TRANSLATIONAL PHYSIOLOGY Programmed cell death protein 4 suppresses CDK1/cdc2 via induction of p21

Göke, R., P. Barth, A. Schmidt, B. Samans, and B. LankatButtgereit. Programmed cell death protein 4 suppresses CDK1/cdc2 via induction of p21. Am J Physiol Cell Physiol 287: C1541– C1546, 2004. First published August 18, 2004; doi:10.1152/ajpcell. 00025.2004.—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 Cip1. p21 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.