Right ventricular pressure overload induced differential activation of S6 kinase isoforms, with p70(S6K) activated >12-fold at 1 hour in the cytosol, followed by sustained p85(S6K) activation.
The study identifies a protein kinase C-mediated pathway that couples pressure overload to cardiac growth induction via differential spatial and temporal activation of S6 kinase isoforms.
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 et al. (Tue,) conducted a other in Cardiac hypertrophy. Right ventricular pressure overload (RVPO) was evaluated on Activation of p70(S6K) and p85(S6K) isoforms. Right ventricular pressure overload induced differential activation of S6 kinase isoforms, with p70(S6K) activated >12-fold at 1 hour in the cytosol, followed by sustained p85(S6K) activation.