jiwon Kong1, JaeHa Song1, Younah Roh1, Dipesh S. Harmalkar2,4, Kwanshik Lee2, Ja-il Goo2, Hye Young Cho5, Ameeq Ul Mushtaq5, Jihye Lee1, Song Hwa Park1, Doyeun Kim1, Byung Soh Min6, Kang Young Lee6, Young Ho Jeon5, Sunkyung Lee3, Kyeong Lee4,* & Sunghoon Kim1,*
1Medicinal Bioconvergence Research Center, Institute for Artificial Intelligence and Biomedical Research, College of Pharmacy & College of Medicine, Gangnam Severance Hospital, Yonsei University, Incheon, Korea. 2Department of Biotechnology, Korea University, Seoul, Korea. 3Drug Information Research Center, Korea Research Institute of Chemical Technology, Daejeon, Korea. 4College of Pharmacy, Dongguk University, Goyang, Korea. 5College of Pharmacy, Korea University, Sejong, Korea. 6Department of Surgery, College of Medicine, Yonsei University, Seoul, Korea. 7These authors contributed equally: Dae Gyu Kim, Yongseok Choi.
*Corresponding author.
Abstract
Recent development of the chemical inhibitors specific to oncogenic KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog) mutants revives much interest to control KRAS-driven cancers. Here, we report that AIMP2-DX2, a variant of the tumor suppressor AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), acts as a cancer-specific regulator of KRAS stability, augmenting KRAS-driven tumorigenesis. AIMP2-DX2 specifically binds to the hypervariable region and G-domain of KRAS in the cytosol prior to farnesylation. Then, AIMP2-DX2 competitively blocks the access of Smurf2 (SMAD Ubiquitination Regulatory Factor 2) to KRAS, thus preventing ubiquitin-mediated degradation. Moreover, AIMP2-DX2 levels are positively correlated with KRAS levels in colon and lung cancer cell lines and tissues. We also identified a small molecule that specifically bound to the KRAS-binding region of AIMP2-DX2 and inhibited the interaction between these two factors. Treatment with this compound reduces the cellular levels of KRAS, leading to the suppression of KRAS-dependent cancer cell growth in vitro and in vivo. These results suggest the interface of AIMP2-DX2 and KRAS as a route to control KRAS-driven cancers.
논문정보
- Research article
- 2022년 05월 (BRIC 등록일 2022-07-26)
- 국내 연구진
- 의약학 > 약학
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