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TRANSLATIONAL PHYSIOLOGY

Programmed cell death protein 4 suppresses CDK1/cdc2 via induction of p21^Waf1/Cip1

¹Clinical Research Unit for Gastrointestinal Endocrinology, ²Institute of Pathology, and ³Institute of Medical Biometry and Epidemiology, University of Marburg, 35033 Marburg, Germany

Submitted 16 January 2004 ; accepted in final form 12 August 2004

We show that the recently discovered tumor suppressor pdcd4 represses the transcription of the mitosis-promoting factor cyclin-dependent kinase (CDK)1/cdc2 via upregulation of p21^Waf1/Cip1. p21^Waf1/Cip1 inhibits CDK4/6 and CDK2. Decrease of CDK4/6 and CDK2 enhances the binding of pRb to E2F/DP, which in turn together bind to and repress the cdc2 promoter. Upregulation of CDK1/cdc2 accompanied by a malignant change was previously reported in colon cancer. We show that expression of pdcd4 as an indirect suppressor of CDK1/cdc2 is lost in progressed carcinomas of lung, breast, colon, and prostate. Furthermore, it seems that localization and expression of pdcd4 directly correlate with tumor progression. Finally, the CDK1/cdc2 inhibitor roscovitine reduces the proliferation of several tumor cell lines, suggesting that inhibition of CDK1/cdc2 may be a useful strategy against malignant transformation. Therefore, pdcd4 might serve as a novel target for antineoplastic therapies.

tumor growth; cell cycle; tumor suppressor gene

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