Richard M. O'Brien, Ph.D.

Professor

richard.obrien@vanderbilt.edu

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Faculty Appointments
Professor of Molecular Physiology and Biophysics
Education
Ph.D., Biochemistry, University of Cambridge, CambridgeB.Sc., Biochemistry, University of Bristol, Bristol
Office Address
8415 MRB IV
TN 0615
Research Description
My laboratory is interested in the glucose-6-phosphatase gene family. There are 3 members of this family designated G6PC, G6PC2 and G6PC3. These genes play a key role determining fasting blood glucose levels, a parameter that is correlated with the risk of cardiovascular-associated mortality. These genes also play important roles in the pathophysiology of type 1 and type 2 diabetes. Our current studies on these genes are focused on the following questions:
1. G6PC, also known as G6Pase, catalyzes the terminal step in glycogenolysis and gluconeogenesis. These pathways are central to hepatic glucose production (HGP). We are interested in the transcriptional regulation of this gene since increased expression of G6Pase contributes to the increased HGP characteristic of both type 1 and type 2 diabetes. Our studies mainly focus on the molecular mechanisms that mediate the regulation of G6Pase gene transcription by hormones, especially insulin, cAMP and glucocorticoids, and transcription factors, such as FOXO1 and PGC-1.
2. G6PC2, also known as IGRP, encodes an islet-specific glucose-6-phosphatase catalytic subunit-related protein. G6PC2 is a major autoantigen in both mouse and human type 1 diabetes. There are three goals for the on-going experiments in this project. The first is to elucide the molecular basis for the islet-specific expression of the G6PC2 gene. The experiments involve the use of both tissue culture cells and transgenic mice. The data suggest that the regulation of G6PC2 gene expression is determined, in part, by novel factors. As such, the identification of these novel factors will potentially aid other investigators who are attempting to understand the process whereby islet stem cells differentiate towards that of a beta cell lineage. The second goal of this project is to determine the biological function of G6PC2 through the analysis of G6PC2 knockout mice. Recent genome wide association studies showed that single nucleotide polymorphisms (SNPs) in the G6PC2 gene contribute to the variation in fasting blood glucose levels in humans and hence the risk of cardiovascular-associated mortality. The third goal of our G6PC2-related studies is to determine whether and then how SNPs in the gene lead to altered gene expression or G6PC2 activity.
3. G6PC3, also known as UGRP, encodes a ubiquitiously expressed glucose-6-phosphatase catalytic subunit-related protein. G6PC3 catalyzes the hydrolysis of glucose-6-phosphate but the role of this protein in vivo is unknown. Addressing that question is the focus of our G6PC3-related studies.

In previous years specific rotation projects have been designed to enable students to learn PCR, DNA cloning and tissue culture, techniques that are used in multiple laboratories at Vanderbilt. However, students that are already familiar with these techniques have the opportunity to learn about the use of gel retardation assays, transgenic mice and adenoviral technology to address questions relating to the regulation of gene transcription and the molecular biology of diabetes.
Research Keywords
Diabetes and the Glucose-6-Phosphatase Gene Family
Publications
Davidson HW, Wenzlau JM, O'Brien RM. Zinc transporter 8 (ZnT8) and ß cell function. Trends Endocrinol. Metab [print-electronic]. 2014 Aug; 25(8): 415-24. PMID: 24751356, PMCID: PMC4112161, PII: S1043-2760(14)00055-1, DOI: 10.1016/j.tem.2014.03.008, ISSN: 1879-3061.

O'Brien RM. Moving on from GWAS: functional studies on the G6PC2 gene implicated in the regulation of fasting blood glucose. Curr. Diab. Rep. 2013 Dec; 13(6): 768-77. PMID: 24142592, PMCID: PMC4041587, DOI: 10.1007/s11892-013-0422-8, ISSN: 1539-0829.

Baerenwald DA, Bonnefond A, Bouatia-Naji N, Flemming BP, Umunakwe OC, Oeser JK, Pound LD, Conley NL, Cauchi S, Lobbens S, Eury E, Balkau B, Lantieri O, , Dadi PK, Jacobson DA, Froguel P, O'Brien RM. Multiple functional polymorphisms in the G6PC2 gene contribute to the association with higher fasting plasma glucose levels. Diabetologia [print-electronic]. 2013 Jun; 56(6): 1306-16. PMID: 23508304, PMCID: PMC4106008, DOI: 10.1007/s00125-013-2875-3, ISSN: 1432-0428.

Pound LD, Oeser JK, O'Brien TP, Wang Y, Faulman CJ, Dadi PK, Jacobson DA, Hutton JC, McGuinness OP, Shiota M, O'Brien RM. G6PC2: a negative regulator of basal glucose-stimulated insulin secretion. Diabetes [print-electronic]. 2013 May; 62(5): 1547-56. PMID: 23274894, PMCID: PMC3636628, PII: db12-1067, DOI: 10.2337/db12-1067, ISSN: 1939-327X.

