Vanderbilt University School of Medicine

O'Brien, Richard M. , Ph.D.
Professor of Molecular Physiology and Biophysics

Lab Url: https://www.mc.vanderbilt.edu/root/vumc.php?site=obrianlab&doc=

Phone Number: 615-936-1503

Email Address:richard.obrien@vanderbilt.edu

O'Brien, Richard's picture

Office Address   Mailing Address

8415 MRB IV

8415 MRB IV 0615


Research Keywords
Biochemistry, Chromosome, Diabetes, Endocrinology, Gene regulation, Gene therapy, Genome, Kidney, Molecular medicine, Mouse, Phosphorylation, Physiology, Receptor, Signal transduction, Transcription, Transcription factor, Tyrosine phosphorylation, Virus,Diabetes,Endocrinology,Gene regulation,Knockout,Mouse,Phosphorylation,Physiology,Post-transcriptional modification,Signal transduction,Stem cells,Transcription,Transcription factor

Research Specialty
Diabetes and the Glucose-6-Phosphatase Gene Family

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.

Publications
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, 60(11), 2922-7, 2011.

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 I?-cell-enriched transcription factor Pdx-1 regulates Slc30a8 gene transcription through an intronic enhancer. Biochem J, 433(1), 95-105, 2011.

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, 47(3), 251-9, 2011.

Hutton, J. C. and Oa??Brien, R. M. . Glucose-6-Phosphatase Catalytic Subunit Gene Family. J. Biol. Chem., 284, 29241-29245, 2009.

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, 417(2), 611-20, 2009. PMCID:2929524

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, 421(3), 371-6, 2009. PMCID:2929527

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., 41, 315-328, 2008.

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, 41(5), 315-28, 2008. PMCID:2614309

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, 51(8), 1505-14, 2008. PMCID:2590337

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 IGRP in Adult Mouse Islets In Vivo. Diabetes, , , 2007.

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, 50(4), 774-8, 2007.

Jones, JJ, Borgmann, S, Wilkins, CL, O''Brien, RM. Characterizing the phospholipid profiles in mammalian tissues by MALDI FTMS. Anal Chem, 78(9), 3062-71, 2006.

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, 20(11), 2831-47, 2006.

Schilling, MM, Oeser, JK, Boustead, JN, Flemming, BP, O''Brien, RM. Gluconeogenesis: re-evaluating the FOXO1-PGC-1alpha connection. Nature, 443(7111), E10-1, 2006.

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, 281(52), 39982-9, 2006.

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, 19(12), 3001-22, 2005.

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, 33(1), 263-80, 2004.

Boustead, J N, Martin, C C, Oeser, J K, Svitek, C A, Hunter, S I, Hutton, J C, O'Brien, R M. Identification and characterization of a cDNA and the gene encoding the mouse ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein. J Mol Endocrinol, 32(1), 33-53, 2004.

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, 53(7), 1754-64, 2004.

Hornbuckle, Lauri A., Everett, Carrie A., Martin, Cyrus C., Gustavson, Stephanie S., Svitek, Christina A., Oeser, James K., Neal, Doss W., Cherrington, Alan D., OBrien, Richard M.. Selective Stimulation of G6Pase Catalytic Subunit but not G6P Transporter Gene Expression by Glucagon In Vivo and cAMP In Situ. Am J Physiol Endocrinol Metab, 286, E795-808, 2004.

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, 279(33), 34277-89, 2004.

Boustead, Jared N, Stadelmaier, Beth T, Eeds, Angela M, Wiebe, Peter O, Svitek, Christina A, Oeser, James K, O'Brien, Richard M. 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, 369(Pt 1), 17-22, 2003. PMCID:1223073

Martin, Cyrus C, Svitek, Christina A, Oeser, James K, Henderson, Eva, Stein, Roland, O'Brien, Richard M. 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, 371(Pt 3), 675-86, 2003. PMCID:1223330

Vander Kooi, Beth T, Streeper, Ryan S, Svitek, Christina A, Oeser, James K, Powell, David R, O'Brien, Richard M. The three insulin response sequences in the glucose-6-phosphatase catalytic subunit gene promoter are functionally distinct. J Biol Chem, 278(14), 11782-93, 2003.

Ayala, Julio E, Streeper, Ryan S, Svitek, Christina A, Goldman, Joshua K, Oeser, James K, O'Brien, Richard M. 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, 277(31), 27935-44, 2002.

Martin, C C, Oeser, J K, Svitek, C A, Hunter, S I, Hutton, J C, O'Brien, R M. Identification and characterization of a human cDNA and gene encoding a ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein. J Mol Endocrinol, 29(2), 205-22, 2002.

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, 31(1), 124-50, 2002.

Thomas, WR, Smith, WA, Hales, BJ, Mills, KL, O''Brien, RM. Characterization and immunobiology of house dust mite allergens. Int Arch Allergy Immunol, 129(1), 1-18, 2002.

