title: Compensation of the AKT signaling by ERK signaling in transgenic mice hearts overexpressing TRIM72.
abstract: The AKT and ERK signaling pathways are known to be involved in cell hypertrophy, proliferation, survival and differentiation. Although there is evidence for crosstalk between these two signaling pathways in cellulo, there is less evidence for cross talk in vivo. Here, we show that crosstalk between AKT and ERK signaling in the hearts of TRIM72-overexpressing transgenic mice (TRIM72-Tg) with alpha-MHC promoter regulates and maintains their heart size. TRIM72, a heart- and skeletal muscle-specific protein, downregulates AKT-mTOR signaling via IRS-1 degradation and reduces the size of rat cardiomyocytes and the size of postnatal TRIM72-Tg hearts. TRIM72 expression was upregulated by hypertrophic inducers in cardiomyocytes, while IRS-1 was downregulated by IGF-1. TRIM72 specifically regulated IGF-1-dependent AKT-mTOR signaling, resulting in a reduction of the size of cardiomyocytes. Postnatal TRIM72-Tg hearts were smaller than control-treated hearts with inhibition of AKT-mTOR signaling. However, adult TRIM72-Tg hearts were larger than of control despite the suppression of AKT-mTOR signaling. Activation of ERK, PKC-α, and JNK were observed to be elevated in adult TRIM72-Tg, and these signals were mediated by ET-1 via the ET receptors A and B. Altogether, these results suggest that AKT signaling regulates cardiac hypertrophy in physiological conditions, and ERK signaling compensates for the absence of AKT signaling during TRIM72 overexpression, leading to pathological hypertrophy.
authors.affiliation: College of Life Science and Biotechnology, Korea University, Seoul, Republic of Korea. youngmi_ham@hms.harvard.edu
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Ham
authors.forename: Sarah Jane
authors.initials: SJ
authors.lastname: Mahoney
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D010766:Phosphorylation; D011247:Pregnancy; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C538824:MG53 protein, mouse; D008565:Membrane Proteins; C551613:Myh7 protein, mouse; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D007334:Insulin-Like Growth Factor I; C546843:mTOR protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D018995:Myosin Heavy Chains