Pound LD, Sarkar SA, Ustione A, Dadi PK, Shadoan MK, Lee CE, Walters JA, Shiota M, McGuinness OP, Jacobson DA, Piston DW, Hutton JC, Powell DR, O'Brien RM. The physiological effects of deleting the mouse SLC30A8 gene encoding zinc transporter-8 are influenced by gender and genetic background. PLoS ONE [print-electronic]. 2012; 7(7): e40972. PMID: 22829903, PMCID: PMC3400647, PII: PONE-D-11-24034, DOI: 10.1371/journal.pone.0040972, ISSN: 1932-6203.

Pound LD, Sarkar SA, Cauchi S, Wang Y, Oeser JK, Lee CE, Froguel P, Hutton JC, O'Brien RM. Characterization of the human SLC30A8 promoter and intronic enhancer. J. Mol. Endocrinol [electronic-print]. 2011 Dec; 47(3): 251-9. PMID: 21798992, PMCID: PMC3185167, PII: JME-11-0055, DOI: 10.1530/JME-11-0055, ISSN: 1479-6813.

Oeser JK, Parekh VV, Wang Y, Jegadeesh NK, Sarkar SA, Wong R, Lee CE, Pound LD, Hutton JC, Van Kaer L, O'Brien RM. Deletion of the G6pc2 gene encoding the islet-specific glucose-6-phosphatase catalytic subunit-related protein does not affect the progression or incidence of type 1 diabetes in NOD/ShiLtJ mice. Diabetes [print-electronic]. 2011 Nov; 60(11): 2922-7. PMID: 21896930, PMCID: PMC3198073, PII: db11-0220, DOI: 10.2337/db11-0220, ISSN: 1939-327X.

Pound LD, Hang Y, Sarkar SA, Wang Y, Milam LA, Oeser JK, Printz RL, Lee CE, Stein R, Hutton JC, O'Brien RM. The pancreatic islet ß-cell-enriched transcription factor Pdx-1 regulates Slc30a8 gene transcription through an intronic enhancer. Biochem. J. 2011 Jan 1/1/2011; 433(1): 95-105. PMID: 20942803, PMCID: PMC4130494, PII: BJ20101488, DOI: 10.1042/BJ20101488, ISSN: 1470-8728.

Pound LD, Sarkar SA, Benninger RK, Wang Y, Suwanichkul A, Shadoan MK, Printz RL, Oeser JK, Lee CE, Piston DW, McGuinness OP, Hutton JC, Powell DR, O'Brien RM. Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion. Biochem. J. 2009 Aug 8/1/2009; 421(3): 371-6. PMID: 19450229, PMCID: PMC2929527, PII: BJ20090530, DOI: 10.1042/BJ20090530, ISSN: 1470-8728.

Onuma H, Oeser JK, Nelson BA, Wang Y, Flemming BP, Scheving LA, Russell WE, O'Brien RM. Insulin and epidermal growth factor suppress basal glucose-6-phosphatase catalytic subunit gene transcription through overlapping but distinct mechanisms. Biochem. J. 2009 Jan 1/15/2009; 417(2): 611-20. PMID: 18847435, PMCID: PMC2929524, PII: BJ20080999, DOI: 10.1042/BJ20080999, ISSN: 1470-8728.

Hutton, J. C. and O'Brien, R. M.. Glucose-6-Phosphatase Catalytic Subunit Gene Family. J. Biol. Chem. 2009; 284: 29241-5.

Martin CC, Flemming BP, Wang Y, Oeser JK, O'Brien RM. Foxa2 and MafA regulate islet-specific glucose-6-phosphatase catalytic subunit-related protein gene expression. J. Mol. Endocrinol [print-electronic]. 2008 Nov; 41(5): 315-28. PMID: 18753309, PMCID: PMC2614309, PII: JME-08-0062, DOI: 10.1677/JME-08-0062, ISSN: 1479-6813.

Schilling MM, Oeser JK, Chandy JK, Flemming BP, Allen SR, O'Brien RM. Sequence variation between the mouse and human glucose-6-phosphatase catalytic subunit gene promoters results in differential activation by peroxisome proliferator activated receptor gamma coactivator-1alpha. Diabetologia [print-electronic]. 2008 Aug; 51(8): 1505-14. PMID: 18563384, PMCID: PMC2590337, DOI: 10.1007/s00125-008-1050-8, ISSN: 0012-186X.

Wang Y, Flemming BP, Martin CC, Allen SR, Walters J, Oeser JK, Hutton JC, O'Brien RM. Long-range enhancers are required to maintain expression of the autoantigen islet-specific glucose-6-phosphatase catalytic subunit-related protein in adult mouse islets in vivo. Diabetes [print-electronic]. 2008 Jan; 57(1): 133-41. PMID: 17942825, PII: db07-0092, DOI: 10.2337/db07-0092, ISSN: 1939-327X.

Martin, C. C., Brian P. Flemming, B. P., Wang, Y, Oeser, J. K. and OBrien, R. M.. Foxa2 and MafA Regulate Islet-specific Glucose-6-Phosphatase Catalytic Subunit-Related Protein (IGRP/G6PC2) Gene Expression. J. Mol. Endocrinol. 2008; 41: 315-28.

Wang Y, Martin CC, Oeser JK, Sarkar S, McGuinness OP, Hutton JC, O'Brien RM. Deletion of the gene encoding the islet-specific glucose-6-phosphatase catalytic subunit-related protein autoantigen results in a mild metabolic phenotype. Diabetologia [print-electronic]. 2007 Apr; 50(4): 774-8. PMID: 17265032, DOI: 10.1007/s00125-006-0564-1, ISSN: 0012-186X.

