Programmed cell death protein 4 suppresses CDK1/cdc2 via induction of p21(Waf1/Cip1).
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.
Göke
R
R
Clinical Research Unit, University Hospital of Marburg, Baldingerstrasse, D-35033 Marburg, Germany. rgoeke@gmx.net
Barth
P
P
Schmidt
A
A
Samans
B
B
Lankat-Buttgereit
B
B
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002276:Carcinoid Tumor; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004701:Endocrine Gland Neoplasms; D005260:Female; D006801:Humans; D007340:Insulinoma; D008175:Lung Neoplasms; D008297:Male; D010190:Pancreatic Neoplasms; D010766:Phosphorylation; D011471:Prostatic Neoplasms; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D000077546:Roscovitine
D051017:Apoptosis Regulatory Proteins; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C114487:PDCD4 protein, human; D047428:Protein Kinase Inhibitors; D011687:Purines; D016601:RNA-Binding Proteins; D016160:Retinoblastoma Protein; D000077546:Roscovitine; D016203:CDC2 Protein Kinase