Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving transferase
Reexamination Certificate
2006-04-04
2009-02-03
Weber, Jon P (Department: 1657)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving transferase
Reexamination Certificate
active
07485434
ABSTRACT:
In accordance with the present invention, it has been discovered that glucose and incretin hormones promote pancreatic islet cell survival via the calcium and cAMP dependent induction, respectively, of the transcription factor CREB. Specifically, a signaling module has been identified which mediates cooperative effects of calcium and cAMP on islet cell gene expression by stimulating the dephosphorylation and nuclear entry of TORC2, a cytoplasmic CREB coactivator. The module comprises a cAMP regulated snf1-like kinase called SIK2 and the calcium regulated phosphatase calcineurin, both of which associate with TORC2 in the cytoplasm. TORC2 is repressed under basal conditions through a phosphorylation dependent interaction with 14-3-3 proteins. cAMP and calcium signals stimulate CREB target gene expression via complementary effects on TORC2 dephosphorylation; cAMP disrupts TORC2-associated activity of SIK2 or related family members, whereas calcium induces TORC2 dephosphorylation via calcineurin. These findings provide a novel mechanism by which CREB activates cellular gene expression, depending on nutrient and energy status, and facilitate development of assays to identify compounds which modulate the role of TORCs. In accordance with the present invention, it has been discovered that fasting and energy-sensing pathways regulate the gluconeogenic program in liver by modulating the nuclear entry of a transcriptional coactivator called Transducer of Regulated CREB Activity 2 (TORC2). Hepatic TORC2 over-expression induces fasting hyperglycemia, whereas knockdown of TORC2 leads to fasting hypoglycemia and silencing of the gluconeogenic program. Since a majority of individuals with Type II diabetes exhibit fasting hyperglycemia due to elevated hepatic gluconeogenesis, compounds that enhance TORC2 phosphorylation will find use as therapeutic agents in this setting.
REFERENCES:
Ahn, et al. (1998) A dominant negative inhibitor of CREB reveals that it is a general mediator stimulus dependent transcription of c-fos.Molec. Cell. Biol. 18: 967-977.
Al-Uzri, et al. (2001). Posttransplant diabetes mellitus in pediatric renal transplant recipients: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation 72: 1020-1024.
Ararnburu, et al. (1998). Selective inhibition of NFAT activation by a peptide spanning the calcineurin targeting site ofNFAT. Mol Cell 1: 627-637.
Arias, et al. (1994). Activation of CAMP and mitogen responsive genes relies on a common nuclear factor. Nature 370: 226-228.
Asahara, et al. (2001). Chromatin Dependent Cooperativity Between Constitutive and Inducible Activation Domains in CREB. Molecular and Cellular Biology 21: 7892-7900.
Banenjee, et al. (2004) Regulation of fasted blood glucose by resistin. Science 303: 1195-8.
Bergeron, et al. (2001) Effect of 5-aminoimidazole-4-carboxamide-1 -beta-Dribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats.Diabetes50: 1076-82.
Bittinger, et al. (2004) Activation of cAMP response element-mediated gene expression by regulated nuclear transport of TORC proteins.Curr Biol14: 2156-61.
Bonni, et al. (1995a). Serine 133 phosphorylated CREB Induces Transcription via a Cooperative Mechanism That May confer Specificity to Neurotrophin Signals. Molecular and Cellular Neurosciences 6: 168-183.
Brunet, et al. (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96: 857-868.
Carling, D. (2004). The AMP-activated protein kinase cascade—a unifying system for energy control. Trends Biochem Sci 29: 18-24.
Chen, et al. (2003). Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding. Mol Cell Biol 23:7488-7497.
Chow and Davis (2000). Integration of calcium and cyclic AMP signaling pathways by 14-3-3. Mol Cell Biol 20:702-712.
Chrivia et al. (1993). Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365: 855-859.
Conkright et al. (2003a). TORCs: transducers of regulated CREB activity. Mol Cell 12: 413-423.