Wang Y, Oeser JK, Yang C, Sarkar S, Hackl SI, Hasty AH, McGuinness OP, Paradee W, Hutton JC, Powell DR, O'Brien RM. Deletion of the gene encoding the ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein (UGRP)/glucose-6-phosphatase catalytic subunit-beta results in lowered plasma cholesterol and elevated glucagon. J. Biol. Chem [print-electronic]. 2006 Dec 12/29/2006; 281(52): 39982-9. PMID: 17023421, PII: M605858200, DOI: 10.1074/jbc.M605858200, ISSN: 0021-9258.

Onuma H, Vander Kooi BT, Boustead JN, Oeser JK, O'Brien RM. Correlation between FOXO1a (FKHR) and FOXO3a (FKHRL1) binding and the inhibition of basal glucose-6-phosphatase catalytic subunit gene transcription by insulin. Mol. Endocrinol [print-electronic]. 2006 Nov; 20(11): 2831-47. PMID: 16840535, PII: me.2006-0085, DOI: 10.1210/me.2006-0085, ISSN: 0888-8809.

Schilling MM, Oeser JK, Boustead JN, Flemming BP, O'Brien RM. Gluconeogenesis: re-evaluating the FOXO1-PGC-1alpha connection. Nature. 2006 Oct 10/5/2006; 443(7111): E10-1. PMID: 17024043, PII: nature05288, DOI: 10.1038/nature05288, ISSN: 1476-4687.

Jones JJ, Borgmann S, Wilkins CL, O'Brien RM. Characterizing the phospholipid profiles in mammalian tissues by MALDI FTMS. Anal. Chem. 2006 May 5/1/2006; 78(9): 3062-71. PMID: 16642994, DOI: 10.1021/ac0600858, ISSN: 0003-2700.

Vander Kooi BT, Onuma H, Oeser JK, Svitek CA, Allen SR, Vander Kooi CW, Chazin WJ, O'Brien RM. The glucose-6-phosphatase catalytic subunit gene promoter contains both positive and negative glucocorticoid response elements. Mol. Endocrinol [print-electronic]. 2005 Dec; 19(12): 3001-22. PMID: 16037130, PII: me.2004-0497, DOI: 10.1210/me.2004-0497, ISSN: 0888-8809.

Martin CC, Oeser JK, O'Brien RM. Differential regulation of islet-specific glucose-6-phosphatase catalytic subunit-related protein gene transcription by Pax-6 and Pdx-1. J. Biol. Chem [print-electronic]. 2004 Aug 8/13/2004; 279(33): 34277-89. PMID: 15180990, PII: M404830200, DOI: 10.1074/jbc.M404830200, ISSN: 0021-9258.

Ayala JE, Boustead JN, Chapman SC, Svitek CA, Oeser JK, Robey RB, O'Brien RM. Insulin-mediated activation of activator protein-1 through the mitogen-activated protein kinase pathway stimulates collagenase-1 gene transcription in the MES 13 mesangial cell line. J. Mol. Endocrinol. 2004 Aug; 33(1): 263-80. PMID: 15291758, ISSN: 0952-5041.

Frigeri C, Martin CC, Svitek CA, Oeser JK, Hutton JC, Gannon M, O'Brien RM. The proximal islet-specific glucose-6-phosphatase catalytic subunit-related protein autoantigen promoter is sufficient to initiate but not maintain transgene expression in mouse islets in vivo. Diabetes. 2004 Jul; 53(7): 1754-64. PMID: 15220199, PII: 53/7/1754, ISSN: 0012-1797.

Hornbuckle LA, Everett CA, Martin CC, Gustavson SS, Svitek CA, Oeser JK, Neal DW, Cherrington AD, O'Brien RM. Selective stimulation of G-6-Pase catalytic subunit but not G-6-P transporter gene expression by glucagon in vivo and cAMP in situ. Am. J. Physiol. Endocrinol. Metab [print-electronic]. 2004 May; 286(5): E795-808. PMID: 14722027, PII: 00455.2003, DOI: 10.1152/ajpendo.00455.2003, ISSN: 0193-1849.

Boustead JN, Martin CC, Oeser JK, Svitek CA, Hunter SI, Hutton JC, O'Brien RM. Identification and characterization of a cDNA and the gene encoding the mouse ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein. J. Mol. Endocrinol. 2004 Feb; 32(1): 33-53. PMID: 14765991, PII: JME14801307, ISSN: 0952-5041.

Martin CC, Svitek CA, Oeser JK, Henderson E, Stein R, O'Brien RM. Upstream stimulatory factor (USF) and neurogenic differentiation/beta-cell E box transactivator 2 (NeuroD/BETA2) contribute to islet-specific glucose-6-phosphatase catalytic-subunit-related protein (IGRP) gene expression. Biochem. J. 2003 May 5/1/2003; 371(Pt 3): 675-86. PMID: 12540293, PMCID: PMC1223330, PII: BJ20021585, DOI: 10.1042/BJ20021585, ISSN: 0264-6021.

