Programmed cell death protein 4 suppresses CDK–1/cdc 2 via induction of p21Waf1/Cip1

Programmed cell death, also termed apoptosis, plays a fundamental role in many biological processes as embryogenesis, normal tissue turnover and immune homeostasis. Although to date a number of caspase-dependent and –independent apoptotic pathways have been identified the mechanisms of cell death are very complex and are still largely unknown. In an attempt to identify genes which are involved in the regulation of apoptosis we cloned rat pdcd4 (=DUG; death upregulated gene). Pdcd4 is constitutively expressed at low levels in normal cells but is upregulated after induction of apoptosis by different stimuli like death ligands and serum/glucose starvation. Pdcd4 is highly conserved during evolution indicating an important biological function of this protein. While the role of pdcd4 during apoptosis is still unclear there is emerging evidence for a tumor suppressive function. In the present study, we show that pdcd4 represses the transcription of the mitosis promoting factor CDK1/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. Previously, upregulation of CDK1/cdc2 accompanied by a malignant change was shown 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.

Key words

cell cycle - colon cancer - pdcd4 - tumor suppressor gene