Down-regulation of Cdc6, a Cell Cycle Regulatory Gene, in Prostate Cancer

Abstract

Prostate cancer is a complex and heterogeneous disease, and it is the most prevalent form of cancer and the second leading cause of cancer death in men (1). Along with the classic methods of diagnosing and prognosticating prostate cancer, utilizing stage, grade, and serum prostate-specific antigen level, molecular markers of aggressive disease are currently being evaluated as adjuncts to improve identification of tumors associated with a poor outcome. Because abnormal regulation of the cell cycle is one of the major causes of tumorigenesis in recent years, major advances have been made to understand the molecular mechanisms of aberrant cell cycle control leading to the development and progression of tumors. Studies on the aberrant expression of cell cycle regulatory genes in prostate carcinoma have identified a cdk 1 inhibitor p27 kip1 (2) and p53 (3) as biomarkers. These markers show a strong correlation with a high, moderate, or low risk of occurrence of prostate cancer. Immunohistochemical analysis of other G 1 /S check point-controlling proteins, including cyclins (4), the cdk inhibitor p16 (5), and retinoblastoma (6), have also been found to be helpful in identifying patients with aggressive prostate cancer.One of the major underlying mechanisms of aberrant cell cycle progression is uncontrolled DNA replication irrespective of cellular signals as a result of G 1 /S checkpoint failure. DNA replication is a highly ordered event controlled by sequential binding to and release of a number of replication proteins from the DNA sequence close to the origin of DNA replication. This also restricts firing of the replication origin to once per cell cycle. The regulation of initiation of DNA replication has been studied extensively in Saccharomyces cerevisiae, whereas understanding of this regulation in the mammalian system has just begun. However, identification of human homologs of yeast replication proteins, such as origin recognition complex (7-10), CDC6 (11), and minichromosome maintenance proteins (MCM) (12, 13), suggests evolutionarily conserved replication machinery. Studies on DNA replication in S. cerevisiae and Xenopus laevis have established a critical role of CDC6 in the initiation of replication (14 -16). In late mitosis, when mitotic cyclin (cyclin B) and cdk are inactive, CDC6 helps to establish the prereplicative complex (Pre-RC) on the chromatin-bound origin recognition complex, a six-subunit initiator protein (17), by recruiting MCM proteins and other factors (18 -20). In middle to late G 1 and at the G 1 /S transition, S-phase cyclins (cyclin E and cyclin A) and cdk2 are expressed (21,22) and initiate DNA replication by phosphorylating CDC6, which causes it to dissociate from Pre-RC (23). Release of CDC6 from chromatin and its translocation to the cytoplasm triggers initiation of DNA replication (24). Another role of CDC6 in S. cerevisiae is to function as an inhibitor of the G 2 /M phase until the S phase is complete (25). This defines CDC6 as a unique and critical protein with a dual role in regul...

Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells

“…Consistent with this role, here Cdc6 transcript was reduced in vivo with castration when proliferation decreases and then levels increased in androgen independence when proliferation resumes. Interestingly, when compared to benign tissue the levels of CDC6 are decreased in PC3 prostate cancer cells that are devoid of both AR and p53 (Robles et al, 2002). NUMA is a mitotic centrosomal component that is essential for the organization and stabilization of spindle poles (Zeng, 2000).…”

Quantitation of CDC6 and MCM5 mRNA in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix

“…Degradation of CDC6 is necessary for entry into the M phase of the cell cycle. 23 This may explain why CDC6 is expressed at relatively lower levels in neoplastic cells when compared with MCM5 mRNA expression. It is possible that as a consequence of neoplastic progression, high-grade neoplastic and malignant cells may find a mechanism to evade CDC6 G2/M phase regulation and thus continue proliferating in the presence of elevated levels of CDC6 protein.…”

CDC6: from DNA replication to cell cycle checkpoints and oncogenesis

“…In the case of non-small cell lung carcinomas, no direct correlation was observed between the levels of CDC6 and proliferation marker Ki67 (82). Another intriguing observation is that CDC6 is downregulated in aggressive prostate cancer (84). This could be an in vivo example of a CDC6 loss-of-function situation leading to aberrant cell proliferation.…”