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Transcription factors and pancreas islets

Pancreas development is orchestrated by the sequential activation of transcription factors during embryogenesis. Several of these key regulators such as Pax4 and Pdx1 also play an important role in sustaining mature islet ß-cell (insulin-secreting) function and mutations in these have been linked to diabetes. Our work, has established that Pax4, through regulation of the proto-oncogene c-myc as well as the anti-apoptotic gene bcl-xl, is critical for modulating islet ß-cell mass in response to physiological stimuli. Mutations in Pax4 provoke a loss of ß-cells which is accompanied by an uncontrolled rise in blood glucose and ultimately the development of diabetes. Similarly, we show that the transcription factor Pdx1 is a key regulator of mitochondrial metabolism and thus insulin secretion through regulation of the nuclear-encoded factor TFAM. Using a combination of genomic and proteomic tools, the group is pursuing the characterization of molecular targets of Pax4 and Pdx1 as well as signal transduction pathways leading to their activation. Establishment of the various gene networks governing ß-cell function and proliferation are also exploited to bioengineer insulin-producing cells derived from human grown-up stem cells or monocytes human beings.

Group's publications

Synaptotagmins bind calcium to release insulin.
AMERICAN JOURNAL OF PHYSIOLOGY. ENDOCRINOLOGY AND METABOLISM
2008 vol. 295(6) pp. 1279-1286
GAUTHIER BR, WOLLHEIM CB

A new conditional mouse mutant reveals specific expression and functions of connexin36 in neurons and pancreatic beta-cells.
EXPERIMENTAL CELL RESEARCH
2008 vol. 314(5) pp. 997-1012
WELLERSHAUS K, DEGEN J, DEUCHARS J, THEIS M, CHAROLLAIS A, CAILLE D, GAUTHIER BENOIT, JANSSEN-BIENHOLD U, SONNTAG S, HERRERA PEDRO, MEDA P, WILLECKE K

Synaptotagmin VII splice variants alpha, beta, and delta are expressed in pancreatic beta-cells and regulate insulin exocytosis.
FASEB JOURNAL
2008 vol. 22(1) pp. 194-206
GAUTHIER BR, DUHAMEL DL, IEZZI M, THEANDER S, SALTEL FREDERIC, FUKUDA M, WEHRLE-HALLER B, WOLLHEIM CB

The diabetes-linked transcription factor Pax4 is expressed in human pancreatic islets and is activated by mitogens and GLP-1.
HUMAN MOLECULAR GENETICS
2008 vol. 17(4) pp. 478-489
BRUN T, HE KH, LUPI R, BOEHM B, WOJTUSCISZYN A, SAUTER N, DONATH M, MARCHETTI P, MAEDLER K, GAUTHIER BR

A focus on the role of Pax4 in mature pancreatic islet beta-cell expansion and survival in health and disease.
JOURNAL OF MOLECULAR ENDOCRINOLOGY
2008 vol. 40(2) pp. 37-45
BRUN T, GAUTHIER BR

Pancreatic insulin content regulation by the estrogen receptor ER alpha.
PLOS ONE
2008 vol. 3(4) pp. 2069-
ALONSO-MAGDALENA P, ROPERO AB, CARRERA MP, CEDERROTH CR, BAQUIE M, GAUTHIER BR, NEF S, STEFANI E, NADAL A

The beta-cell specific transcription factor Nkx6.1 inhibits glucagon gene transcription by interfering with Pax6
BIOCHEMICAL JOURNAL
2007 vol. 403(3) pp. 593-601
GAUTHIER BENOIT R., GOSMAIN YVAN, MAMIN ALINE, PHILIPPE JACQUES

Transcriptional response of pancreatic beta cells to metabolic stimulation: large scale identification of immediate-early and secondary response genes
BMC MOLECULAR BIOLOGY [COMPUTER FILE]
2007 vol. 8 pp. 54-
GLAUSER DOMINIQUE A, BRUN THIERRY, GAUTHIER BENOIT, SCHLEGEL WERNER

