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The Ras/cAMP pathway in yeast: identification and analysis of new downstream effectors involved in cell proliferation control

A fundamental goal in biology is to understand how cells control proliferative growth. Important progress towards this goal has been made by the discovery of the cyclins and the cyclin-dependent protein kinases (Cdks) that allow cells to pass checkpoints in the cell cycle. In the yeast Saccharomyces cerevisiae, initiation of a new round of cell division is dependent on G1-specific cyclins, which trigger the checkpoint START through activation of the Cdk Cdc28. Cell division and growth are coordinated at START by processes, which are dependent on a functional Ras/cAMP signalling pathway. Accordingly, cells deficient in cAMP-dependent protein kinase (cAPK) activity stop growth, arrest in G1, and show physiological changes normally associated with nutrient deprivation while cells with elevated, unregulated cAPK activity fail to arrest in G1 even under conditions of nutrient deprivation. Based on these results it was suggested that the central role of the yeast Ras/cAMP pathway is in signalling the nutrient status, thereby participating in the cell's decision to enter a quiescent state in G1 which is equivalent to the G0 state of higher eukaryotes. Although recent evidence suggests that the Ras/cAMP pathway may control cell proliferation via regulation of G1-cyclin expression, the underlying molecular mechanisms by which this pathway coordinates cell division and growth remain elusive. The central goal of our research is to elucidate these mechanisms by identifying and analyzing new downstream effectors of the Ras/cAMP pathway that are specifically involved in cell proliferation. The protein kinase Rim15, which we identified in the framework of our currently running project, represents such a new effector that acts immediately downstream of cAPK to control entry into G0 in response to nutrient limitation. Genetic approaches, which aimed at identifying targets and/or regulators of Rim15, provided us with a set of new genes whose products are likely to act in cAPK/Rim15-dependent cell proliferation control. One of these gene products, the zinc finger protein Gis1, may act downstream of Rim15 and stimulate the transcription of growth inhibitory genes via activation of the post-diauxic shift element. Interestingly, some of the newly identified genes, which we are currently studying in further detail, encode proteins that are likely to either function as growth and/or cell cycle-specific targets of Rim15, or be involved in - possibly cAPK-independent - regulation of Rim15. Detailed molecular and biochemical characterization of the most promising candidates is expected to yield intriguing, new insights into the mechanisms of how nutrient signalling pathways in general, and the Ras/cAMP pathway in particular, control cell proliferation.

Group's publications

Regulation of G0 entry by the Pho80-Pho85 cyclin-CDK complex
EMBO JOURNAL
2005 vol. 24 pp. 4271-4278
WANKE VALERIA, PEDRUZZI IVO, CAMERONI ELISABETTA, DUBOULOZ FREDERIQUE, DE VIRGILIO CLAUDIO

The Bud14p-Glc7p complex functions as a cortical regulator of dynein in budding yeast
EMBO JOURNAL
2005 vol. 24 pp. 3000-3011
MICHÈLE KNAUS, CAMERONI ELISABETTA, PEDRUZZI IVO, KELLY TATCHELL, DE VIRGILIO CLAUDIO, MATTHIAS PETER

A platform for high-throughput expression of recombinant human enzymes secreted by insect cells
JOURNAL OF BIOTECHNOLOGY
2005 vol. 120 pp. 59-71
LOREDANA REDAELLI, FRANCESCA ZOLEZZI, VANESSA NARDESE, BEATRICE BELLANTI, WANKE VALERIA, DANIELE CARETTONI

The Ccr4-not complex independently controls both Msn2-dependent transcriptional activation-via a newly identified Glc7/Bud14 type 1 protein phosphatase module-and TFIID promoter distribution
MOLECULAR AND CELLULAR BIOLOGY : MCB
2005 vol. 25 pp. 488-498
LENSSEN EVE, JAMES FARESSE NICOLE, PEDRUZZI IVO, DUBOULOZ FREDERIQUE, CAMERONI ELISABETTA, BISIG RUTH, MAILLET LAURENT, MICHEL WERNER, JOHNNY ROOSEN, KATARINA PETROVIC, JORIS WINDERICKX, COLLART MARTINE, DE VIRGILIO CLAUDIO

The TOR and EGO protein complexes orchestrate microautophagy in yeast
MOLECULAR CELL
2005 vol. 19 pp. 15-26
DUBOULOZ FREDERIQUE, DELOCHE OLIVIER, WANKE VALERIA, CAMERONI ELISABETTA, DE VIRGILIO CLAUDIO

