Methods for indentifying compounds that modulate gluconeogenesis through the binding of CREB to the PGC-1 promoter

• US 6,974,671 B1
• Filed: 09/11/2002
• Issued: 12/13/2005
• Est. Priority Date: 09/12/2001
• Status: Expired due to Fees

• Current Assignee: Salk Institute for Biological Studies
• Original Assignee: Salk Institute for Biological Studies
• Inventors: Spiegelman, Bruce M., Montminy, Marc R., Herzig, Stephan
• Primary Examiner(s): Nguyen, Dave Trong
• Assistant Examiner(s): Kelly, Robert M.
• Application Number:
  US10/244,045
• Time in Patent Office: 1,189 Days
• Field of Search: 536/23.1, 536/23.5, 536/24.1, 514/44, 424/93.1, 435/325, 435/455, 435/6, 800/21, 436/94, 204/450
• US Class Current: 435/6.13
• CPC Class Codes: C07H 19/00 Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: C12Q 1/6897 involving reporter genes operably linked to promoters

Abstract

In accordance with the present invention, it has been discovered that CREB regulates hepatic gluconeogenesis via the co-activator, PGC-1. PGC-1 potentiated glucocorticoid induction of the gene for PEPCK, the rate limiting enzyme in gluconeogenesis, via the glucocorticoid response unit in the promoter, indicating that activation of PGC-1 by CREB in liver contributes to the pathogenesis of diabetes mellitus. In accordance with the above discoveries, the present invention provides a method of identifying a compound that modulates gluconeogenesis. The invention method comprises contacting CREB and a nucleic acid comprising a PGC-1 promoter with a test compound, and determining if the test compound modulates binding between CREB and the PGC-1 promoter.

Claims

1. An in vitro method of identifying a compound that modulates gluconeogenesis, said method comprising:

contacting CREB and a nucleic acid comprising a PGC-1 promoter with a test compound, and

determining if the test compound modulates binding between CREB and the PGC-1 promoter,

wherein said PGC-1 promoter comprises position minus 116 to minus 133 of the human PGC-1 gene.

2. The method of claim 1 wherein said test compound is the dominant negative mutant of CREB, A-CREB.

3. The method of claim 1 wherein said test compound reduces binding between CREB and said PGC-1 promoter.