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Molecular and Cellular Biology, November 1998, p. 6729-6736, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

A Ras-Dependent Pathway Regulates RNA Polymerase II Phosphorylation in Cardiac Myocytes: Implications for Cardiac Hypertrophy

Maha Abdellatif,1,* Sharon E. Packer,1 Lloyd H. Michael,1 Dou Zhang,1 Min Ji Charng,1,dagger and Michael D. Schneider1,2

Molecular Cardiology Unit, Department of Medicine1 and Departments of Cell Biology and Molecular Physiology & Biophysics,2 Baylor College of Medicine, Houston, Texas 77030

Received 23 April 1998/Returned for modification 19 June 1998/Accepted 4 August 1998

Despite extensive evidence implicating Ras in cardiac muscle hypertrophy, the mechanisms involved are unclear. We previously reported that Ras, through an effector-like function of Ras GTPase-activating protein (GAP) in neonatal cardiac myocytes (M. Abdellatif et al., J. Biol. Chem. 269:15423-15426, 1994; M. Abdellatif and M. D. Schneider, J. Biol. Chem. 272:527-533, 1997), can up-regulate expression from a comprehensive set of promoters, including both cardiac cell-specific and constitutive ones. To investigate the mechanism(s) underlying these earlier findings, we have used recombinant adenoviruses harboring a dominant negative Ras (17N Ras) allele or the N-terminal domain of GAP (nGAP), responsible for the Ras-like effector function. Inhibition of endogenous Ras reduced basal levels of [3H]uridine and [3H]phenylalanine incorporation into total RNA, mRNA, and protein, with parallel changes in apparent cell size. In addition, 17N Ras markedly inhibited phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (pol II), known to regulate transcript elongation, accompanied by down-regulation of its principal kinase, cyclin-dependent kinase 7 (Cdk7). In contrast, nGAP elicited the opposite effects on each of these parameters. Furthermore, cotransfection of constitutively active Ras (12R Ras) with wild-type pol II, rather than a truncated mutant lacking the CTD, demonstrated that Ras activation of transcription was dependent on the pol II CTD. Consistent with a potential role for this pathway in the development of cardiac myocyte hypertrophy, alpha 1-adrenergic stimulation similarly enhanced pol II phosphorylation and Cdk7 expression, where both effects were inhibited by dominant negative Ras, while pressure overload hypertrophy led to an increase in both hyperphosphorylated and hypophosphorylated pol II in addition to Cdk7.

* Corresponding author. Mailing address: Department of Medicine, Molecular Cardiology Unit, One Baylor Plaza, Room 506C, Houston, TX 77030. Phone: (713) 798-6912. Fax: (713) 798-7437. E-mail: mahaa{at}bcm.tmc.edu.

dagger Present address: Department of Medicine, Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan.

Molecular and Cellular Biology, November 1998, p. 6729-6736, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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