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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,
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,
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.
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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