Hcm1 integrates signals from Cdk1 and calcineurin to control cell proliferation.
Cyclin-dependent kinase (Cdk1) orchestrates progression through the cell cycle by coordinating the activities of cell-cycle regulators. Although phosphatases that oppose Cdk1 are likely to be necessary to establish dynamic phosphorylation, specific phosphatases that target most Cdk1 substrates have not been identified. In budding yeast, the transcription factor Hcm1 activates expression of genes that regulate chromosome segregation and is critical for maintaining genome stability. Previously we found that Hcm1 activity and degradation are stimulated by Cdk1 phosphorylation of distinct clusters of sites. Here we show that, upon exposure to environmental stress, the phosphatase calcineurin inhibits Hcm1 by specifically removing activating phosphorylations and that this regulation is important for cells to delay proliferation when they encounter stress. Our work identifies a mechanism by which proliferative signals from Cdk1 are removed in response to stress and suggests that Hcm1 functions as a rheostat that integrates stimulatory and inhibitory signals to control cell proliferation.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01520.
Heather E
HE
Arsenault
Department of Biology, Stanford University, Stanford, CA 94305.
Jagoree
J
Roy
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01520.
Claudine E
CE
Mapa
Department of Biology, Stanford University, Stanford, CA 94305.
Martha S
MS
Cyert
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01520 jennifer.benanti@umassmed.edu.
Jennifer A
JA
Benanti
D016203:CDC2 Protein Kinase / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D004718:Saccharomycetales / Q000166:cytology / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
D051858:Forkhead Transcription Factors; C079874:HCM1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D016203:CDC2 Protein Kinase; D019703:Calcineurin; D010744:Phosphoric Monoester Hydrolases