Two new competing pathways establish the threshold for cyclin-B–Cdk1 activation at the meiotic G2/M transition

Abstract

Extracellular ligands control biological phenomena. Cells distinguish physiological stimuli from weak noise stimuli by establishing a ligandconcentration threshold. Hormonal control of the meiotic G2/M transition in oocytes is essential for reproduction. However, the mechanism for threshold establishment is unclear. In starfish oocytes, maturation-inducing hormones activate the PI3K-Akt pathway through the G βγ complex of heterotrimeric G-proteins. Akt directly phosphorylates both Cdc25 phosphatase and Myt1 kinase, resulting in activation of cyclin-B-Cdk1, which then induces meiotic G2/M transition. Here, we show that cyclin-B-Cdk1 is partially activated after subthreshold hormonal stimuli, but this triggers negative feedback, resulting in dephosphorylation of Akt sites on Cdc25 and Myt1, thereby canceling the signal. We also identified phosphatase activity towards Akt substrates that exists independent of stimuli. In contrast to these negative regulatory activities, an atypical G βγ -dependent pathway enhances PI3K-Akt-dependent phosphorylation. Based on these findings, we propose a model for threshold establishment in which hormonal dose-dependent competition between these new pathways establishes a threshold; the atypical G βγ -pathway becomes predominant over Cdk-dependent negative feedback when the stimulus exceeds this threshold. Our findings provide a regulatory connection between cell cycle and signal transduction machineries.

A novel topoisomerase I inhibitor DIA-001 induces DNA damage mediated cell cycle arrest and apoptosis in cancer cell

“…Consistent with this, using U2OS cell line treated with DIA-001, we showed that PARP cleavage was enhanced. We also show that cyclin A levels increase after treatment with DIA-001 but cyclin B level increase only slightly suggesting cell cycle progression through the S/G2 transition but arrested at the G2/M phase (15)(16)(17). Together, the data from our study indicates that treatment with DIA-001 may induce cell cycle arrest in G2 phase and apoptosis in cancer cells.…”

Placenta‐specific 1 regulates oocyte meiosis and fertilization through furin

“…Hence, it seems that Plac1 knockdown affected both Akt and MPF activity. Of interest, in meiotic starfish oocytes, Akt directly phosphorylates both Cdc25 phosphatase and Myt1 kinase, which results in the activation of cyclin B-Cdk1 and meiosis resumption (40), further supporting to idea that the Akt pathway might the primary downstream signal of Plac1.…”

Protein kinase Cδ (PKCδ) involved in the regulation of pAkt1 (Ser473) on the release of mouse oocytes from diplotene arrest

“…16 In vertebrate cells, the entry of MPF into the nucleus during prophase was thought to be essential for the induction and coordination of M-phase events. 30,31 During the mitosis, Akt may regulate the intracellular localization and activation of Cdc2 by phosphorylating Cdc25B. [32][33][34][35] In this study, we used SH-6, a specific inhibitor of pAkt1 (Ser473), to track the function of pAkt1 (Ser473) in the release of diplotene arrest of mouse oocytes.…”