The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells
ONCOGENE : AN INTERNATIONAL JOURNAL
2007 vol. 26(29) pp. 4261-4271
BRUN T, DUHAMEL DL, HE HE KH, WOLLHEIM CB, GAUTHIER BR

The Fas pathway is involved in pancreatic beta cell secretory function
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2007 vol. 104 pp. 2861-2866
SCHUMANN DM, MAEDLER K, FRANKLIN I, KONRAD D, STORLING J, BONI-SCHNETZLER M, GJINOVCI A, KURRER MO, GAUTHIER BR, BOSCO D, ANDRES A, BERNEY T, GRETER M, BECHER B, CHERVONSKY AV, HALBAN PA, MANDRUP-POULSEN T, WOLLHEIM CB, DONATH MY

Low concentration of interleukin-1beta induces FLICE-inhibitory protein-mediated beta-cell proliferation in human pancreatic islets
DIABETES
2006 vol. 55(10) pp. 2713-2722
MAEDLER KATHRIN ET AL.

Characterization of two distinct liver progenitor cell subpopulations of hematopoietic and hepatic origins
EXPERIMENTAL CELL RESEARCH
2006 vol. 312(15) pp. 2826-2836
CORCELLE V, STIEGER B, GJINOVCI A, WOLLHEIM CB, GAUTHIER B

Dopamine modulates von Willebrand factor secretion in endothelial cells via D2-D4 receptors
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
2006 vol. 4(7) pp. 1588-1595
ZAREI S, FRIEDEN M, RUBI BLANCA, VILLEMIN P, GAUTHIER BR, MAECHLER P, VISCHER UM

Glucose homeostasis ribo-regulated by microRNA
M S-MEDECINE SCIENCES
2006 vol. 22 pp. 463-465
GAUTHIER BR, WOLLHEIM CB

MicroRNAs: 'ribo-regulators' of glucose homeostasis.
NATURE MEDICINE
2006 vol. 12(1) pp. 36-38
GAUTHIER BR, WOLLHEIM CB

Association of childhood type 1 diabetes mellitus with a variant of PAX4: possible link to beta cell regenerative capacity.
DIABETOLOGIA
2005 vol. 48 pp. 900-905
BIASON-LAUBER A, BOEHM B, LANG-MURITANO M, GAUTHIER BENOIT, BRUN THIERRY, WOLLHEIM CLAES, SCHOENLE EJ

Suppression of Pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells.
DIABETOLOGIA
2005 vol. 48 pp. 720-731
WANG HAIYAN, IEZZI-BAKHTIARI MARIELLA, THEANDER STEN, ANTINOZZI PETER, GAUTHIER BENOIT, HALBAN PHILIPPE A., WOLLHEIM CLAES

[Pax4, islet plasticity and diabetes]
M S-MEDECINE SCIENCES
2005 vol. 21 pp. 358-359
BRUN THIERRY, WOLLHEIM CLAES, GAUTHIER BENOIT

Oligonucleotide microarray analysis reveals PDX1 as an essential regulator of mitochondrial metabolism in rat islets
JOURNAL OF BIOLOGICAL CHEMISTRY
2004 vol. 279(30) pp. 31121-31130
GAUTHIER BENOIT, BRUN THIERRY, SARRET EVE-JULIE, ISHIHARA HISAMITSU, SCHAAD OLIVIER, DESCOMBES PATRICK, WOLLHEIM CLAES

The diabetes-linked transcription factor PAX4 promotes {beta}-cell proliferation and survival in rat and human islets
JOURNAL OF CELL BIOLOGY
2004 vol. 167(6) pp. 1123-1135
BRUN THIERRY, FRANKLIN ISOBEL, ST-ONGE L, BIASON-LAUBER A, SCHOENLE EJ, WOLLHEIM CLAES, GAUTHIER BENOIT

CD14 is an acute-phase protein
JOURNAL OF IMMUNOLOGY
2004 vol. 172 pp. 4470-4479
BAS SYLVETTE, GAUTHIER BENOIT, SPENATO URSULA, STINGELIN SIBYLLE CHRISTINE, GABAY CEM

