MAP KINASE-DEPENDENT AND RHO-DEPENDENT SIGNALS INTERACT TO REGULATE GENE-EXPRESSION BUT NOT ACTIN MORPHOLOGY IN CARDIAC-MUSCLE-CELLS

Post-natal growth of cardiac muscle cells occurs by hypertrophy rather than division and is associated with changes in gene expression and m uscle fiber morphology. We show here that the protein kinase MEKK1 can induce reporter gene expression from the atrial natriuretic factor (A NF) promoter, a genetic marker that is activated during in vivo hypert rophy, MEKK1 induced both stress-activated protein kinase (SAPK) and e xtracellular signal-regulated protein kinase (ERK) activity; however, while the SAPK cascade stimulated ANF expression, activation of the ER K cascade inhibited expression, C3 transferase, a specific inhibitor o f the small GTPase Rho, also inhibited both MEKK- and phenylephrine-in duced ANF expression, indicating an additional requirement for Rho-dep endent signals, Microinjection or transfection of C3 transferase into the same cells did not disrupt actin muscle fiber morphology, indicati ng that Rho-dependent pathways do not regulate actin morphology in car diac muscle cells. While active MEKK1 was a potent activator of hypert rophic gene expression, this kinase did not induce actin organization and prevented phenylephrine-induced organization, These data suggest t hat multiple signals control hypertrophic phenotypes. Positive and neg ative signals mediated by parallel MAP kinase cascades interact with R ho-dependent pathways to regulate hypertrophic gene expression while o ther signals induce muscle fiber morphology in cardiac muscle cells.