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Molecular and Cellular Biology, November 2001, p. 7607-7616, Vol. 21, No. 22
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.22.7607-7616.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Distinct Effects of Mitogens and the Actin Cytoskeleton on CREB and Pocket Protein Phosphorylation Control the Extent and Timing of Cyclin A Promoter Activity

Maria Elena Bottazzi,1 Monica Buzzai,1 Xiaoyun Zhu,1,dagger Chantal Desdouets,2 Christian Bréchot,2 and Richard K. Assoian1,*

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084,1 and Institut National de la Santé et de la Recherche Médicale U370, Faculté Necker, 75742 Paris Cedex 15, France2

Received 3 April 2001/Returned for modification 8 May 2001/Accepted 13 August 2001

Soluble mitogens and adhesion-dependent organization of the actin cytoskeleton are required for cells to enter S phase in fibroblasts. The induction of cyclin A is also required for S-phase entry, and we now report that distinct effects of mitogens and the actin cytoskeleton on the phosphorylation of CREB and pocket proteins regulate the extent and timing of cyclin A promoter activity, respectively. First, we show that CREB phosphorylation and binding to the cyclic AMP response element (CRE) determines the extent, but not the timing, of cyclin A promoter activity. Second, we show that pocket protein inactivation regulates the timing, but not the extent, of cyclin A promoter activity. CREB phosphorylation and CRE occupancy are regulated by soluble mitogens alone, while the phosphorylation of pocket proteins requires both mitogens and the organized actin cytoskeleton. Mechanistically, cytoskeletal integrity controls pocket protein phosphorylation by allowing for sustained ERK signaling and, thereby, the expression of cyclin D1. Our results lead to a model of cyclin A gene regulation in which mitogens play a permissive role by stimulating early G1-phase phosphorylation of CREB and a distinct regulatory role by cooperating with the organized actin cytoskeleton to regulate the duration of ERK signaling, the expression of cyclin D1, and the timing of pocket protein phosphorylation.

* Corresponding author. Mailing address: Department of Pharmacology, University of Pennsylvania School of Medicine, 167 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104-6084. Phone: (215) 898-7157. Fax: (215) 573-5656. E-mail: rka{at}pharm.med.upenn.edu.

dagger Present address: Sunol Molecular Corp., Miramar, Fla.

Molecular and Cellular Biology, November 2001, p. 7607-7616, Vol. 21, No. 22
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.22.7607-7616.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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