Carcinogenesis Advance Access originally published online on July 21, 2009
Carcinogenesis 2009 30(9):1638-1644; doi:10.1093/carcin/bgp170
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Multidirectional tumor-suppressive activity of AIMP2/p38 and the enhanced susceptibility of AIMP2 heterozygous mice to carcinogenesis
1 Center for Medicinal Protein Network and Systems Biology
2 National Research Laboratory of Molecular Carcinogenesis and Chemoprevention
3 WCU Department of Molecular Medicine and Biopharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea
4 Integrated Bioscience and Biotechnology Institute, Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270, Korea
* To whom correspondence should be addressed. Tel: +82 2 880 8180; Fax: +82 2 875 2621; Email: sungkim{at}snu.ac.kr
Aminoacyl-transfer ribonucleic acid (tRNA) synthetases-interacting multifunctional protein (AIMP) 2 is a factor associated with the macromolecular protein synthesis machinery consisting of nine different aminoacyl-tRNA synthetases and three non-enzymatic factors. However, it was shown to work as a multifaceted regulator through the versatile interactions with diverse signal mediators. For instance, it can mediate pro-apoptotic response to DNA damage and tumor necrosis factor-
(TNF-) stimulus and growth-arresting signal by transforming growth factor (TGF)-β. Considering that these pathways are critically implicated in the control of tumorigenesis, AIMP2 is expected to work as a potent tumor suppressor with broad coverage against different cancer types. Here we investigated whether AIMP2 would give gene dosage effect on its pro-apoptotic and anti-proliferative activities using the wild-type, hetero- and homozygous AIMP2 cells and whether AIMP2 would be critical in preventing tumorigenesis using different in vivo tumor models. Both the apoptotic responses to DNA damage and TNF- and sensitivity to growth arresting TGF-β signal were reduced in AIMP2 hetero- and homozygous cells compared with the wild-type cells in dose-dependent manner. In all the in vivo carcinogenesis experiments, reduction of AIMP2 level in heterozygous AIMP2 mice provided higher susceptibility to tumor formation. Thus, this work proves the functional significance of AIMP2 in determination of cell proliferation and death, and as a haploinsufficient tumor suppressor.
Abbreviations: AIMP, aminoacyl-transfer ribonucleic acid synthetases-interacting multifunctional protein; ARS, aminoacyl-transfer ribonucleic acid synthetases; BP, benzo[a]pyrene; BPDE, anti-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide; MEF, mouse embryonic fibroblast; NF-
B, nuclear factor B; TGF, transforming growth factor; TNF-, tumor necrosis factor-; TUNNEL, terminal deoxynucleotidyl transferase mediated dUTP-digoxigenin nick and labeling; UV, ultraviolet
Received April 13, 2009; revised June 26, 2009; accepted July 1, 2009.