Endogenous mono-ADP-ribosylation mediates smooth muscle cell proliferation and migration via protein kinase N-dependent induction of c-fos expression

Authors


  • Enzymes: poly(ADP-ribose) polymerase (EC 2.4.2.30); mono-ADP-ribosyltransferase, arginine-dependent (EC 2.4.2.31); protein kinase N/PRK1 (EC 2.7.1.37); extracellular signal-regulated (MAP) kinase (EC 2.7.1.37); 1-phosphatidylinositol 3-kinase (EC 2.7.1.137); Rho (EC 3.6.1.47).

P. Zahradka, Institute of Cardiovascular Sciences, Boniface Research Centre, 351 Tache Avenue, Winnipeg, MB, Canada., Fax: +1 204 233 6723, Tel.: +1 204 235 3507, E-mail: peterz@sbrc.ca

Abstract

ADP-ribosylation has been coupled to intracellular events associated with smooth muscle cell vasoreactivity, cytoskeletal integrity and free radical damage. Additionally, there is evidence that ADP-ribosylation is required for smooth muscle cell proliferation. Our investigation employed selective inhibitors to establish that mono-ADP-ribosylation and not poly(ADP-ribosyl)ation was necessary for the stimulation of DNA synthesis by mitogens. Mitogen treatment increased concomitantly the activity of both soluble and particulate mono-ADP-ribosyltransferase, as well as the number of modified proteins. Inclusion of meta-iodobenzylguanidine (MIBG), a selective decoy substrate of arginine-dependent mono-ADP-ribosylation, prevented the modification of these proteins. MIBG also blocked the stimulation of DNA and RNA synthesis, prevented smooth muscle cell migration and suppressed the induction of c-fos and c-myc gene expression. An examination of relevant signal transduction pathways showed that MIBG did not interfere with MAP kinase and phosphatidylinositol 3-kinase stimulation; however, it did inhibit phosphorylation of the Rho effector, PRK1/2. This novel observation suggests that mono-ADP-ribosylation participates in a Rho- dependent signalling pathway that is required for immediate early gene expression.

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