Vander Kooi BT, Streeper RS, Svitek CA, Oeser JK, Powell DR, O'Brien RM. The three insulin response sequences in the glucose-6-phosphatase catalytic subunit gene promoter are functionally distinct. J. Biol. Chem [print-electronic]. 2003 Apr 4/4/2003; 278(14): 11782-93. PMID: 12556524, PII: M212570200, DOI: 10.1074/jbc.M212570200, ISSN: 0021-9258.

Boustead JN, Stadelmaier BT, Eeds AM, Wiebe PO, Svitek CA, Oeser JK, O'Brien RM. Hepatocyte nuclear factor-4 alpha mediates the stimulatory effect of peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1 alpha) on glucose-6-phosphatase catalytic subunit gene transcription in H4IIE cells. Biochem. J. 2003 Jan 1/1/2003; 369(Pt 1): 17-22. PMID: 12416993, PMCID: PMC1223073, PII: BJ20021382, DOI: 10.1042/BJ20021382, ISSN: 0264-6021.

Martin CC, Oeser JK, Svitek CA, Hunter SI, Hutton JC, O'Brien RM. Identification and characterization of a human cDNA and gene encoding a ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein. J. Mol. Endocrinol. 2002 Oct; 29(2): 205-22. PMID: 12370122, PII: JME01150, ISSN: 0952-5041.

Thomas WR, Smith WA, Hales BJ, Mills KL, O'Brien RM. Characterization and immunobiology of house dust mite allergens. Int. Arch. Allergy Immunol. 2002 Sep; 129(1): 1-18. PMID: 12372994, PII: 65179, DOI: 65179, ISSN: 1018-2438.

Ayala JE, Streeper RS, Svitek CA, Goldman JK, Oeser JK, O'Brien RM. Accessory elements, flanking DNA sequence, and promoter context play key roles in determining the efficacy of insulin and phorbol ester signaling through the malic enzyme and collagenase-1 AP-1 motifs. J. Biol. Chem [print-electronic]. 2002 Aug 8/2/2002; 277(31): 27935-44. PMID: 12032154, PII: M203682200, DOI: 10.1074/jbc.M203682200, ISSN: 0021-9258.

O'Brien RM, Stockard J. Variations in age-specific homicide death rates: a cohort explanation for charges in the age distribution of homicide deaths. Soc Sci Res. 2002 Mar; 31(1): 124-50. PMID: 11949672, ISSN: 0049-089X.

Hornbuckle LA, Edgerton DS, Ayala JE, Svitek CA, Oeser JK, Neal DW, Cardin S, Cherrington AD, O'Brien RM. Selective tonic inhibition of G-6-Pase catalytic subunit, but not G-6-P transporter, gene expression by insulin in vivo. Am. J. Physiol. Endocrinol. Metab. 2001 Oct; 281(4): E713-25. PMID: 11551847, ISSN: 0193-1849.

O'Brien RM, Streeper RS, Ayala JE, Stadelmaier BT, Hornbuckle LA. Insulin-regulated gene expression. Biochem. Soc. Trans. 2001 Aug; 29(Pt 4): 552-8. PMID: 11498027, ISSN: 0300-5127.

Martin CC, Bischof LJ, Bergman B, Hornbuckle LA, Hilliker C, Frigeri C, Wahl D, Svitek CA, Wong R, Goldman JK, Oeser JK, Leprêtre F, Froguel P, O'Brien RM, Hutton JC. Cloning and characterization of the human and rat islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) genes. J. Biol. Chem [print-electronic]. 2001 Jul 7/6/2001; 276(27): 25197-207. PMID: 11297555, PII: M101549200, DOI: 10.1074/jbc.M101549200, ISSN: 0021-9258.

Streeper RS, Hornbuckle LA, Svitek CA, Goldman JK, Oeser JK, O'Brien RM. Protein kinase A phosphorylates hepatocyte nuclear factor-6 and stimulates glucose-6-phosphatase catalytic subunit gene transcription. J. Biol. Chem [print-electronic]. 2001 Jun 6/1/2001; 276(22): 19111-8. PMID: 11279202, PII: M101442200, DOI: 10.1074/jbc.M101442200, ISSN: 0021-9258.

Bischof LJ, Martin CC, Svitek CA, Stadelmaier BT, Hornbuckle LA, Goldman JK, Oeser JK, Hutton JC, O'Brien RM. Characterization of the mouse islet-specific glucose-6-phosphatase catalytic subunit-related protein gene promoter by in situ footprinting: correlation with fusion gene expression in the islet-derived betaTC-3 and hamster insulinoma tumor cell lines. Diabetes. 2001 Mar; 50(3): 502-14. PMID: 11246869, ISSN: 0012-1797.

Streeper RS, Svitek CA, Goldman JK, O'Brien RM. Differential role of hepatocyte nuclear factor-1 in the regulation of glucose-6-phosphatase catalytic subunit gene transcription by cAMP in liver- and kidney-derived cell lines. J. Biol. Chem. 2000 Apr 4/21/2000; 275(16): 12108-18. PMID: 10766845, ISSN: 0021-9258.