Ectopic expression of the beta-cell specific transcription factor Pdx1 inhibits glucagon gene transcription.
DIABETOLOGIA
2003 vol. 46(6) pp. 810-821
RITZ-LASER B, GAUTHIER BR, ESTREICHER VON ROZBIERSKI A, MAMIN A, BRUN T, RIS F, SALMON P, HALBAN PA, TRONO D, PHILIPPE J

Experimental models of transcription factor-associated maturity-onset diabetes of the young.
DIABETES
2002 vol. 51 pp. 333-342
WANG H, HAGENFELDT-JOHANSSON K, LUC A. OTTEN, GAUTHIER BR, HERRERA PL, WOLLHEIM CB

The pancreatic beta-cell-specific transcription factor Pax-4 inhibits glucagon gene expression through Pax-6
DIABETOLOGIA
2002 vol. 45(1) pp. 97-107
RITZ-LASER B, ESTREICHER A, GAUTHIER BR, MAMIN A, EDLUND H, PHILIPPE J

Foxa2 (HNF3b) controls multiple genes implicated in metabolism-secretion coupling of glucose- induced insulin release
JOURNAL OF BIOLOGICAL CHEMISTRY
2002 vol. 277 pp. 17564-17570
WANG H, GAUTHIER BR, HAGENFELDT-JOHANSSON K, IEZZI MB, WOLLHEIM CB

Hepatic nuclear factors-3 (HNF-3 or Foxa2) regulates glucagon gene transpcription by binding to the G1 and G2 prometer elements
MOLECULAR ENDOCRINOLOGY
2002 vol. 16 pp. 170-183
GAUTHIER BR, SCHWITZGEBEL VM, ZAIKO M, MAMIN A, RITZ-LASER B, PHILIPPE J

