A Potent G2‐Phase Checkpoint Response to Adriamycin‐Induced DNA Damage Requires Cyclin G2 Upregulation

• Published in: The FASEB journal 2006-03, Vol.20 (5), p.LB49-LB49
• Main Authors: Don, Aruni S. Arachchige, Dallapiazza, Robert, Cowan, Colleen, Horne, Mary
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.20.5.LB49-a

Cyclin G2 (G2) is a stress response protein with intrinsic growth inhibitory activity. G2 expression is induced by DNA damage and other stresses, but inhibited by activation of the PI3K pathway. Treatment of HER2 + breast cancer cells with Herceptin® (blocks HER2 receptor mediated PI3K activation) or with the PI3K inhibitor (Ly294002), potently elevates G2 levels. Ectopic G2 expression results in a p53‐dependent cell cycle arrest, although the mechanism is unknown. Cyclin G2 is a centrosomal and nucleo‐cytoplasmic shuttling protein. We hypothesize that dysregulation of G2 expression, interactions, or subcellular localization leads to a loss of proper cell cycle control. We examined whether elevation of G2 is necessary for the growth inhibitory effects induced by anti‐cancer agents. Here, we show that Adriamycin® (Adr) potently upregulates G2. We treated cells with Adr in the presence of G2‐specific shRNAs and remarkably, depletion of endogenous G2 abrogates the Adr‐induced G2‐phase cell cycle arrest. Moreover, overexpression of G2 promotes the activation of the DNA damage response kinase, Chk2, and the cell cycle arrest induced by ectopic G2 requires Chk2. Combined Herceptin® plus Adriamycin® therapy improves survival rates and reduces the risks of breast cancer recurrence in premenopausal women. As these anti‐cancer agents upregulate G2 and G2 exhibits growth inhibitory activity, understanding how G2 modulates checkpoint responses is highly warranted. Supported by NIH R01 GM56900 & DOD BCRP BC045656.