Programmed cell death protein 4 suppresses CDK-1/cdc 2 via induction of p21

We show that the recently discovered tumor suppressor pdcd4 represses the transcription of the mitosis promoting factor CDK1/cdc2 via upregulation of p21. 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. Previously, upregulation of CDK1/cdc2 accompanied by a malignant change was 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 correlates with tumor progression. Finally, the CDK1/cdc2 inhibitor roscovitine reduced 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.