O'Brien RM, Xu H, Rolland JM, Byron KA, Thomas WR. Allergen-specific production of interferon-gamma by peripheral blood mononuclear cells and CD8 T cells in allergic disease and following immunotherapy. Clin. Exp. Allergy. 2000 Mar; 30(3): 333-40. PMID: 10691890, PII: cea700, ISSN: 0954-7894.

O'Brien, R.M. and Granner, D.K. Gene Regulation. Diabetes Mellitus. A Fundamental and Clinical Text. LeRoith, D., Taylor, S.I. and Olefsky, J.M., eds. Lippincott-Raven. 2000; Chapter 28: 291-305.

Ayala JE, Streeper RS, Desgrosellier JS, Durham SK, Suwanichkul A, Svitek CA, Goldman JK, Barr FG, Powell DR, O'Brien RM. Conservation of an insulin response unit between mouse and human glucose-6-phosphatase catalytic subunit gene promoters: transcription factor FKHR binds the insulin response sequence. Diabetes. 1999 Sep; 48(9): 1885-9. PMID: 10480625, ISSN: 0012-1797.

Pierreux CE, Stafford J, Demonte D, Scott DK, Vandenhaute J, O'Brien RM, Granner DK, Rousseau GG, Lemaigre FP. Antiglucocorticoid activity of hepatocyte nuclear factor-6. Proc. Natl. Acad. Sci. U.S.A. 1999 Aug 8/3/1999; 96(16): 8961-6. PMID: 10430878, PMCID: PMC17715, ISSN: 0027-8424.

O'Brien RM, Tait BD, Varney MD, Thomas WR. HLA-DPB1 alleles in house dust mite allergic patients. Eur. J. Immunogenet. 1999 Aug; 26(4): 281-4. PMID: 10457892, ISSN: 0960-7420.

Chapman SC, Ayala JE, Streeper RS, Culbert AA, Eaton EM, Svitek CA, Goldman JK, Tavar JM, O'Brien RM. Multiple promoter elements are required for the stimulatory effect of insulin on human collagenase-1 gene transcription. Selective effects on activator protein-1 expression may explain the quantitative difference in insulin and phorbol ester action. J. Biol. Chem. 1999 Jun 6/25/1999; 274(26): 18625-34. PMID: 10373474, ISSN: 0021-9258.

Ebert DH, Bischof LJ, Streeper RS, Chapman SC, Svitek CA, Goldman JK, Mathews CE, Leiter EH, Hutton JC, O'Brien RM. Structure and promoter activity of an islet-specific glucose-6-phosphatase catalytic subunit-related gene. Diabetes. 1999 Mar; 48(3): 543-51. PMID: 10078554, ISSN: 0012-1797.

Arden SD, Zahn T, Steegers S, Webb S, Bergman B, O'Brien RM, Hutton JC. Molecular cloning of a pancreatic islet-specific glucose-6-phosphatase catalytic subunit-related protein. Diabetes. 1999 Mar; 48(3): 531-42. PMID: 10078553, ISSN: 0012-1797.

Clarke AH, O'Brien RM, Rolland JM, Thomas WR. Allergic respiratory responses to Der p 1 in mice. Int. Arch. Allergy Immunol. 1999 Feb; 118(2-4): 287-8. PMID: 10224413, PII: 24102, DOI: 24102, ISSN: 1018-2438.

O'Brien RM, Stockard J, Isaacson L. The enduring effects of cohort characteristics on age-specific homicide rates, 1960-1995. Am. J. Sociol. 1999 Jan; 104(4): 1061-95. PMID: 11623716, ISSN: 0002-9602.

Arden, S.D., Zahn, T., Steegers, S., Webb, S., Bergman, B., O'Brien, R.M. and Hutton, J.C. Molecular Cloning of a Pancreatic Islet-Specific Glucose-6-Phosphatase Related Protein. Diabetes. 1999; 48: 531-42.

Streeper RS, Chapman SC, Ayala JE, Svitek CA, Goldman JK, Cave A, O'Brien RM. A phorbol ester-insensitive AP-1 motif mediates the stimulatory effect of insulin on rat malic enzyme gene transcription. Mol. Endocrinol. 1998 Nov; 12(11): 1778-91. PMID: 9817602, DOI: 10.1210/mend.12.11.0199, ISSN: 0888-8809.

Dickens M, Svitek CA, Culbert AA, O'Brien RM, Tavaré JM. Central role for phosphatidylinositide 3-kinase in the repression of glucose-6-phosphatase gene transcription by insulin. J. Biol. Chem. 1998 Aug 8/7/1998; 273(32): 20144-9. PMID: 9685358, ISSN: 0021-9258.

Streeper RS, Eaton EM, Ebert DH, Chapman SC, Svitek CA, O'Brien RM. Hepatocyte nuclear factor-1 acts as an accessory factor to enhance the inhibitory action of insulin on mouse glucose-6-phosphatase gene transcription. Proc. Natl. Acad. Sci. U.S.A. 1998 Aug 8/4/1998; 95(16): 9208-13. PMID: 9689059, PMCID: PMC21317, ISSN: 0027-8424.

Streeper RS, Svitek CA, Chapman S, Greenbaum LE, Taub R, O'Brien RM. A multicomponent insulin response sequence mediates a strong repression of mouse glucose-6-phosphatase gene transcription by insulin. J. Biol. Chem. 1997 May 5/2/1997; 272(18): 11698-701. PMID: 9115220, ISSN: 0021-9258.

