McCourt P, Gallo-Ebert C, Gonghong Y, Jiang Y, Nickels JT

Maintaining accurate progression through the cell cycle requires the proper temporal expression and regulation of cyclins. The mammalian D-type cyclins promote G 1-S transition. D1 cyclin protein stability is regulated through its ubiquitylation and resulting proteolysis catalyzed by the SCF E3 ubiquitin ligase complex containing the F-box protein, Fbx4. SCF ...

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E3-ligase-dependent ubiquitylation of D1 is trigged by an increase in the phosphorylation status of the cyclin. As inhibition of ubiquitin-dependent D1 degradation is seen in many human cancers, we set out to uncover how D-type cyclin phosphorylation is regulated. Here we show that in S. cerevisiae, a heterotrimeric protein phosphatase 2A (PP2A (Cdc55) ) containing the mammalian PPP2R2/PR55 B subunit ortholog Cdc55 regulates the stability of the G 1 cyclin Cln2 by directly regulating its phosphorylation state. Cells lacking Cdc55 contain drastically reduced Cln2 levels caused by degradation due to cdk-dependent hyperphosphorylation, as a Cln2 mutant unable to be phosphorylated by the yeast cdk Cdc28 is highly stable in cdc55-null cells. Moreover, cdc55-null cells become inviable when the SCF (Grr1) activity known to regulate Cln2 levels is eliminated or when Cln2 is overexpressed, indicating an critical relationship between SCF and PP2A functions in regulating cell cycle progression through modulation of G 1-S cyclin degradation/stability. In sum, our results indicate that PP2A is absolutely required to maintain G 1-S cyclin levels through modulating their phosphorylation status, an event necessary to properly transit through the cell cycle.

Date: Mar. 21, 2013

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