Research's domains




DATABASE-RESEARCH	GROUP OF BASIC RESEARCH

Benoit GAUTHIER	Head of group CV	Research subject	Members of the group


	Links about the group Dr. Benoit GAUTHIER CMU/ Dpt PHYME Rue Michel-Servet, 1 1211 Genève 4 Suisse Benoit.Gauthier@unige.ch Tel.: 022 379 55 55/7 Fax: 022 379 58 02 Comments Pages updated the 17.11.2015		Reseach's subject \| Group's publications \| Research's domains Transcription factors and pancreas islets Pancreas development is orchestrated by the sequential activation of transcription factors during embryogenesis. Several of these key regulators such as Pax4 and Pdx1 also play an important role in sustaining mature islet ß-cell (insulin-secreting) function and mutations in these have been linked to diabetes. Our work, has established that Pax4, through regulation of the proto-oncogene c-myc as well as the anti-apoptotic gene bcl-xl, is critical for modulating islet ß-cell mass in response to physiological stimuli. Mutations in Pax4 provoke a loss of ß-cells which is accompanied by an uncontrolled rise in blood glucose and ultimately the development of diabetes. Similarly, we show that the transcription factor Pdx1 is a key regulator of mitochondrial metabolism and thus insulin secretion through regulation of the nuclear-encoded factor TFAM. Using a combination of genomic and proteomic tools, the group is pursuing the characterization of molecular targets of Pax4 and Pdx1 as well as signal transduction pathways leading to their activation. Establishment of the various gene networks governing ß-cell function and proliferation are also exploited to bioengineer insulin-producing cells derived from human grown-up stem cells or monocytes human beings. Group's publications Synaptotagmins bind calcium to release insulin. AMERICAN JOURNAL OF PHYSIOLOGY. ENDOCRINOLOGY AND METABOLISM 2008 vol. 295(6) pp. 1279-1286 GAUTHIER BR, WOLLHEIM CB A new conditional mouse mutant reveals specific expression and functions of connexin36 in neurons and pancreatic beta-cells. EXPERIMENTAL CELL RESEARCH 2008 vol. 314(5) pp. 997-1012 WELLERSHAUS K, DEGEN J, DEUCHARS J, THEIS M, CHAROLLAIS A, CAILLE D, GAUTHIER BENOIT, JANSSEN-BIENHOLD U, SONNTAG S, HERRERA PEDRO, MEDA P, WILLECKE K Synaptotagmin VII splice variants alpha, beta, and delta are expressed in pancreatic beta-cells and regulate insulin exocytosis. FASEB JOURNAL 2008 vol. 22(1) pp. 194-206 GAUTHIER BR, DUHAMEL DL, IEZZI M, THEANDER S, SALTEL FREDERIC, FUKUDA M, WEHRLE-HALLER B, WOLLHEIM CB The diabetes-linked transcription factor Pax4 is expressed in human pancreatic islets and is activated by mitogens and GLP-1. HUMAN MOLECULAR GENETICS 2008 vol. 17(4) pp. 478-489 BRUN T, HE KH, LUPI R, BOEHM B, WOJTUSCISZYN A, SAUTER N, DONATH M, MARCHETTI P, MAEDLER K, GAUTHIER BR A focus on the role of Pax4 in mature pancreatic islet beta-cell expansion and survival in health and disease. JOURNAL OF MOLECULAR ENDOCRINOLOGY 2008 vol. 40(2) pp. 37-45 BRUN T, GAUTHIER BR Pancreatic insulin content regulation by the estrogen receptor ER alpha. PLOS ONE 2008 vol. 3(4) pp. 2069- ALONSO-MAGDALENA P, ROPERO AB, CARRERA MP, CEDERROTH CR, BAQUIE M, GAUTHIER BR, NEF S, STEFANI E, NADAL A The beta-cell specific transcription factor Nkx6.1 inhibits glucagon gene transcription by interfering with Pax6 BIOCHEMICAL JOURNAL 2007 vol. 403(3) pp. 593-601 GAUTHIER BENOIT R., GOSMAIN YVAN, MAMIN ALINE, PHILIPPE JACQUES Transcriptional response of pancreatic beta cells to metabolic stimulation: large scale identification of immediate-early and secondary response genes BMC MOLECULAR BIOLOGY [COMPUTER FILE] 2007 vol. 8 pp. 54- GLAUSER DOMINIQUE A, BRUN THIERRY, GAUTHIER BENOIT, SCHLEGEL WERNER The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells ONCOGENE : AN INTERNATIONAL JOURNAL 2007 vol. 26(29) pp. 4261-4271 BRUN T, DUHAMEL DL, HE HE KH, WOLLHEIM CB, GAUTHIER