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J. Biol. Chem., Vol. 283, Issue 20, 13923-13933, May 16, 2008

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Direct Regulation of Genes Involved in Glucose Utilization by the Calcium/Calcineurin Pathway^*

Amparo Ruiz, Raquel Serrano, and Joaquín Ariño, Recipient of an Ajut de Suport a les Activitats dels Grups de Recerca (Grant 2005SGR-00542, Generalitat de Catalunya)¹

From the Departament de Bioquímica i Biologia Molecular and Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Edificio V, Campus de Bellaterra, Cerdanyola, Barcelona 08193, Spain

Failure to use glucose as carbon source results in transcriptional activation of numerous genes whose expression is otherwise repressed. HXT2 encodes a yeast high affinity glucose transporter that is only expressed under conditions of glucose limitation. We show that HXT2 is rapidly and potently induced by environmental alkalinization, and this requires both the Snf1 and the calcineurin pathways. Regulation by calcineurin is mediated by the transcription factor Crz1, which rapidly translocates to the nucleus upon high pH stress, and acts through a previously unnoticed Crz1-binding element (calcineurin-dependent response element) in the HXT2 promoter (-507 GGGGCTG -501). We demonstrate that, in addition to HXT2, many other genes required for adaptation to glucose shortage, such as HXT7, MDH2, or ALD4, transcriptionally respond to calcium and high pH signaling through binding of Crz1 to their promoters. Therefore, calcineurin-dependent transcriptional regulation appears to be a common feature for many genes encoding carbohydrate-metabolizing enzymes. Remarkably, extracellular calcium allows growth of a snf1 mutant on low glucose in a calcineurin/Crz1-dependent manner, indicating that activation of calcineurin is sufficient to override a major deficiency in the glucose-repression pathway. We propose that alkalinization of the medium results in impaired glucose utilization and that activation of certain glucose-metabolizing genes by calcineurin contributes to yeast survival under this stress situation.

Received for publication, October 19, 2007 , and in revised form, February 13, 2008.

^* This work was supported in part by the Ministerio de Educación y Ciencia, Spain and Fondo Europeo de Desarrollo Regional (Grant BFU2005-06388-C4-04-BMC to J. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2.

¹ To whom correspondence should be addressed: Tel.: 34-93-581-2182; Fax: 34-93-581-2006; E-mail: Joaquin.Arino{at}UAB.ES.