Background: DNA damage triggers cell cycle checkpoints to halt cell division ahead of DNA repair. Results: Ectopic cyclin G2 (CycG2) induces a Chk2-dependent cell cycle arrest, and depletion of endogenous CycG2 attenuates doxorubicin-induced G 2 /M-phase cell cycle arrest. Conclusion: CycG2 influences checkpoint signaling and is required for G 2 /M arrest responses to genotoxic stress. Significance: Proper checkpoint function is important for genomic integrity and tumor suppression.

Definition of cell cycle control proteins that modify tumor cell resistance to estrogen (E2) signaling antagonists could inform clinical choice for estrogen receptor positive (ER+) breast cancer (BC) therapy. Cyclin G2 (CycG2) is upregulated during cell cycle arrest responses to cellular stresses and growth inhibitory signals and its gene, CCNG2, is directly repressed by E2-bound ER complexes. Our previous studies showed that blockade of HER2, PI3K and mTOR signaling upregulates CycG2 expression in HER2+ BC cells, and that CycG2 overexpression induces cell cycle arrest. Moreover, insulin and insulin-like growth factor-1 (IGF-1) receptor signaling strongly represses CycG2. Here we show that blockade of ER-signaling in MCF7 and T47D BC cell lines enhances the expression and nuclear localization of CycG2. Knockdown of CycG2 attenuated the cell cycle arrest response of E2-depleted and fulvestrant treated MCF7 cells. These muted responses were accompanied by sustained inhibitory phosphorylation of retinoblastoma (RB) protein, expression of cyclin D1, phospho-activation of ERK1/2 and MEK1/2 and expression of cRaf. Our work indicates that CycG2 can form complexes with CDK10, a CDK linked to modulation of RAF/MEK/MAPK signaling and tamoxifen resistance. We determined that metformin upregulates CycG2 and potentiates fulvestrant-induced CycG2 expression and cell cycle arrest. CycG2 knockdown blunts the enhanced anti-proliferative effect of metformin on fulvestrant treated cells. Meta-analysis of BC tumor microarrays indicates that CCNG2 expression is low in aggressive, poor-prognosis BC and that high CCNG2 expression correlates with longer periods of patient survival. Together these findings indicate that CycG2 contributes to signaling networks that limit BC.

Learning and memory as well as long-term potentiation (LTP) depend on Ca 2+ influx through the NMDA-type glutamate receptor (NMDAR) and the resulting activation of the Ca 2+ and calmodulin-dependent protein kinase (CaMKII). Ca 2+ influx via the NMDAR triggers CaMKII binding to the NMDAR for enhanced CaMKII accumulation at post-synaptic sites that experience heightened activity as occurring during LTP. Previously, we generated knock-in (KI) mice in which we replaced two residues in the NMDAR GluN2B subunit to impair CaMKII binding to GluN2B. Various forms of LTP at the Schaffer collateral synapses in CA1 are reduced by 50%. Nevertheless, working memory in the win-shift 8 arm maze and learning of the Morris water maze (MWM) task was normal in the KI mice although recall of the task was impaired in these mice during the period of early memory consolidation. We now show that massed training in the MWM task within a single day resulted in impaired learning. However, learning and recall of the Barnes maze task and contextual fear conditioning over one or multiple days were surprisingly unaffected. The differences observed in the MWM compared to the Barnes maze and contextual fear conditioning suggest a differential involvement of CaMKII and the specific interaction with GluN2B, probably depending on varying degrees of stress, cognitive demand or even potentially different plasticity mechanisms associated with the diverse tasks.

These results are the first description of visual response properties of the most commonly studied marsupial model organism, the short-tailed opossum (Monodelphis domestica). Further, these results are the first to demonstrate experience-dependent plasticity in the visual system of a marsupial species. Thus the ability of cortical neurons to alter their properties based on the dynamics of the visual environment predates the emergence of eutherian mammals and was likely present in our earliest mammalian ancestors.

Resistance to estrogen (E2) receptor (ER) antagonists limits long‐term abatement of ER+ breast cancer (BC). Defining cell cycle control proteins that modify tumor cell resistance to ER‐antagonists tamoxifen and fulvestrant will improve therapeutic approaches. Cyclin G2 (CycG2) is encoded by the ER repressed gene, CCNG2, and upregulated during cell cycle arrest responses to cellular stresses. Here we show that blockade of ER‐signaling enhances the expression and nuclear localization of CycG2 in E2‐dependent BC cell lines. Knockdown of CycG2 in E2‐deprived and fulvestrant‐treated MCF7 cells dampened their cell cycle arrest response. Moreover, loss of CycG2 increases phospho‐activation of MEK1 and inhibition of RB. Our work also indicates that CycG2 forms complexes with the CDK linked to inhibition of tamoxifen resistance and modulation of RAF/MEK/MAPK signaling, CDK10. We reported that signaling through insulin and IGF‐1R receptors strongly represses CycG2 expression. Recent studies suggest the insulin‐sensitizer metformin (MTFN) inhibits BC cell growth by promoting AMPK–mediated suppression of mTOR. Patients taking MTFN exhibit a dose‐dependent reduction in cancer risk. We found that MTFN treatment stimulates CycG2 expression and potentiates fulvestrant‐mediated upregulation of CycG2 and growth arrest of MCF7 cells. Moreover knockdown of CycG2 blunts MTFN‐enhancement of fulvestrant effects. Importantly, analysis of BC tumor microarrays indicates that CCNG2 transcripts are reduced in aggressive, poor‐prognosis BC and that high CCNG2 expression correlates with longer relapse free survival.