Differential activation of p70 and p85 S6 kinase isoforms during cardiac hypertrophy in the adult mammal.
An adult feline right ventricular pressure overload (RVPO) model was used to examine the two S6 kinase (S6K) isoforms, p70(S6K) and p85(S6K), that are involved in translational and transcriptional activation. Biochemical and confocal microscopy analyses at the level of the cardiocyte revealed that p70(S6K) is present predominantly in the cytosol, substantially activated in 1-h RVPO (>12 fold), and phosphorylated in the pseudosubstrate domain at the Ser-411, Thr-421, and Ser-424 sites. p85(S6K), which was localized exclusively in the nucleus, showed activation subsequent to p70(S6K), with a sustained increase in phosphorylation for up to 48 h of RVPO at equivalent sites of p70(S6K), Thr-421 and Ser-424, but not at Ser-411. Neither isoform translocated between the cytosol and the nucleus. Further studies to determine potential upstream elements of S6K activation revealed: (i) similar time course of activation for protein kinase C isoforms (alpha, gamma, and epsilon) and c-Raf, (ii) absence of accompanying phosphatidylinositol 3-kinase activation, (iii) activation of c-Src subsequent to p70(S6K), and (iv) similar changes in adult cardiocytes after treatment with 12-O-tetradecanoylphorbol-13-acetate. Thus, these studies suggest that a protein kinase C-mediated pathway couples pressure overload to growth induction via differential activation of S6K isoforms in cardiac hypertrophy.
Laser
M
M
Cardiology Division, Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Kasi
V S
VS
Hamawaki
M
M
Cooper
G
G
Kerr
C M
CM
Kuppuswamy
D
D
D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology; D002415:Cats; D002462:Cell Membrane / Q000201:enzymology; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation; D005260:Female; D007527:Isoenzymes / Q000302:isolation & purification / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008322:Mammals; D018613:Microscopy, Confocal; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000302:isolation & purification / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D019893:Ribosomal Protein S6 Kinases; D013755:Tetradecanoylphorbol Acetate