Role of hCDC4 as a Tumor Suppressor Gene in Genomic Instability Underlying Prostate Cancer

摘要

This study investigates the role of a newly identified gene called hCDC4 in prostate cancer. The hCDC4/FBXW7 gene encodes a protein that functions in a cellular process called proteolysis, or protein degradation. hCdc4 degrades a protein called cyclin E1, which is a central component of the cell division machinery. Cyclin E1 is involved in initiating DNA replication in cells. However, in many types of human tumors cyclin E1 protein level is aberrant and this phenotype has been shown in vitro and in vivo to be oncogenic. Very little is known regarding cyclin E1/hCdc4 in prostate tumors. We are exploring whether hCDC4/FBXW7 functions as a tumor suppressor gene in prostate cancer. We have completed a genetic screen of prostate tumors and found an hCDC4/FBXW7 gene mutation. We have shown that this mutant hCdc4 cannot bind cyclin E1 substrate in vivo and mislocalizes in cells. We are currently exploring the effects of hCDC4/FBXW7 knockdown in prostate cancer progression and identifying substrates of dysregulation of cyclin E1 kinase activity due to hCDC4/FBXW7 inactivation using protein array technology.