PKA and Sch9 control a molecular switch important for the proper adaptation to nutrient availability
MOLECULAR MICROBIOLOGY
2005 vol. 55 pp. 862-880
JOHNNY ROOSEN, KRISTOF ENGELEN, KATHLEEN MARCHAL, JANICK MATHYS, GERARD GRIFFIOEN, CAMERONI ELISABETTA, JOHAN M. THEVELEIN, DE VIRGILIO CLAUDIO, BART DE MOOR, JORIS WINDERICKX

Global analysis of protein phosphorylation in yeast
NATURE
2005 vol. 438 pp. 679-684
JASON PTACEK ET AL.

TOR and PKA signaling pathways converge on the protein kinase Rim15 to control entry into G0
MOLECULAR CELL
2003 vol. 12 pp. 1607-1613
PEDRUZZI I, DUBOULOZ F, CAMERONI E, WANKE V, ROOSEN J, WINDERICKX J, DE VIRGILIO C

Disruption in Candida albicans of the TPS2 gene encoding trehalose-6-phosphate phosphatase affects cell integrity and decreases infectivity.
MICROBIOLOGY
2002 vol. 148 pp. 1281-1290
ZARAGOZA O, DE VIRGILIO C, PONTON J, GANCEDO C

Bni5p, a septin-interacting protein, is required for normal septin function and cytokinesis in Saccharomyces cerevisiae.
MOLECULAR AND CELLULAR BIOLOGY : MCB
2002 vol. 22 pp. 6906-6920
LEE PR, SONG S, RO HS, PARK CJ, LIPPINCOTT J, LI R, PRINGLE JR, DE VIRGILIO C, LONGTINE MS, LEE KS

Saccharomyces cerevisiae Ccr4-not complex contributes to the control of Msn2p-dependent transcription by the Ras/cAMP pathway
MOLECULAR MICROBIOLOGY
2002 vol. 43 pp. 1023-1037
LENSSEN E, OBERHOLZER U, LABARRE J, DE VIRGILIO C, COLLART MA

Bud8p and Bud9p, proteins that may mark the sites for bipolar budding in yeast.
MOLECULAR BIOLOGY OF THE CELL
2001 vol. 12 pp. 2497-2518
HARKINS HA, PAGE N, SCHENKMAN LR, DE VIRGILIO C, SHAW S, BUSSEY H, PRINGLE JR

Saccharomyces cerevisiae Ras/cAMP pathway controls post-diauxic shift element-dependent transcription through the zinc finger protein Gis1.
EMBO JOURNAL
2000 vol. 19 pp. 2569-2579
PEDRUZZI I, BURCKERT N, EGGER P, DE VIRGILIO C

The thermophilic yeast Hansenula polymorpha does not require trehalose synthesis for growth at high temperatures but does for normal acquisition of thermotolerance.
JOURNAL OF BACTERIOLOGY
1999 vol. 181 pp. 4665-4668
REINDERS A, ROMANO I, WIEMKEN A, DE VIRGILIO C

Expression of a functional barley sucrose-fructan 6-fructosyltransferase in the methylotrophic yeast Pichia pastoris.
FEBS LETTERS
1998 vol. 440 pp. 356-360
HOCHSTRASSER U, LUSCHER M, DE VIRGILIO C, BOLLER T, WIEMKEN A

Saccharomyces cerevisiae cAMP-dependent protein kinase controls entry into stationary phase through the Rim15p protein kinase.
GENES AND DEVELOPMENT
1998 vol. 12 pp. 2943-2955
REINDERS A, BURCKERT N, BOLLER T, WIEMKEN A, DE VIRGILIO C

Trehalose synthesis is important for the acquisition of thermotolerance in Schizosaccharomyces pombe.
MOLECULAR MICROBIOLOGY
1997 vol. 25 pp. 571-581
RIBEIRO MJ, REINDERS A, BOLLER T, WIEMKEN A, DE VIRGILIO C

