Role of Ubiquitin E3 Ligase SCF-SKP2 in Prostate Cancer Development

摘要

Low or absent expression of CDK inhibitor p27Kip1 is associated with malignant prostatecarcinomas. Loss of tumor suppressors p53 and Pten is also associated with prostate cancers. We found that p27 is regulated byboth SCF-SKP2 and a novel ubiquitin E3 ligase containing CUL4-DDB1-WD40-repeat proteins. In addition, we have identified that a specific CUL4A-DDB1-L2DTL/CDT2-PCNA ubiquitin E3 ligase binds and targets p53 polyubiquitination- dependentproteolysis in cooperation with MDM2. By interacting with a WD40-repeat proteins as asubstrate targetingsubunit, the CUL4-DDB1 ubiquitin E3 ligase regulates a wide array of biological events including cell cycle regulation, genome stability, andhistone methylation;alteration of these events have been shown to associate with the development of prostatecarcinogenesis. We in additionfound that expression of SKP2 and Pten heterozygosity do notcooperate inthe mouse prostate carcinoma models, suggesting that SKP2 may act downstream ofPten pathway. Our work provides novel insights into the mechanism of prostate tumorigenesis.