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Hog1 mediates cell-cycle arrest in G1 phase by the dual targeting of Sic1

Abstract

Activation of stress-activated protein kinases (SAPKs) is essential for proper cell adaptation to extracellular stimuli. The exposure of yeast cells to high osmolarity, or mutations that lead to activation of the Hog1 SAPK, result in cell-cycle arrest1,2,3,4. The mechanisms by which Hog1 and SAPKs in general regulate cell-cycle progression are not completely understood5,6,7,8. Here we show that Hog1 regulates cell cycle progression at the G1 phase by a dual mechanism that involves downregulation of cyclin expression and direct targeting of the CDK-inhibitor protein Sic1. Hog1 interacts physically with Sic1 in vivo and in vitro, and phosphorylates a single residue at the carboxyl terminus of Sic1, which, in combination with the downregulation of cyclin expression, results in Sic1 stabilization and inhibition of cell-cycle progression. Cells lacking Sic1 or containing a Sic1 allele mutated in the Hog1 phosphorylation site are unable to arrest at G1 phase after Hog1 activation, and become sensitive to osmostress. Together, our data indicate that the Sic1 CDK-inhibitor is the molecular target for the SAPK Hog1 that is required to modulate cell-cycle progression in response to stress.

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Figure 1: Mutation in SIC1 prevents cell-cycle arrest in response to Hog1 activation.
Figure 2: Activation of Hog1 results in the increased concentration of the CDK-inhibitor Sic1.
Figure 3: Sic1 is a downstream target of the Hog1 MAPK.
Figure 4: Phosphorylation of Sic1-Thr173 by Hog1 is critical for Sic1 stabilization and cell-cycle arrest.

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Acknowledgements

We thank M. Carmona for technical assistance and E. Garí and M. Aldea for helpful advice and reagents. X.E. is the recipient of an F.P.I fellowship (Ministerio de Ciencia y Tecnología (MCyT), Spanish Government) and M.Z. is the recipient of a Ramón Areces PhD fellowship. This work was supported by grants from MCyT (BMC2003-00321), 'Distinció de la Generalitat de Catalunya per a la Promoció de la Recerca Universitaria. Joves Investigadors' DURSI (Generalitat de Catalunya), and the European Molecular Biology Organization Young Investigtors Programme to F.P.

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Correspondence to Francesc Posas.

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Escoté, X., Zapater, M., Clotet, J. et al. Hog1 mediates cell-cycle arrest in G1 phase by the dual targeting of Sic1. Nat Cell Biol 6, 997–1002 (2004). https://doi.org/10.1038/ncb1174

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