Conkright et al. (2003b). Genome Wide Analysis of CREB Target Genes Reveals A Core Promoter Requirement for CAMP Responsiveness. Mol Cell 11: 1101-1108.
Crabtree and Olson (2002). NFAT signaling: choreographing the social lives of cells. Cell 109 Suppl, S67-79.
Doi et al. (2002). Salt inducible kinase represses CAMP-dependent protein kinase-mediated activation of human cholesterol side chain cleavage cytochrome P450 promoter through the CREB basic leucine zipper domain. J Biol Chem 277: 15629-15637.
Dougherty and Morrison (2004). Unlocking the code of 14-3-3. J Cell Science 117:1875-1884.
Durocher et al., (2000). The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms. Mol Cell 6: 1169-1 182.
Enlund et al. (2004). Altered Notch signaling resulting from expression of a WAMTPI-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors. Exp Cell Res 292: 21-28.
Filler et al. (2000). Tacrolimus reversibly reduces insulin secretion in paediatric renal transplant recipients. Nephrol Dial Transplant 15: 867-871.
Gonzalez and Montminy (1989). Cyclic AMP stimulates somatostatin gene transcription by phosphyorylation of CREB at Serine 133. Cell 59: 675-680.
Goodman and Smolik. (2000). CBPIp300 in cell growth, transformation, and development. Genes Dev 14: 1553-1577.
Hall and Granner (1999) Insulin regulates expression of metabolic genes through divergent signaling pathways.J Basic Clin Physiol Pharmacol10: 119-133.
Hanson and Reshef (1997) Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression.Annu Rev Biochem66: 581-611.
Herzig et al. (2001) CREB Regulates Hepatic Gluconeogenesis via the Co-activator PGC-I.Nature413: 179-183.
Hogan et al. (2003) Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 17: 2205-2232.
Horike et al. (2003).Adipose-specific expression, phosphorylation of Ser794in insulin receptor substrate-1, and activation in diabetic animals of salt-induced kinase-2. J. Biol. Chem. 278:18440-18447.
Hui et al. (2003). Glucagon-like peptide-I inhibits apoptosis of insulin-secreting cells via a cyclic 5′- adenosine monophosphate dependent protein kinase A- and a phosphatidylinositol 3-kinase-dependent pathway. Endocrinology 144: 1444-1455.
Iourgenko et al. (2003). Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells. Proc Natl Acad Sci U S A 100: 12147-52.
Jhala et al. (2003). cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of LRS2. Genes Dev 17: 1575-1580.
Kahn et al. (2005) AMP-activated protein kinase: Ancient energy gauge provides clues to modem understanding of metabolism.Cell Metabolism1: 15-25.
Kasper et al. (2002). A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis. Nature 41 9: 738-743.
Katoh et al., (2004). Salt-inducible kinase (SIK) isoforms: their involvement in steroidogenesis and adipogenesis. Mol Cell Endocrinol 217:109-12.
Katoh et al. (2004) Salt-inducible kinase-I represses cAMP response element-binding protein activity both in the nucleus and in the cytoplasm.Eur J Biochem271: 4307-19.
Koo et al. (2004) PGC-1 promotes insulin resistance in liver through PPAR-alpha dependent induction of TRB-3.Nat Med10(5): 530-534 and 755.
Koo et al. (2005) The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437: 1109-1114.
Kornhauser et al. (2002). CREB transcriptional activity in neurons is regulated by multiple, calcium-specific phosphorylation events. Neuron 34: 221-233.
Kwok et al. (1994). Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature 370: 223-226.
Lemaigre et al. (1993). The cAMP response element binding protein, CREB, is a potent inhibitor of diverse transcriptional activators. Nucleic Acids Res 21:2907-2911.
Lin et al. (2004) Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-I
Foley & Lardner LLP
Reiter Stephen E.
Shen Bin
The Salk Institute for Biological Studies
Weber Jon P
LandOfFree
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