Stern, Bodo; (1997) Control of G1 progression in fisson yeast. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Extracellular signals control differentiation and cell cycle progression in eukaryotes. In the yeasts, cell-type specific peptide pheromones block cell cycle progression in G1 and initiate conjugation between two haploid mating partners. I have investigated the mechanism of pheromone induced G1 arrest in the fission yeast Schizosaccharomyces pombe. Entry into S-phase in fission yeast requires the activation of the cyclin-dependent kinases (CDK) cdc2p and the cdc10p-reslp transcription factor which activates the cell cycle periodic expression of genes needed for S-phase. While activation of the transcription factor is not affected by pheromone, the G1-function of cdc2p is blocked in the presence of pheromone. The main cyclin-partner of cdc2p in G1 is the B-cyclin cig2p but it can be compensated for by the mitotic B-cyclin cdc13p. Cig2p and cdc13p associated cdc2p kinase activities are downregulated after exposure to pheromone, and this inhibition of cyclinB-cdc2p kinase is crucial as overexpression of cdc13p or cig2p overcomes pheromone induced G1 arrest. Pheromone does not inhibit the cyclinB-cdc2p activity in highly enlarged cells with the result that these cells fail to arrest in G1. This suggests that the inhibitory pheromone signal and an activating cell size signal oppose each other in controlling the cyclinB-cdc2p kinase activity in G1. The cdc2p inhibitor rum1p and the cyclosome complex which mediates ubiquitin dependent cyclinB degradation are both essential to brings about pheromone induced G1 arrest. Rum1p is induced in pheromone, binds to cdc13p and specifically inhibits cdc13p-cdc2p kinase activity. Rum1p is also required for cylosome mediated cdc13p proteolysis indicating that it might act as an adapter specifically targeting cdc13p for cyclosome dependent proteolysis. Downregulation of the cig2p associated kinase activity in pheromone treated cells can occur in a rum1 independent manner and involves cyclosome dependent cig2p degradation. Thus, a combination of rum1p mediated inhibition of cdc13p-cdc2p kinase and cyclosome dependent degradation of cdc13p- and cig2p-cyclins brings about pheromone induced G1 arrest.

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