Downregulation of lamin A by tumor suppressor AIMP3/p18 leads to a progeroid phenotype in mice.
Although AIMP3/p18 is normally associated with the macromolecular tRNA synthetase complex, recent reports have revealed a new role of AIMP3 in tumor suppression. In this study, we generated a transgenic mouse that overexpresses AIMP3 and characterized the associated phenotype in vivo and in vitro. Surprisingly, the AIMP3 transgenic mouse exhibited a progeroid phenotype, and the cells that overexpressed AIMP3 showed accelerated senescence and defects in nuclear morphology. We found that overexpression of AIMP3 resulted in proteasome-dependent degradation of mature lamin A, but not of lamin C, prelamin A, or progerin. The resulting imbalance in the protein levels of lamin A isoforms, namely altered stoichiometry of prelamin A and progerin to lamin A, appeared to be responsible for a phenotype that resembled progeria. An increase in the level of endogenous AIMP3 has been observed in aged human tissues and cells. The findings in this report suggest that AIMP3 is a specific regulator of mature lamin A and imply that enhanced expression of AIMP3 might be a factor driving cellular and/or organismal aging.
Oh
Young Sun
YS
Center for Medicinal Protein Network and Systems Biology, Seoul National University, Korea.
Kim
Dae Gyu
DG
Kim
Gyuyoup
G
Choi
Eung-Chil
EC
Kennedy
Brian K
BK
Suh
Yousin
Y
Park
Bum Joon
BJ
Kim
Sunghoon
S
D000375:Aging; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D006367:HeLa Cells; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010445:Peptide Elongation Factors / Q000378:metabolism*; D010641:Phenotype; D011371:Progeria / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C529799:EEF1E1 protein, human; D034904:Lamin Type A; D010445:Peptide Elongation Factors; D025521:Tumor Suppressor Proteins; D046988:Proteasome Endopeptidase Complex