Programmed cell death protein 4 suppresses CDK1/cdc2 via induction of p21(Waf1/Cip1).

Abstract	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.
Authors	R Göke, P Barth, A Schmidt, B Samans, B Lankat-Buttgereit
Journal	American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 287 Issue 6 Pg. C1541-6 (Dec 2004) ISSN: 0363-6143 [Print] United States
PMID	15317660 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Apoptosis Regulatory Proteins CDKN1A protein, human Cell Cycle Proteins Cyclin-Dependent Kinase Inhibitor p21 PDCD4 protein, human Protein Kinase Inhibitors Purines RNA-Binding Proteins Retinoblastoma Protein Roscovitine CDC2 Protein Kinase
Topics	Apoptosis (physiology) Apoptosis Regulatory Proteins Breast Neoplasms CDC2 Protein Kinase (antagonists & inhibitors, metabolism) Carcinoid Tumor Cell Cycle Proteins (metabolism) Cell Division (physiology) Cell Line, Tumor Colonic Neoplasms Cyclin-Dependent Kinase Inhibitor p21 Endocrine Gland Neoplasms Female Humans Insulinoma Lung Neoplasms Male Pancreatic Neoplasms Phosphorylation Prostatic Neoplasms Protein Kinase Inhibitors (pharmacology) Purines (pharmacology) RNA-Binding Proteins (genetics, metabolism) Retinoblastoma Protein (metabolism) Roscovitine

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