Altered regulation of cyclin G in human breast cancer and its specific localization at replication foci in response to DNA damage in p53+/+ cells

Cyclin G, a recent addition to the cyclin family, was initially identified in screens for new src kinase family members and soon thereafter by differe ntial screening for transcriptional targets of the tumor suppressor gene, p 53. We have identified cyclin G as being overexpressed in breast and prosta te cancer cells using differential display polymerase chain reaction screen ing. We demonstrate here that cyclin G is overexpressed in human breast and prostate cancer cells and in cancer cells in sifu from tumor specimens. Cy clin G expression was tightly regulated throughout the cell cycle in normal breast cells, peaking at the S and G(2)/M phases of the cell cycle with lo wer levels in G(1). The cell cycle-dependent expression was absent in breas t cancer cells. Following DNA damage in normal p53+/+ cells, cyclin G is tr iggered to cluster in discrete nuclear DNA replication foci that contain re plication-associated proteins such as proliferating cell nuclear antigen (P CNA). While p53-/- cells displayed a faint cyclin G nuclear staining patter n, there was no increased expression and no change in distribution of the s taining pattern after DNA damage. The specific subcellular localization of cyclin G at DNA replication foci provides an additional link between p53-me diated growth arrest and cell cycle regulation and suggests that cyclin G m ay act as an effector of p53-mediated events by functional association with replication foci protein(s).