O'Brien RM, Byron KA, Varigos GA, Thomas WR. House dust mite immunotherapy results in a decrease in Der p 2-specific IFN-gamma and IL-4 expression by circulating T lymphocytes. Clin. Exp. Allergy. 1997 Jan; 27(1): 46-51. PMID: 9117880, ISSN: 0954-7894.

O'Brien RM, Granner DK. Regulation of gene expression by insulin. Physiol. Rev. 1996 Oct; 76(4): 1109-61. PMID: 8874496, ISSN: 0031-9333.

Wang JC, Strömstedt PE, O'Brien RM, Granner DK. Hepatic nuclear factor 3 is an accessory factor required for the stimulation of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. Mol. Endocrinol. 1996 Jul; 10(7): 794-800. PMID: 8813720, DOI: 10.1210/mend.10.7.8813720, ISSN: 0888-8809.

Sutherland C, O'Brien RM, Granner DK. New connections in the regulation of PEPCK gene expression by insulin. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 1996 Feb 2/29/1996; 351(1336): 191-9. PMID: 8650266, DOI: 10.1098/rstb.1996.0016, ISSN: 0962-8436.

Ludwig DS, Vidal-Puig A, O'Brien RM, Printz RL, Granner DK, Moller DE, Flier JS. Examination of the phosphoenolpyruvate carboxykinase gene promoter in patients with noninsulin-dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 1996 Feb; 81(2): 503-6. PMID: 8636258, DOI: 10.1210/jcem.81.2.8636258, ISSN: 0021-972X.

Gabbay RA, Sutherland C, Gnudi L, Kahn BB, O'Brien RM, Granner DK, Flier JS. Insulin regulation of phosphoenolpyruvate carboxykinase gene expression does not require activation of the Ras/mitogen-activated protein kinase signaling pathway. J. Biol. Chem. 1996 Jan 1/26/1996; 271(4): 1890-7. PMID: 8567635, ISSN: 0021-9258.

O'Brien, R.M. and Granner, D.K. Gene Regulation. Diabetes Mellitus. A Fundamental and Clinical Text. LeRoith, D., Taylor, S.I. and Olefsky, J.M., eds. Lippincott-Raven. 1996; Chapter 25: 234-42.

O'Brien RM, Printz RL, Halmi N, Tiesinga JJ, Granner DK. Structural and functional analysis of the human phosphoenolpyruvate carboxykinase gene promoter. Biochim. Biophys. Acta. 1995 Dec 12/27/1995; 1264(3): 284-8. PMID: 8547315, ISSN: 0006-3002.

O'Brien RM, Granner DK. Why there is an IRS [editorial]. J. Clin. Invest. 1995 Dec; 96(6): 2546. PMID: 8675617, PMCID: PMC185957, DOI: 10.1172/JCI118317, ISSN: 0021-9738.

O'Brien RM, Halmi N, Stromstedt PE, Printz RL, Granner DK. Expression cloning of a zinc-finger cyclic AMP-response-element-binding protein. Biochem. J. 1995 Nov 11/15/1995; 312 ( Pt 1): 17-21. PMID: 7492309, PMCID: PMC1136221, ISSN: 0264-6021.

O'Brien RM, Thomas WR, Nicholson I, Lamb JR, Tait BD. An immunogenetic analysis of the T-cell recognition of the major house dust mite allergen Der p 2: identification of high- and low-responder HLA-DQ alleles and localization of T-cell epitopes. Immunology. 1995 Oct; 86(2): 176-82. PMID: 7490115, PMCID: PMC1383992, ISSN: 0019-2805.

Sutherland C, O'Brien RM, Granner DK. Phosphatidylinositol 3-kinase, but not p70/p85 ribosomal S6 protein kinase, is required for the regulation of phosphoenolpyruvate carboxykinase (PEPCK) gene expression by insulin. Dissociation of signaling pathways for insulin and phorbol ester regulation of PEPCK gene expression. J. Biol. Chem. 1995 Jun 6/30/1995; 270(26): 15501-6. PMID: 7797543, ISSN: 0021-9258.

O'Brien RM, Noisin EL, Suwanichkul A, Yamasaki T, Lucas PC, Wang JC, Powell DR, Granner DK. Hepatic nuclear factor 3- and hormone-regulated expression of the phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein 1 genes. Mol. Cell. Biol. 1995 Mar; 15(3): 1747-58. PMID: 7532283, PMCID: PMC230399, ISSN: 0270-7306.

O'Brien, R.M. and Granner, D.K. Why there is an IRS. J. Clin. Invest. 1995; 96: 2546.

O'Brien RM, Lucas PC, Yamasaki T, Noisin EL, Granner DK. Potential convergence of insulin and cAMP signal transduction systems at the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter through CCAAT/enhancer binding protein (C/EBP). J. Biol. Chem. 1994 Dec 12/2/1994; 269(48): 30419-28. PMID: 7982956, ISSN: 0021-9258.

O'Brien RM, Noisin EL, Granner DK. Comparison of the effects of insulin and okadaic acid on phosphoenolpyruvate carboxykinase gene expression. Biochem. J. 1994 Nov 11/1/1994; 303 ( Pt 3): 737-42. PMID: 7980440, PMCID: PMC1137608, ISSN: 0264-6021.

