title: Transgenic overexpression of USP15 in the heart induces cardiac remodeling in mice.
abstract: We found a novel protein-protein interaction between ubiquitin-specific protease 15 (USP15) and skeletal muscle LIM protein 1 (SLIM1): USP15 and SLIM1 directly bound under cell-free conditions and co-immunoprecipitated from the lysates of the cells, where they were co-expressed; and USP15 deubiquitinated SLIM1, resulting in the increase of protein levels of SLIM1. Because SLIM1 is strongly implicated in the pathogenesis of myopathies and cardiomyopathies, we generated transgenic (TG) mice with cardiac-specific overexpression of human USP15. Heart weight to body weight ratios and mRNA levels of fetal gene markers in the heart were significantly higher in USP15-TG mice than in wild-type (WT) mice. Also, protein levels of endogenous murine SLIM1 in the heart were significantly higher in USP15-TG mice than in WT mice. Furthermore, the protein of alternatively spliced isoform of SLIM1 was only detected in the heart of USP15-TG mice, and mRNA levels of this isoform were higher as compared to WT mice. These results indicate that USP15 is involved in the regulation of hypertrophic responses in cardiac muscle through transcriptional and post-translational modulation of SLIM1.
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Isumi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hirata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saitoh
authors.forename: Tomoya
authors.initials: T
authors.lastname: Miyakawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Murakami
authors.forename: Gen
authors.initials: G
authors.lastname: Kudoh
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Doi
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Ishibashi
authors.forename: Hiroto
authors.initials: H
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D060588:LIM Domain Proteins; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D064570:Ubiquitin-Specific Proteases
chemical_list: C101149:FHL1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D010450:Endopeptidases; C579226:USP15 protein, human; D064570:Ubiquitin-Specific Proteases; C579225:Usp15 protein, mouse