Abstract
The cyclin B/CDK1 complex is a key regulator of mitotic entry. Using PP242, a specific ATP-competitive inhibitor of mTOR kinase, we provide evidence that the mTOR signalling pathway controls cyclin B mRNA translation following fertilization in Sphaerechinus granularis and Paracentrotus lividus. We show that PP242 inhibits the degradation of the cap-dependent translation repressor 4E-BP (eukaryotic initiation factor 4E-Binding Protein). PP242 inhibits global protein synthesis, delays cyclin B accumulation, cyclin B/CDK1 complex activation and consequently entry into the mitotic phase of the cell cycle triggered by fertilization. PP242 inhibits cyclin B mRNA recruitment into active polysomes triggered by fertilization. An amount of cyclin B mRNA present in active polysomes appears to be insensitive to PP242 treatment. Taken together, our results suggest that, following sea urchin egg fertilization, cyclin B mRNA translation is controlled by two independent mechanisms: a PP242-sensitive and an additional PP242-insentitive mechanism.
Highlights
Cyclins and their catalytic kinase partners CDKs (Cyclin-Dependent Kinases) control cell cycle progression [1]
We previously showed in the sea urchin Spharechinus granularis that 4E-BP degradation triggered by fertilization allows Eukaryotic Initiation Factor 4E (eIF4E) association with eukaryotic Initiation Factor 4G (eIF4G) and the consequent accumulation of cyclin B [31, 32]. 4E-BP degradation induced by fertilization of sea urchin eggs is affected by rapamycin treatment, suggesting that it reflects two distinct complexes named mTOR Complex 1 (TORC1) signalling [31]
PP242 induced a dose-dependent delay in the occurrence of cell division as judged by the percent of first cleavage measured during 4 hours post fertilization
Summary
Cyclins and their catalytic kinase partners CDKs (Cyclin-Dependent Kinases) control cell cycle progression [1]. The mitotic cyclins A and B were first discovered in sea urchin as key proteins, which are synthetized and degraded during M-phase at each cell division [2]. Different mechanisms that underlie the control of mitotic cyclin B translation during the cell cycle and development transitions of model organisms have been reported [3]. In sea urchin and clams, cyclin B is synthetized continuously and rapidly destroyed shortly before the metaphase-anaphase transition of the mitotic cell cycles [2]. CDK1-mediated negative feedback loop was shown to decrease cyclin B translation and drive Xenopus early embryonic cell cycle oscillations [5].
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