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Cyclin D1 Degradation Is Sufficient to Induce G₁ Cell Cycle Arrest despite Constitutive Expression of Cyclin E2 in Ovarian Cancer Cells

Departments of ¹ Biochemistry and Molecular Biology and ² Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Requests for reprints: Doris Mangiaracina Benbrook, Department of Obstetrics and Gynecology, Oklahoma University Health Science Center, Oklahoma City, OK 73104. Phone: 405-271-5523; Fax: 405-271-3874; E-mail: Doris-Benbrook{at}ouhsc.edu.

Key Words: cyclin D1 • cyclin E2 • G₁ arrest • p21 • pRb

D- and E-type cyclins mediate G₁-S phase cell cycle progression through activation of specific cyclin-dependent kinases (cdk) that phosphorylate the retinoblastoma protein (pRb), thereby alleviating repression of E2F-DP transactivation of S-phase genes. Cyclin D1 is often overexpressed in a variety of cancers and is associated with tumorigenesis and metastasis. Loss of cyclin D can cause G₁ arrest in some cells, but in other cellular contexts, the downstream cyclin E protein can substitute for cyclin D and facilitate G₁-S progression. The objective of this study was to determine if a flexible heteroarotinoid anticancer compound, SHetA2, regulates cell cycle proteins and cell cycle progression in ovarian cancer cells. SHetA2 induced cyclin D1 phosphorylation, ubiquitination, and proteasomal degradation, causing G₁ arrest in ovarian cancer cells despite continued cyclin E2 expression and independently of p53 and glycogen synthase kinase-3β. Cyclin D1 loss inhibited pRb S780 phosphorylation by cyclin D1-cdk4/6 and released p21 from cyclin D1-cdk4/6-p21 protein complexes to form cyclin E2-cdk2-p21 complexes, which repressed phosphorylation of pRb S612 by cyclin E2-cdk2 and ultimately E2F-DP transcriptional activity. G₁ arrest was prevented by overexpression or preventing degradation of cyclin D1 but not by restoration of pRb S612 phosphorylation through p21 knockdown. In conclusion, we show that loss of cyclin D1 in ovarian cancer cells treated with SHetA2 is sufficient to induce G₁ cell cycle arrest and this strategy is not impeded by the presence of cyclin E2. Therefore, cyclin D1 is a sufficient therapeutic target in ovarian cancer cells. [Cancer Res 2009;69(16):6565–72]