title: Deletion of ribosomal S6 kinases does not attenuate pathological, physiological, or insulin-like growth factor 1 receptor-phosphoinositide 3-kinase-induced cardiac hypertrophy.
abstract: Ribosomal S6 kinases (S6Ks) have been depicted as critical effectors downstream of growth factor pathways, which play an important role in the regulation of protein synthesis by phosphorylating the ribosomal protein, S6. The goal of this study was to determine whether S6Ks regulate heart size, are critical for the induction of cardiac hypertrophy in response to a pathological or physiological stimulus, and whether S6Ks are critical downstream effectors of the insulin-like growth factor 1 (IGF1)-phosphoinositide 3-kinase (PI3K) pathway. For this purpose, we generated and characterized cardiac-specific S6K1 and S6K2 transgenic mice and subjected S6K1(-/-), S6K2(-/-), and S6K1(-/-) S6K2(-/-) mice to a pathological stress (aortic banding) or a physiological stress (exercise training). To determine the genetic relationship between S6Ks and the IGF1-PI3K pathway, S6K transgenic and knockout mice were crossed with cardiac-specific transgenic mice overexpressing the IGF1 receptor (IGF1R) or PI3K mutants. Here we show that overexpression of S6K1 induced a modest degree of hypertrophy, whereas overexpression of S6K2 resulted in no obvious cardiac phenotype. Unexpectedly, deletion of S6K1 and S6K2 had no impact on the development of pathological, physiological, or IGF1R-PI3K-induced cardiac hypertrophy. These studies suggest that S6Ks alone are not essential for the development of cardiac hypertrophy.
authors.affiliation: Beth Israel Deaconess Medical Center, Cardiovascular Division, 330 Brookline Ave., SL-408, Boston, MA 02215, USA. jmcmulle@bidmc.harvard.edu
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shioi
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Oleg
authors.initials: O
authors.lastname: Tarnavski
authors.forename: Megan C
authors.initials: MC
authors.lastname: Sherwood
authors.forename: Adam L
authors.initials: AL
authors.lastname: Dorfman
authors.forename: Sarah
authors.initials: S
authors.lastname: Longnus
authors.forename: Mario
authors.initials: M
authors.lastname: Pende
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Martin
authors.forename: John
authors.initials: J
authors.lastname: Blenis
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.forename: Seigo
authors.initials: S
authors.lastname: Izumo
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D001011:Aorta / Q000473:pathology; D006332:Cardiomegaly / Q000378:metabolism*; D005260:Female; D005333:Fetus / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009929:Organ Size; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000378:metabolism; D013314:Stress, Mechanical; D013550:Swimming
chemical_list: D000903:Antibiotics, Antineoplastic; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D020123:Sirolimus