O'Brien RM, Thomas WR. Immune reactivity to Der p I and Der p II in house dust mite sensitive patients attending paediatric and adult allergy clinics. Clin. Exp. Allergy. 1994 Aug; 24(8): 737-42. PMID: 7982123, ISSN: 0954-7894.

Faber S, O'Brien RM, Imai E, Granner DK, Chalkley R. Dynamic aspects of DNA/protein interactions in the transcriptional initiation complex and the hormone-responsive domains of the phosphoenolpyruvate carboxykinase promoter in vivo. J. Biol. Chem. 1993 Nov 11/25/1993; 268(33): 24976-85. PMID: 8227059, ISSN: 0021-9258.

O'Brien RM, Lucas PC, Yamasaki T, Granner DK. The physiological importance of insulin regulated gene expression: metabolic and molecular studies. Adv. Second Messenger Phosphoprotein Res. 1993; 28: 245-53. PMID: 8398410, ISSN: 1040-7952.

O'Brien RM, Lucas PC, Yamasaki T, Bonovich MT, Forest CD, Granner DK. Insulin and phorbol esters act through the same DNA element to inhibit phosphoenolpyruvate carboxykinase gene transcription. Biochem. Soc. Trans. 1992 Aug; 20(3): 686-90. PMID: 1330786, ISSN: 0300-5127.

Granner DK, O'Brien RM. Molecular physiology and genetics of NIDDM. Importance of metabolic staging. Diabetes Care. 1992 Mar; 15(3): 369-95. PMID: 1559407, ISSN: 0149-5992.

O'Brien RM, Granner DK. Regulation of gene expression by insulin. Biochem. J. 1991 Sep 9/15/1991; 278 ( Pt 3): 609-19. PMID: 1898350, PMCID: PMC1151391, ISSN: 0264-6021.

O'Brien RM, Bonovich MT, Forest CD, Granner DK. Signal transduction convergence: phorbol esters and insulin inhibit phosphoenolpyruvate carboxykinase gene transcription through the same 10-base-pair sequence. Proc. Natl. Acad. Sci. U.S.A. 1991 Aug 8/1/1991; 88(15): 6580-4. PMID: 1650476, PMCID: PMC52130, ISSN: 0027-8424.

Lucas PC, O'Brien RM, Mitchell JA, Davis CM, Imai E, Forman BM, Samuels HH, Granner DK. A retinoic acid response element is part of a pleiotropic domain in the phosphoenolpyruvate carboxykinase gene. Proc. Natl. Acad. Sci. U.S.A. 1991 Mar 3/15/1991; 88(6): 2184-8. PMID: 1848696, PMCID: PMC51194, ISSN: 0027-8424.

O'Brien, R.M.,, Bonovich, M.T., Forest, C.D. and Granner, D.K. Phorbol esters and insulin inhibit PEPCK gene transcription through the same ten base pair sequence. Proc. Natl. Acad. Sci. USA. 1991; 88: 6580-4.

Granner, D.K. And O'Brien, R.M. Regulation of transcription by insulin. The hormonal control/regulation of gene transcription, P. Cohen and J.G. Foulkes, eds. Elsevier Science Publishers. 1991; 203-26.

Forest CD, O'Brien RM, Lucas PC, Magnuson MA, Granner DK. Regulation of phosphoenolpyruvate carboxykinase gene expression by insulin. Use of the stable transfection approach to locate an insulin responsive sequence. Mol. Endocrinol. 1990 Sep; 4(9): 1302-10. PMID: 2172798, DOI: 10.1210/mend-4-9-1302, ISSN: 0888-8809.

O'Brien RM, Lucas PC, Forest CD, Magnuson MA, Granner DK. Identification of a sequence in the PEPCK gene that mediates a negative effect of insulin on transcription. Science. 1990 Aug 8/3/1990; 249(4968): 533-7. PMID: 2166335, ISSN: 0036-8075.

O'Brien RM, Granner DK. PEPCK gene as model of inhibitory effects of insulin on gene transcription. Diabetes Care. 1990 Mar; 13(3): 327-39. PMID: 2407480, ISSN: 0149-5992.

O'Brien, R.M.,, Lucas, P.C., Forest, C.D., Magnuson, M.A. and Granner, D.K. Identification of a sequence in the PEPCK gene that mediates a negative effect of insulin on transcription. Science. 1990; 249: 533-7.

O'Brien, R.M., and Granner, D.K. PEPCK gene as model of inhibitory effects of insulin on gene transcription. Diabetes Care. 1990; 13: 327-39.

Houslay MD, Pyne NJ, O'Brien RM, Siddle K, Strassheim D, Palmer T, Spence S, Woods M, Wilson A, Lavan B. Guanine nucleotide regulatory proteins in insulin's action and in diabetes. Biochem. Soc. Trans. 1989 Aug; 17(4): 627-9. PMID: 2504628, ISSN: 0300-5127.

