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Molecular and Cellular Biology, September 2009, p. 4891-4905, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00222-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Coupling Phosphate Homeostasis to Cell Cycle-Specific Transcription: Mitotic Activation of Saccharomyces cerevisiae PHO5 by Mcm1 and Forkhead Proteins {triangledown}

Santhi Pondugula,1,{dagger} Daniel W. Neef,1,{dagger},{ddagger} Warren P. Voth,2 Russell P. Darst,1 Archana Dhasarathy,1,§ M. Megan Reynolds,1 Shinya Takahata,2 David J. Stillman,2 and Michael P. Kladde1*

Department of Biochemistry and Molecular Biology and UF Shands Cancer Center Program in Cancer Genetics, Epigenetics and Tumor Virology, University of Florida College of Medicine, 1376 Mowry Road, Box 103633, Gainesville, Florida 32610,1 Department of Pathology, University of Utah, 15 North Medical Drive East, Salt Lake City, Utah 841122

Received 18 February 2009/ Returned for modification 2 April 2009/ Accepted 30 June 2009

Cells devote considerable resources to nutrient homeostasis, involving nutrient surveillance, acquisition, and storage at physiologically relevant concentrations. Many Saccharomyces cerevisiae transcripts coding for proteins with nutrient uptake functions exhibit peak periodic accumulation during M phase, indicating that an important aspect of nutrient homeostasis involves transcriptional regulation. Inorganic phosphate is a central macronutrient that we have previously shown oscillates inversely with mitotic activation of PHO5. The mechanism of this periodic cell cycle expression remains unknown. To date, only two sequence-specific activators, Pho4 and Pho2, were known to induce PHO5 transcription. We provide here evidence that Mcm1, a MADS-box protein, is essential for PHO5 mitotic activation. In addition, we found that cells simultaneously lacking the forkhead proteins, Fkh1 and Fkh2, exhibited a 2.5-fold decrease in PHO5 expression. The Mcm1-Fkh2 complex, first shown to transactivate genes within the CLB2 cluster that drive G2/M progression, also associated directly at the PHO5 promoter in a cell cycle-dependent manner in chromatin immunoprecipitation assays. Sds3, a component specific to the Rpd3L histone deacetylase complex, was also recruited to PHO5 in G1. These findings provide (i) further mechanistic insight into PHO5 mitotic activation, (ii) demonstrate that Mcm1-Fkh2 can function combinatorially with other activators to yield late M/G1 induction, and (iii) couple the mitotic cell cycle progression machinery to cellular phosphate homeostasis.

* Corresponding author. Mailing address: University of Florida Shands Cancer Center, University of Florida College of Medicine, 1376 Mowry Road, Box 103633, Gainesville, FL 32610-3633. Phone: (352) 273-8142. Fax: (352) 273-8299. E-mail: kladde{at}ufl.edu

{triangledown} Published ahead of print on 13 July 2009.

{dagger} S.P. and D.W.N. contributed equally to this study.

{ddagger} Present address: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710.

§ Present address: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences (NIEHS/NIH), Room D-428, MD D4-04, P.O. Box 12233, Research Triangle Park, NC 27709.

Molecular and Cellular Biology, September 2009, p. 4891-4905, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00222-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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