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Cancer-Associated Splicing Variant of Tumor Suppressor AIMP2/p38: Pathological Implication in Tumorigenesis

Jin Woo Choi1, Dae Gyu Kim1, Al-Eum Lee1, Hye Rim Kim1, Jin Young Lee1, Nam Hoon Kwon1, Young Kee Shin2, Soon-Kyung Hwang3, Seung-Hee Chang3, Myung-Haing Cho3, Yoon-La Choi4, Jhingook Kim5, Seung Hyun Oh6, Bora Kim6, Soo-Youl Kim6, Hyo-Sung Jeon7, Jae Yong Park8, Hyunseok Peter Kang9, Bum Joon Park10, Jung Min Han1,11, Sunghoon Kim1,11*

1 Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea, 2 Laboratory of Molecular Pathology, College of Pharmacy, Seoul National University, Seoul, Korea, 3 College of Veterinary Medicine, Seoul National University, Seoul, Korea, 4 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, 5 Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, 6 National Cancer Center, Research Institute, Goyang, Korea, 7 Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu, Korea, 8 Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea, 9 Department of Pathology and Laboratory Medicine, Roswell Cancer Park Institute, Buffalo, New York, United States of America, 10 Department of Molecular Biology, Pusan National University, Pusan, Korea, 11 WCU Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Suwon, Korea

Although ARS-interacting multifunctional protein 2 (AIMP2, also named as MSC p38) was first found as a component for a macromolecular tRNA synthetase complex, it was recently discovered to dissociate from the complex and work as a potent tumor suppressor. Upon DNA damage, AIMP2 promotes apoptosis through the protective interaction with p53. However, it was not demonstrated whether AIMP2 was indeed pathologically linked to human cancer. In this work, we found that a splicing variant of AIMP2 lacking exon 2 (AIMP2-DX2) is highly expressed by alternative splicing in human lung cancer cells and patient's tissues. AIMP2-DX2 compromised pro-apoptotic activity of normal AIMP2 through the competitive binding to p53. The cells with higher level of AIMP2-DX2 showed higher propensity to form anchorage-independent colonies and increased resistance to cell death. Mice constitutively expressing this variant showed increased susceptibility to carcinogen-induced lung tumorigenesis. The expression ratio of AIMP2-DX2 to normal AIMP2 was increased according to lung cancer stage and showed a positive correlation with the survival of patients. Thus, this work identified an oncogenic splicing variant of a tumor suppressor, AIMP2/p38, and suggests its potential for anti-cancer target.

Author Summary
Lung cancer is one of the most common cancers and a leading cause of death resulting from cancer. Despite intensive investigation, effective therapeutic targets and reliable biomarkers are still limited. Here we found that a tumor suppressor, AIMP2 (MSC p38), produces a variant lacking a part of its structure in cancer tissues. We designated it AIMP2-DX2. This smaller version of AIMP2 compromises the normal tumor suppressive activity of AIMP2 and induces tumor formation. We also found that the expression of AIMP2-DX2 was increased according to cancer progression. In addition, the patients with higher expression of AIMP2-DX2 showed lower survival than those with lower levels of this variant. Suppression of AIMP2-DX2 slowed tumor growth, suggesting it as a new therapeutic target. In summary, this work newly identified a tumor-inducing factor, AIMP2-DX2, that can be used as a therapeutic target and biomarker associated with lung cancer.

Citation: Choi JW, Kim DG, Lee A-E, Kim HR, Lee JY, et al. (2011) Cancer-Associated Splicing Variant of Tumor Suppressor AIMP2/p38: Pathological Implication in Tumorigenesis. PLoS Genet 7(3): e1001351. doi:10.1371/journal.pgen.1001351

Editor: Bruce E. Clurman, Fred Hutchinson Cancer Research Center, United States of America

Received: September 13, 2010; Accepted: February 23, 2011; Published: March 31, 2011

Copyright: ⓒ 2011 Choi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by the Global Frontier (NRF-M1AXA002-2010-0029785), Acceleration Research (R17-2007-020-01000-0), and 21st Frontier Functional Proteomics Research (M108KM010027-08K1301-02710) grants of National Research Foundation funded by the Ministry of Education, Science, and Technology of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

2011년 선정
- 형식: Research article
- 게재일: 2011년 03월 (BRIC 등록일 2011-04-04)
- 연구진: 국내(교신)+국외 연구진태극기
- 분야: Genetics
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발표: 김현민 (KAIST)
일자: 2020년 9월 29일 (화) 오후 02시 (한국시간)
언어: 한국어
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