BR The Fas pathway is involved in pancreatic beta cell secretory function PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2007 vol. 104 pp. 2861-2866 SCHUMANN DM, MAEDLER K, FRANKLIN I, KONRAD D, STORLING J, BONI-SCHNETZLER M, GJINOVCI A, KURRER MO, GAUTHIER BR, BOSCO D, ANDRES A, BERNEY T, GRETER M, BECHER B, CHERVONSKY AV, HALBAN PA, MANDRUP-POULSEN T, WOLLHEIM CB, DONATH MY Low concentration of interleukin-1beta induces FLICE-inhibitory protein-mediated beta-cell proliferation in human pancreatic islets DIABETES 2006 vol. 55(10) pp. 2713-2722 MAEDLER KATHRIN ET AL. Characterization of two distinct liver progenitor cell subpopulations of hematopoietic and hepatic origins EXPERIMENTAL CELL RESEARCH 2006 vol. 312(15) pp. 2826-2836 CORCELLE V, STIEGER B, GJINOVCI A, WOLLHEIM CB, GAUTHIER B Dopamine modulates von Willebrand factor secretion in endothelial cells via D2-D4 receptors JOURNAL OF THROMBOSIS AND HAEMOSTASIS 2006 vol. 4(7) pp. 1588-1595 ZAREI S, FRIEDEN M, RUBI BLANCA, VILLEMIN P, GAUTHIER BR, MAECHLER P, VISCHER UM Glucose homeostasis ribo-regulated by microRNA M S-MEDECINE SCIENCES 2006 vol. 22 pp. 463-465 GAUTHIER BR, WOLLHEIM CB MicroRNAs: 'ribo-regulators' of glucose homeostasis. NATURE MEDICINE 2006 vol. 12(1) pp. 36-38 GAUTHIER BR, WOLLHEIM CB Association of childhood type 1 diabetes mellitus with a variant of PAX4: possible link to beta cell regenerative capacity. DIABETOLOGIA 2005 vol. 48 pp. 900-905 BIASON-LAUBER A, BOEHM B, LANG-MURITANO M, GAUTHIER BENOIT, BRUN THIERRY, WOLLHEIM CLAES, SCHOENLE EJ Suppression of Pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells. DIABETOLOGIA 2005 vol. 48 pp. 720-731 WANG HAIYAN, IEZZI-BAKHTIARI MARIELLA, THEANDER STEN, ANTINOZZI PETER, GAUTHIER BENOIT, HALBAN PHILIPPE A., WOLLHEIM CLAES [Pax4, islet plasticity and diabetes] M S-MEDECINE SCIENCES 2005 vol. 21 pp. 358-359 BRUN THIERRY, WOLLHEIM CLAES, GAUTHIER BENOIT Oligonucleotide microarray analysis reveals PDX1 as an essential regulator of mitochondrial metabolism in rat islets JOURNAL OF BIOLOGICAL CHEMISTRY 2004 vol. 279(30) pp. 31121-31130 GAUTHIER BENOIT, BRUN THIERRY, SARRET EVE-JULIE, ISHIHARA HISAMITSU, SCHAAD OLIVIER, DESCOMBES PATRICK, WOLLHEIM CLAES The diabetes-linked transcription factor PAX4 promotes {beta}-cell proliferation and survival in rat and human islets JOURNAL OF CELL BIOLOGY 2004 vol. 167(6) pp. 1123-1135 BRUN THIERRY, FRANKLIN ISOBEL, ST-ONGE L, BIASON-LAUBER A, SCHOENLE EJ, WOLLHEIM CLAES, GAUTHIER BENOIT CD14 is an acute-phase protein JOURNAL OF IMMUNOLOGY 2004 vol. 172 pp. 4470-4479 BAS SYLVETTE, GAUTHIER BENOIT, SPENATO URSULA, STINGELIN SIBYLLE CHRISTINE, GABAY CEM Ectopic expression of the beta-cell specific transcription factor Pdx1 inhibits glucagon gene transcription. DIABETOLOGIA 2003 vol. 46(6) pp. 810-821 RITZ-LASER B, GAUTHIER BR, ESTREICHER VON ROZBIERSKI A, MAMIN A, BRUN T, RIS F, SALMON P, HALBAN PA, TRONO D, PHILIPPE J Experimental models of transcription factor-associated maturity-onset diabetes of the young. DIABETES 2002 vol. 51 pp. 333-342 WANG H, HAGENFELDT-JOHANSSON K, LUC A. OTTEN, GAUTHIER BR, HERRERA PL, WOLLHEIM CB The pancreatic beta-cell-specific transcription factor Pax-4 inhibits glucagon gene expression through Pax-6 DIABETOLOGIA 2002 vol. 45(1) pp. 97-107 RITZ-LASER B, ESTREICHER A, GAUTHIER BR, MAMIN A, EDLUND H, PHILIPPE J Foxa2 (HNF3b) controls multiple genes implicated in metabolism-secretion coupling of glucose- induced insulin release JOURNAL OF BIOLOGICAL CHEMISTRY 2002 vol. 277 pp. 17564-17570 WANG H, GAUTHIER BR, HAGENFELDT-JOHANSSON K, IEZZI MB, WOLLHEIM CB Hepatic nuclear factors-3 (HNF-3 or Foxa2) regulates glucagon gene transpcription by binding to the G1 and G2 prometer elements MOLECULAR ENDOCRINOLOGY 2002 vol. 16 pp. 170-183 GAUTHIER BR, SCHWITZGEBEL VM, ZAIKO M, MAMIN A, RITZ-LASER B, PHILIPPE J Research's domains