Cdc7-Dbf4 Kinase Overexpression in Multiple Cancers and Tumor Cell Lines Is Correlated with p53 Inactivation

Abstract

Cdc7 is a conserved serine/threonine kinase essential for the initiation of DNA replication, likely by activating the MCM DNA helicase at the G1- to S-phase transition. Cdc7 kinase activity requires association with its regulatory subunit Dbf4/activator of S-phase kinase. Cdc7-Dbf4 is also downstream of the conserved Ataxia telangectasia and RAD3-related kinase that responds to stalled replication forks or DNA damage. In this study, we found that Cdc7 protein was very low or undetectable in normal tissues and cell lines but had increased expression in ∼50% of the 62 human tumor cell lines we examined. Most cell lines with increased Cdc7 protein levels also had increased Dbf4 abundance, and some tumor cell lines had extra copies of the DBF4 gene. A high expression of Cdc7 protein was also detected in primary breast, colon, and lung tumors but not in the matched normal tissues. We also found a high correlation between p53 loss and increased CDC7 and DBF4 expression in primary breast cancers (P = 3.6 × 10−9 and 1.8 × 10−10, respectively) and in the cancer cell lines we studied. Therefore, increased Cdc7-Dbf4 abundance may be a common occurrence in human malignancies.