Soos MA, O'Brien RM, Brindle NP, Stigter JM, Okamoto AK, Whittaker J, Siddle K. Monoclonal antibodies to the insulin receptor mimic metabolic effects of insulin but do not stimulate receptor autophosphorylation in transfected NIH 3T3 fibroblasts. Proc. Natl. Acad. Sci. U.S.A. 1989 Jul; 86(14): 5217-21. PMID: 2546147, PMCID: PMC297592, ISSN: 0027-8424.

Soos, M.A., O'Brien, R.M.,, Brindle, N.P.J., Stigter, J.M., Okamoto, A.K., Whittaker, J., and Siddle, K. Monoclonal antibodies to the insulin receptor mimic metabolic effects of insulin but do not stimulate receptor autophosphorylation in transfected NIH 3T3 fibroblasts. Proc. Natl. Acad. Sci. USA. 1989; 86: 5217-21.

O'Brien, R., Houslay, M.D., Brindle, N.P.J., Milligan, G.,Whittaker, J., and Siddle, K. Binding to GDP agarose identifies a novel 60kDa substrate for the insulin receptor tyrosyl kinase in mouse NIG-3T3 cells ex- pressing high concentrations of the human insulin receptor. Biochem. and Biophys. Res. Commun. 1989; 158: 743-8.

Tavaré JM, O'Brien RM, Siddle K, Denton RM. Analysis of insulin-receptor phosphorylation sites in intact cells by two-dimensional phosphopeptide mapping. Biochem. J. 1988 Aug 8/1/1988; 253(3): 783-8. PMID: 3178737, PMCID: PMC1149371, ISSN: 0264-6021.

Tavare, J.M., O'Brien, R.M.,, Siddle, K., and Denton, R.M. Analysis of insulin receptor phosphorylation sites in intact cells by two-dimensional phosphopeptide mapping. Biochem. J. 1988; 253: 783-8.

O'Brien RM, Soos MA, Siddle K. Monoclonal antibodies to the insulin receptor stimulate the intrinsic tyrosine kinase activity by cross-linking receptor molecules. EMBO J. 1987 Dec 12/20/1987; 6(13): 4003-10. PMID: 2832148, PMCID: PMC553880, ISSN: 0261-4189.

O'Brien RM, Siddle K, Houslay MD, Hall A. Interaction of the human insulin receptor with the ras oncogene product p21. FEBS Lett. 1987 Jun 6/15/1987; 217(2): 253-9. PMID: 3109943, PII: 0014-5793(87)80673-7, ISSN: 0014-5793.

O'Brien RM, Houslay MD, Milligan G, Siddle K. The insulin receptor tyrosyl kinase phosphorylates holomeric forms of the guanine nucleotide regulatory proteins Gi and Go. FEBS Lett. 1987 Feb 2/23/1987; 212(2): 281-8. PMID: 3028864, PII: 0014-5793(87)81361-3, ISSN: 0014-5793.

Siddle K, Soos MA, O'Brien RM, Ganderton RH, Taylor R. Monoclonal antibodies as probes of the structure and function of insulin receptors. Biochem. Soc. Trans. 1987 Feb; 15(1): 47-51. PMID: 3549387, ISSN: 0300-5127.

O'Brien, R.M., Soos, M.A., and Siddle, K. Monoclonal antibodies to the insulin receptor stimulate the intrinsic tyrosine kinase activity by cross-linking receptor molecules. EMBO J. 1987; 6: 4003-10.

O'Brien, R.M., Siddle, K., Houslay, M.D., and Hall, A. Interaction of the human insulin receptor with the ras oncogene product p21. Febs Letters. 1987; 217: 253-249.

O'Brien, R.M., Houslay, M.D., Milligan, G., and Siddle, K. The insulin receptor tyrosyl kinase phospho rylates holomeric forms of the guanine nucleotide regulatory proteins Gi and Go. Febs Letters. 1987; 212: 281-8.

O'Brien, R.M., Soos, M.A., and Siddle, K. Immunoaffinity purification of insulin receptor by use of mono-clonal antibodies. Biochem. Soc. Trans. 1986; 14: 316-7.

Available Postdoctoral Position Details
My laboratory is interested in the transcriptional regulation of genes whose altered expression may contribute to the pathophysiology of diabetes. We are currently working on two such genes as follows: 1. Glucose-6-Phosphatase. Glucose-6-phosphatase (G6Pase) catalyzes the terminal step in glycogenolysis and gluconeogenesis. Increased expression of G6Pase contributes to the increased hepatic glucose production characteristic of both type I and type II diabetes. Our studies mainly focus on the molecular mechanisms that mediate the regulation of G6Pase gene transcription by hormones, especially insulin. 2. IGRP. We have cloned a novel gene that encodes an islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). The goal of the on-going experiments in this project is the elucidation of the molecular basis for the islet-specific expression of the IGRP gene. These experiments involve the use of both tissue culture cells and transgenic mice. The data suggest that the regulation of IGRP gene expression is determined, in part, by novel factors. As such, the identification of these novel factors will potentially aid other investigators who are attempting to understand the process whereby islet stem cells differentiate towards that of a beta cell lineage. In addition, although its biological function is unknown, IGRP has recently been identified as a major autoantigen in type 1 diabetes. Genetic data suggests that suppression of IGRP gene expression might prevent the development of type 1 diabetes in children. Post doctoral positions are available for both of these projects.