Research's domains

GENE EXPRESSION
MICROBIOLOGY
CELL BIOLOGY




DATABASE-RESEARCH	GROUP OF BASIC RESEARCH

Claudio DE VIRGILIO	Head of group CV	Research subject	Members of the group


	Links about the group Pr. C. DE VIRGILIO CMU/ Dpt MIMO Rue Michel-Servet 1 1211 Genève 4 Suisse Tel.: 022 379 54 95 Fax: 022 379 55 02 Group's web site / department Comments Pages updated the 17.11.2015		Reseach's subject \| Group's publications \| Research's domains The Ras/cAMP pathway in yeast: identification and analysis of new downstream effectors involved in cell proliferation control A fundamental goal in biology is to understand how cells control proliferative growth. Important progress towards this goal has been made by the discovery of the cyclins and the cyclin-dependent protein kinases (Cdks) that allow cells to pass checkpoints in the cell cycle. In the yeast Saccharomyces cerevisiae, initiation of a new round of cell division is dependent on G1-specific cyclins, which trigger the checkpoint START through activation of the Cdk Cdc28. Cell division and growth are coordinated at START by processes, which are dependent on a functional Ras/cAMP signalling pathway. Accordingly, cells deficient in cAMP-dependent protein kinase (cAPK) activity stop growth, arrest in G1, and show physiological changes normally associated with nutrient deprivation while cells with elevated, unregulated cAPK activity fail to arrest in G1 even under conditions of nutrient deprivation. Based on these results it was suggested that the central role of the yeast Ras/cAMP pathway is in signalling the nutrient status, thereby participating in the cell's decision to enter a quiescent state in G1 which is equivalent to the G0 state of higher eukaryotes. Although recent evidence suggests that the Ras/cAMP pathway may control cell proliferation via regulation of G1-cyclin expression, the underlying molecular mechanisms by which this pathway coordinates cell division and growth remain elusive. The central goal of our research is to elucidate these mechanisms by identifying and analyzing new downstream effectors of the Ras/cAMP pathway that are specifically involved in cell proliferation. The protein kinase Rim15, which we identified in the framework of our currently running project, represents such a new effector that acts immediately downstream of cAPK to control entry into G0 in response to nutrient limitation. Genetic approaches, which aimed at identifying targets and/or regulators of Rim15, provided us with a set of new genes whose products are likely to act in cAPK/Rim15-dependent cell proliferation control. One of these gene products, the zinc finger protein Gis1, may act downstream of Rim15 and stimulate the transcription of growth inhibitory genes via activation of the post-diauxic shift element. Interestingly, some of the newly identified genes, which we are currently studying in further detail, encode proteins that are likely to either function as growth and/or cell cycle-specific targets of Rim15, or be involved in - possibly cAPK-independent - regulation of Rim15. Detailed molecular and biochemical characterization of the most promising candidates is expected to yield intriguing, new insights into the mechanisms of how nutrient signalling pathways in general, and the Ras/cAMP pathway in particular, control cell proliferation. Group's publications Regulation of G0 entry by the Pho80-Pho85 cyclin-CDK complex EMBO JOURNAL 2005 vol. 24 pp. 4271-4278 WANKE VALERIA, PEDRUZZI IVO, CAMERONI ELISABETTA, DUBOULOZ FREDERIQUE, DE VIRGILIO CLAUDIO The Bud14p-Glc7p complex functions as a cortical regulator of dynein in budding yeast EMBO JOURNAL 2005 vol. 24 pp. 3000-3011 MICHÈLE KNAUS, CAMERONI ELISABETTA, PEDRUZZI IVO, KELLY TATCHELL, DE VIRGILIO