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Originally published In Press as doi:10.1074/jbc.M102047200 on September 10, 2001

J. Biol. Chem., Vol. 276, Issue 46, 42834-42842, November 16, 2001
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Protein Kinase C Isoforms Involved in the Transcriptional Activation of Cyclin D1 by Transforming Ha-Ras*

Sonja KampferDagger §, Michaela WindeggerDagger §, Franz HochholdingerDagger , Wolfgang SchwaigerDagger , Richard G. Pestell, Gottfried Baier||, Hans H. GrunickeDagger , and Florian ÜberallDagger **

From the Dagger  Institute of Medical Chemistry and Biochemistry, University of Innsbruck, A-6020 Innsbruck, Austria, the  Albert Einstein College of Medicine, Bronx, New York 10461, and the || Institute of Medical Biology and Human Genetics, University of Innsbruck, A-6020 Innsbruck, Austria

Transcriptional activation of the cyclin D1 by oncogenic Ras appears to be mediated by several pathways leading to the activation of multiple transcription factors which interact with distinct elements of the cyclin D1 promoter. The present investigations revealed that cyclin D1 induction by transforming Ha-Ras is MEK- and Rac-dependent and requires the PKC isotypes epsilon , lambda , and zeta , but not cPKC-alpha . This conclusion is based on observations indicating that cyclin D1 induction by transforming Ha-Ras was depressed in a dose-dependent manner by PD98059, a selective inhibitor of the mitogen-activated kinase kinase MEK-1, demonstrating that Ha-Ras employs extracellular signal-regulated kinases (ERKs) for signal transmission to the cyclin D1 promoter. Evidence is presented that PKC isotypes epsilon  and zeta , but not lambda  are required for the Ras-mediated activation of ERKs. Expression of kinase-defective, dominant negative (DN) mutants of nPKC-epsilon or aPKC-zeta inhibit ERK activation by constitutively active Raf-1. Phosphorylation within the TEY motif and subsequent activation of ERKs by constitutively active MEK-1 was significantly inhibited by DN aPKC-zeta , indicating that aPKC-zeta functions downstream of MEK-1 in the pathway leading to cyclin D1 induction. In contrast, TEY phosphorylation induced by constitutively active MEK-1 was not effected by nPKC-epsilon , suggesting another position for this kinase within the cascade investigated. Transformation by oncogenic Ras requires activation of several Ras effector pathways which may be PKC-dependent and converge on the cyclin D1 promoter. Therefore, we investigated a role for PKC isotypes in the Ras-Rac-mediated transcriptional regulation of cyclin D1. We have been able to reveal that cyclin D1 induction by oncogenic Ha-Ras is Rac-dependent and requires the PKC isotypes epsilon , lambda , and zeta , but not cPKC-alpha . Evidence is presented that aPKC-lambda acts upstream of Rac, between Ras and Rac, whereas the PKC isotypes epsilon  and zeta  act downstream of Rac and are required for the activation of ERKs.

* This work was supported in part by Austrian Research Council Grant F208 (FWF), Special Research Centre (SFB) Biological communication systems, P-12104-MED, and Byk-Gulden Lomberg Chemische Fabrik, Konstanz, Germany.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Contributed equally to the results of this work.

** To whom correspondence should be addressed: Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Fritz Preglstr. 3, A-6020 Innsbruck, Austria. Tel.: 43-512-507-3536; Fax: 43-512-507-2872; E-mail: Florian.Ueberall@uibk.ac.at.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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