Bischof, L J, Martin, C C, Svitek, C A, Stadelmaier, B T, Hornbuckle, L A, Goldman, J K, Oeser, J K, Hutton, J C, O'Brien, R M. 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, 50(3), 502-14, 2001.

Hornbuckle, L A, Edgerton, D S, Ayala, J E, Svitek, C A, Oeser, J K, Neal, D W, Cardin, S, Cherrington, A D, O'Brien, R M. 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, 281(4), E713-25, 2001.

Martin, C C, Bischof, L J, Bergman, B, Hornbuckle, L A, Hilliker, C, Frigeri, C, Wahl, D, Svitek, C A, Wong, R, Goldman, J K, Oeser, J K, Lepr??tre, F, Froguel, P, O'Brien, R M, Hutton, J C. Cloning and characterization of the human and rat islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) genes. J Biol Chem, 276(27), 25197-207, 2001.

O'brien, R M, Streeper, R S, Ayala, J E, Stadelmaier, B T, Hornbuckle, L A. Insulin-regulated gene expression. Biochem Soc Trans, 29(Pt 4), 552-8, 2001.

Streeper, R S, Hornbuckle, L A, Svitek, C A, Goldman, J K, Oeser, J K, O'Brien, R M. Protein kinase A phosphorylates hepatocyte nuclear factor-6 and stimulates glucose-6-phosphatase catalytic subunit gene transcription. J Biol Chem, 276(22), 19111-8, 2001.

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, 30(3), 333-40, 2000.

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, Chapter 28, 291-305, 2000.

Streeper, R S, Svitek, C A, Goldman, J K, O'Brien, R M. 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, 275(16), 12108-18, 2000.

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, 48, 531-542, 1999.

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, 48(3), 531-42, 1999.

Ayala, J E, Streeper, R S, Desgrosellier, J S, Durham, S K, Suwanichkul, A, Svitek, C A, Goldman, J K, Barr, F G, Powell, D R, O'Brien, R M. 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, 48(9), 1885-9, 1999.

Chapman, S C, Ayala, J E, Streeper, R S, Culbert, A A, Eaton, E M, Svitek, C A, Goldman, J K, Tavar, J M, O'Brien, R M. 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, 274(26), 18625-34, 1999.

Clarke, AH, O''Brien, RM, Rolland, JM, Thomas, WR. Allergic respiratory responses to Der p 1 in mice. Int Arch Allergy Immunol, 118(2-4), 287-8, 1999.

Ebert, D H, Bischof, L J, Streeper, R S, Chapman, S C, Svitek, C A, Goldman, J K, Mathews, C E, Leiter, E H, Hutton, J C, O'Brien, R M. Structure and promoter activity of an islet-specific glucose-6-phosphatase catalytic subunit-related gene. Diabetes, 48(3), 543-51, 1999.

O''Brien, RM, Stockard, J, Isaacson, L. The enduring effects of cohort characteristics on age-specific homicide rates, 1960-1995. AJS, 104(4), 1061-95, 1999.

O''Brien, RM, Tait, BD, Varney, MD, Thomas, WR. HLA-DPB1 alleles in house dust mite allergic patients. Eur J Immunogenet, 26(4), 281-4, 1999.

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, 96(16), 8961-6, 1999. PMCID:17715

Dickens, M., Svitek, C.A., Culbert, A.A., O'Brien, R.M. and Tavare J.M. (1998) Central Role for Phosphatidylinositide 3-Kinase in the Repression of Glucose-6-phosphatase Gene Transcription by Insulin. J. Biol. Chem. 273: 20144-20149.

Dickens, M, Svitek, CA, Culbert, AA, O''Brien, RM, Tavar??, JM. Central role for phosphatidylinositide 3-kinase in the repression of glucose-6-phosphatase gene transcription by insulin. J Biol Chem, 273(32), 20144-9, 1998.

Streeper, R S, Chapman, S C, Ayala, J E, Svitek, C A, Goldman, J K, Cave, A, O'Brien, R M. A phorbol ester-insensitive AP-1 motif mediates the stimulatory effect of insulin on rat malic enzyme gene transcription. Mol Endocrinol, 12(11), 1778-91, 1998.

Streeper, R S, Eaton, E M, Ebert, D H, Chapman, S C, Svitek, C A, O'Brien, R M. 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, 95(16), 9208-13, 1998. PMCID:21317

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, 27(1), 46-51, 1997.

Streeper, R S, Svitek, C A, Chapman, S, Greenbaum, L E, Taub, R, O'Brien, R M. A multicomponent insulin response sequence mediates a strong repression of mouse glucose-6-phosphatase gene transcription by insulin. J Biol Chem, 272(18), 11698-701, 1997.

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, 271(4), 1890-7, 1996.

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, 81(2), 503-6, 1996.

