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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,
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.

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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