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J. Biol. Chem., Vol. 278, Issue 29, 26533-26540, July 18, 2003

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Cyclic AMP-dependent Phosphorylation of Cyclin D3-bound CDK4 Determines the Passage through the Cell Cycle Restriction Point in Thyroid Epithelial Cells^*

Sabine Paternot  , Katia Coulonval  ¶, Jacques E. Dumont  and Pierre P. Roger  ¶ ||

From the Institute of Interdisciplinary Research and ^¶Protein Chemistry Department, Faculté de Médecine, Université Libre de Bruxelles, Campus Erasme, B-1070 Brussels, Belgium

According to current concepts, the cell cycle commitment after restriction (R) point passage requires the sustained stimulation by mitogens of the synthesis of labile D-type cyclins, which associate with cyclin-dependent kinase (CDK) 4/6 to phosphorylate pRb family proteins and sequester the CDK inhibitor p27^kip1. In primary cultures of dog thyroid epithelial cells, the cAMP-dependent cell cycle induced by a sustained stimulation by thyrotropin or forskolin differs from growth factor mitogenic pathways, as cAMP does not upregulate D-type cyclins but increases p27 levels. Instead, cAMP induces the assembly of required cyclin D3-CDK4 complexes, which associate with nuclear p27. In this study, the arrest of forskolin stimulation rapidly slowed down the entry of dog thyrocytes into S phase and the phosphorylation of pRb family proteins. The pRb kinase activity, but not the formation, of the cyclin D3-CDK4-p27 complex was strongly reduced. Using two-dimensional gel electrophoresis, a phosphorylated form of CDK4 was separated. It appeared in response to forskolin and was bound to both cyclin D3 and p27, presumably reflecting the activating Thr-172 phosphorylation of CDK4. Upon forskolin withdrawal or after cycloheximide addition, this CDK4 phosphoform unexpectedly persisted in p27 complexes devoid of cyclin D3 but it disappeared from the more labile cyclin D3 complexes. These data demonstrate that the assembly of the cyclin D3-CDK4-p27 holoenzyme and the subsequent phosphorylation and activation of CDK4 depend on distinct cAMP actions. This provides a first example of a crucial regulation of CDK4 phosphorylation by a mitogenic cascade and a novel mechanism of cell cycle control at the R point.

Received for publication, March 11, 2003 , and in revised form, April 25, 2003.

^* This study was supported by grants from the National Fund for Scientific Research (FNRS), the Belgian Fund for Scientific Medical Research (FRSM), Télévie, and the Fortis Bank cancer research fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Fellow of the Fonds pour la Formation à la Recherche dans l'Industrie et l'Agriculture (FRIA).

^|| Research Associate of the FNRS. To whom correspondence should be addressed: I.R.I.B.H.M., ULB, Campus Erasme, Bldg. C, 808 Route de Lennik, B-1070 Brussels, Belgium. Tel.: 322-555-4153; Fax: 322-555-4655; E-mail: proger{at}ulb.ac.be.

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