title: Cyclin G1 regulates the outcome of taxane-induced mitotic checkpoint arrest.
abstract: Anti-mitotic chemotherapeutic agents such as taxanes activate the spindle assembly checkpoint (SAC) to arrest anaphase onset, but taxane-exposed cells eventually undergo slippage to exit mitosis. The therapeutic efficacy of taxanes depends on whether slippage after SAC arrest culminates in continued cell survival, or in death by apoptosis. However, the mechanisms that determine these outcomes remain unclear. Here, we identify a novel role for cyclin G1 (CCNG1), an atypical cyclin. Increased CCNG1 expression accompanies paclitaxel-induced, SAC-mediated mitotic arrest, independent of p53 integrity or signaling through the SAC component, BUBR1. CCNG1 overexpression promotes cell survival after paclitaxel exposure. Conversely, CCNG1 depletion by RNA interference delays slippage and enhances paclitaxel-induced apoptosis. Consistent with these observations, CCNG1 amplification is associated with significantly shorter post-surgical survival in patients with ovarian cancer who have received adjuvant chemotherapy with taxanes and platinum compounds. Collectively, our findings implicate CCNG1 in regulating slippage and the outcome of taxane-induced mitotic arrest, with potential implications for cancer therapy.
authors: University of Cambridge, Department of Oncology and The Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, UK.
authors: P
authors: P
authors: Russell
authors: B T
authors: BT
authors: Hennessy
authors: J
authors: J
authors: Li
authors: M S
authors: MS
authors: Carey
authors: R C
authors: RC
authors: Bast
authors: T
authors: T
authors: Freeman
authors: A R
authors: AR
authors: Venkitaraman
mesh_terms: D050256:Antimitotic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D056766:Cyclin G1 / Q000235:genetics / Q000502:physiology*; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D008938:Mitosis / Q000187:drug effects* / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D050256:Antimitotic Agents; D056766:Cyclin G1; D043823:Taxoids; D017239:Paclitaxel