CLAUDIO, MATTHIAS PETER A platform for high-throughput expression of recombinant human enzymes secreted by insect cells JOURNAL OF BIOTECHNOLOGY 2005 vol. 120 pp. 59-71 LOREDANA REDAELLI, FRANCESCA ZOLEZZI, VANESSA NARDESE, BEATRICE BELLANTI, WANKE VALERIA, DANIELE CARETTONI The Ccr4-not complex independently controls both Msn2-dependent transcriptional activation-via a newly identified Glc7/Bud14 type 1 protein phosphatase module-and TFIID promoter distribution MOLECULAR AND CELLULAR BIOLOGY : MCB 2005 vol. 25 pp. 488-498 LENSSEN EVE, JAMES FARESSE NICOLE, PEDRUZZI IVO, DUBOULOZ FREDERIQUE, CAMERONI ELISABETTA, BISIG RUTH, MAILLET LAURENT, MICHEL WERNER, JOHNNY ROOSEN, KATARINA PETROVIC, JORIS WINDERICKX, COLLART MARTINE, DE VIRGILIO CLAUDIO The TOR and EGO protein complexes orchestrate microautophagy in yeast MOLECULAR CELL 2005 vol. 19 pp. 15-26 DUBOULOZ FREDERIQUE, DELOCHE OLIVIER, WANKE VALERIA, CAMERONI ELISABETTA, DE VIRGILIO CLAUDIO PKA and Sch9 control a molecular switch important for the proper adaptation to nutrient availability MOLECULAR MICROBIOLOGY 2005 vol. 55 pp. 862-880 JOHNNY ROOSEN, KRISTOF ENGELEN, KATHLEEN MARCHAL, JANICK MATHYS, GERARD GRIFFIOEN, CAMERONI ELISABETTA, JOHAN M. THEVELEIN, DE VIRGILIO CLAUDIO, BART DE MOOR, JORIS WINDERICKX Global analysis of protein phosphorylation in yeast NATURE 2005 vol. 438 pp. 679-684 JASON PTACEK ET AL. TOR and PKA signaling pathways converge on the protein kinase Rim15 to control entry into G0 MOLECULAR CELL 2003 vol. 12 pp. 1607-1613 PEDRUZZI I, DUBOULOZ F, CAMERONI E, WANKE V, ROOSEN J, WINDERICKX J, DE VIRGILIO C Disruption in Candida albicans of the TPS2 gene encoding trehalose-6-phosphate phosphatase affects cell integrity and decreases infectivity. MICROBIOLOGY 2002 vol. 148 pp. 1281-1290 ZARAGOZA O, DE VIRGILIO C, PONTON J, GANCEDO C Bni5p, a septin-interacting protein, is required for normal septin function and cytokinesis in Saccharomyces cerevisiae. MOLECULAR AND CELLULAR BIOLOGY : MCB 2002 vol. 22 pp. 6906-6920 LEE PR, SONG S, RO HS, PARK CJ, LIPPINCOTT J, LI R, PRINGLE JR, DE VIRGILIO C, LONGTINE MS, LEE KS Saccharomyces cerevisiae Ccr4-not complex contributes to the control of Msn2p-dependent transcription by the Ras/cAMP pathway MOLECULAR MICROBIOLOGY 2002 vol. 43 pp. 1023-1037 LENSSEN E, OBERHOLZER U, LABARRE J, DE VIRGILIO C, COLLART MA Bud8p and Bud9p, proteins that may mark the sites for bipolar budding in yeast. MOLECULAR BIOLOGY OF THE CELL 2001 vol. 12 pp. 2497-2518 HARKINS HA, PAGE N, SCHENKMAN LR, DE VIRGILIO C, SHAW S, BUSSEY H, PRINGLE JR Saccharomyces cerevisiae Ras/cAMP pathway controls post-diauxic shift element-dependent transcription through the zinc finger protein Gis1. EMBO JOURNAL 2000 vol. 19 pp. 2569-2579 PEDRUZZI I, BURCKERT N, EGGER P, DE VIRGILIO C The thermophilic yeast Hansenula polymorpha does not require trehalose synthesis for growth at high temperatures but does for normal acquisition of thermotolerance. JOURNAL OF BACTERIOLOGY 1999 vol. 181 pp. 4665-4668 REINDERS A, ROMANO I, WIEMKEN A, DE VIRGILIO C Expression of a functional barley sucrose-fructan 6-fructosyltransferase in the methylotrophic yeast Pichia pastoris. FEBS LETTERS 1998 vol. 440 pp. 356-360 HOCHSTRASSER U, LUSCHER M, DE VIRGILIO C, BOLLER T, WIEMKEN A Saccharomyces cerevisiae cAMP-dependent protein kinase controls entry into stationary phase through the Rim15p protein kinase. GENES AND DEVELOPMENT 1998 vol. 12 pp. 2943-2955 REINDERS A, BURCKERT N, BOLLER T, WIEMKEN A, DE VIRGILIO C Trehalose synthesis is important for the acquisition of thermotolerance in Schizosaccharomyces pombe. MOLECULAR MICROBIOLOGY 1997 vol. 25 pp. 571-581 RIBEIRO MJ, REINDERS A, BOLLER T, WIEMKEN A, DE VIRGILIO C Research's domains GENE EXPRESSION MICROBIOLOGY CELL BIOLOGY