O'Brien, R M, Granner, D K. Regulation of gene expression by insulin. Physiol Rev, 76(4), 1109-61, 1996.

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, Chapter 25, 234-242, 1996.

Sutherland, C, O'Brien, R M, Granner, D K. New connections in the regulation of PEPCK gene expression by insulin. Philos Trans R Soc Lond B Biol Sci, 351(1336), 191-9, 1996.

Wang, J C, Str??mstedt, P E, O'Brien, R M, Granner, D K. Hepatic nuclear factor 3 is an accessory factor required for the stimulation of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. Mol Endocrinol, 10(7), 794-800, 1996.

O''Brien, RM, Granner, DK. Why there is an IRS. J Clin Invest, 96(6), 2546, 1995. PMCID:185957

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, 86(2), 176-82, 1995. PMCID:1383992

O'Brien, R M, Halmi, N, Stromstedt, P E, Printz, R L, Granner, D K. Expression cloning of a zinc-finger cyclic AMP-response-element-binding protein. Biochem J, 312 ( Pt 1), 17-21, 1995. PMCID:1136221

O'Brien, R M, Noisin, E L, Suwanichkul, A, Yamasaki, T, Lucas, P C, Wang, J C, Powell, D R, Granner, D K. Hepatic nuclear factor 3- and hormone-regulated expression of the phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein 1 genes. Mol Cell Biol, 15(3), 1747-58, 1995. PMCID:230399

O'Brien, R M, Printz, R L, Halmi, N, Tiesinga, J J, Granner, D K. Structural and functional analysis of the human phosphoenolpyruvate carboxykinase gene promoter. Biochim Biophys Acta, 1264(3), 284-8, 1995.

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

Sutherland, C, O'Brien, R M, Granner, D K. 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, 270(26), 15501-6, 1995.

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, 24(8), 737-42, 1994.

O'Brien, R M, Lucas, P C, Yamasaki, T, Noisin, E L, Granner, D K. 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, 269(48), 30419-28, 1994.

O'Brien, R M, Noisin, E L, Granner, D K. Comparison of the effects of insulin and okadaic acid on phosphoenolpyruvate carboxykinase gene expression. Biochem J, 303 ( Pt 3), 737-42, 1994. PMCID:1137608

Faber, S, O'Brien, R M, Imai, E, Granner, D K, 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, 268(33), 24976-85, 1993.

O'Brien, R M, Lucas, P C, Yamasaki, T, Granner, D K. The physiological importance of insulin regulated gene expression: metabolic and molecular studies. Adv Second Messenger Phosphoprotein Res, 28, 245-53, 1993.

Granner, D K, O'Brien, R M. Molecular physiology and genetics of NIDDM. Importance of metabolic staging. Diabetes Care, 15(3), 369-95, 1992.

O'Brien, R M, Lucas, P C, Yamasaki, T, Bonovich, M T, Forest, C D, Granner, D K. Insulin and phorbol esters act through the same DNA element to inhibit phosphoenolpyruvate carboxykinase gene transcription. Biochem Soc Trans, 20(3), 686-90, 1992.

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, , 203-226, 1991.

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, 88(6), 2184-8, 1991. PMCID:51194

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, 88(15), 6580-4, 1991. PMCID:52130

O''Brien, RM, Granner, DK. Regulation of gene expression by insulin. Biochem J, 278 ( Pt 3), 609-19, 1991. PMCID:1151391

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 , 88, 6580-6584, 1991.

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, 4(9), 1302-10, 1990.

O''Brien, RM, Granner, DK. PEPCK gene as model of inhibitory effects of insulin on gene transcription. Diabetes Care, 13(3), 327-39, 1990.

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, 249(4968), 533-7, 1990.

O'Brien, R.M., and Granner, D.K. PEPCK gene as model of inhibitory effects of insulin on gene transcription. Diabetes Care, 13, 327-339, 1990.

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, 249, 533-537, 1990.

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, 17(4), 627-9, 1989.

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, 158, 743-748, 1989.

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 , 86, 5217-5221, 1989.

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, 86(14), 5217-21, 1989. PMCID:297592

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., 253, 783-788, 1988.

Tavar??, JM, O''Brien, RM, Siddle, K, Denton, RM. Analysis of insulin-receptor phosphorylation sites in intact cells by two-dimensional phosphopeptide mapping. Biochem J, 253(3), 783-8, 1988. PMCID:1149371

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, 212(2), 281-8, 1987.

O''Brien, RM, Siddle, K, Houslay, MD, Hall, A. Interaction of the human insulin receptor with the ras oncogene product p21. FEBS Lett, 217(2), 253-9, 1987.

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, 6(13), 4003-10, 1987. PMCID:553880

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. , 212, 281-288, 1987.

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Postdoctoral Position Available
Yes

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.

Updated Date
05/28/2012



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