한빛사 논문
Semi Lim1,6, Hye Young Cho2,6, Dae Gyu Kim1, Younah Roh1, Se-Young Son2, Ameeq Ul Mushtaq2, Minkyoung Kim3, Deepak Bhattarai3, Aneesh Sivaraman3, Youngjin Lee4, Jihye Lee1, Won Suk Yang1, Hoi Kyoung Kim1, Myung Hee Kim4, Kyeong Lee3, Young Ho Jeon2 and Sunghoon Kim1,5,*
1 Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
2 College of Pharmacy, Korea University, Sejong, Republic of Korea.
3 College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea.
4 Infection and Immunity Research Laboratory, Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
5 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
6 These authors contributed equally: Semi Lim, Hye Young Cho.
*Correspondence to Sunghoon Kim
Abstract
A tumorigenic factor, AIMP2 lacking exon 2 (AIMP2-DX2), is often upregulated in many cancers. However, how its cellular level is determined is not understood. Here, we report heat-shock protein HSP70 as a critical determinant for the level of AIMP2-DX2. Interaction of the two factors was identified by interactome analysis and structurally determined by X-ray crystallography and NMR analyses. HSP70 recognizes the amino (N)-terminal flexible region, as well as the glutathione S-transferase domain of AIMP2-DX2, via its substrate-binding domain, thus blocking the Siah1-dependent ubiquitination of AIMP2-DX2. AIMP2-DX2-induced cell transformation and cancer progression in vivo was further augmented by HSP70. A positive correlation between HSP70 and AIMP2-DX2 levels was shown in various lung cancer cell lines and patient tissues. Chemical intervention in the AIMP2-DX2–HSP70 interaction suppressed cancer cell growth in vitro and in vivo. Thus, this work demonstrates the importance of the interaction between AIMP2-DX2 and HSP70 on tumor progression and its therapeutic potential against cancer.
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