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J. Biol. Chem., Vol. 279, Issue 7, 5387-5396, February 13, 2004

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Expression of Cyclin E Renders Cyclin D-CDK4 Dispensable for Inactivation of the Retinoblastoma Tumor Suppressor Protein, Activation of E2F, and G₁-S Phase Progression^*

Susan M. Keenan, Nathan H. Lents, and Joseph J. Baldassare¶

From the Department of Pharmacological and Physiological Sciences, Saint Louis University School of Medicine, Saint Louis, Missouri 63104

The activation of CDK2-cyclin E in late G₁ phase has been shown to play a critical role in retinoblastoma protein (pRb) inactivation and G₁-S phase progression of the cell cycle. The phosphatidylinositol 3-OH-kinase inhibitor LY294002 has been shown to block cyclin D1 accumulation, CDK4 activity and, thus, G₁ progression in -thrombin-stimulated IIC9 cells (Chinese hamster embryonic fibroblasts). Our previous results show that expression of cyclin E rescues S phase progression in -thrombin-stimulated IIC9 cells treated with LY294002, arguing that cyclin E renders CDK4 activity dispensable for G₁ progression. In this work we investigate the ability of -thrombin-induced CDK2-cyclin E activity to inactivate pRb in the absence of prior CDK4-cyclin D1 activity. We report that in the absence of CDK4-cyclin D1 activity, CDK2-cyclin E phosphorylates pRb in vivo on at least one residue and abolishes pRb binding to E2F response elements. We also find that expression of cyclin E rescues E2F activation and cyclin A expression in cyclin D kinase-inhibited, -thrombin-stimulated cells. Furthermore, the rescue of E2F activity, cyclin A expression, and DNA synthesis by expression of E can be blocked by the expression of either CDK2(D145N) or Rb^CDK, a constitutively active mutant of pRb. However, restoring four known cyclin E-CDK2 phosphorylation sites to Rb^CDK renders it susceptible to inactivation in late G₁, as assayed by E2F activation, cyclin A expression, and S phase progression. These data indicate that CDK2-cyclin E, without prior CDK4-cyclin D activity, can phosphorylate and inactivate pRb, activate E2F, and induce DNA synthesis.

Received for publication, September 21, 2003 , and in revised form, November 21, 2003.

^* 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.

Contributed equally to this work.

Present address: Dept. of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854.

^¶ To whom correspondence should be addressed: Dept. of Pharmacological and Physiological Sciences, Saint Louis University School of Medicine, Saint Louis, MO 63104. Tel.: 314-577-8543; E-mail: baldasjj{at}slu.edu.

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