title: Reversible modulation of SIRT1 activity in a mouse strain.
abstract: The SIRT1 protein deacetylase is reported to have a remarkably wide spectrum of biological functions affecting such varied processes as aging, cancer, metabolism, neurodegeneration and immunity. However, the SIRT1 literature is also full of contradictions. To help establish the role(s) of SIRT1 in these and other biological processes, we set out to create a mouse in which the SIRT1 activity could be toggled between on and off states by fusing the estrogen receptor ligand-binding domain (ER) to the C terminus of the SIRT1 protein. We found that the catalytic activity of the SIRT1-ER fusion protein increased 4-5 fold in cells treated with its ligand, 4-hydroxy-tamoxifen (4OHT). The 4OHT-induced activation of SIRT1-ER was due in large part to a 2 to 4-fold increase in abundance of the SIRT1-ER protein in cells in culture and in tissues in vivo. This increase is reversible and is a consequence of 4OHT-induced stabilization of the SIRT1-ER protein. Since changes in SIRT1 level or activity of 2-4 fold are frequently reported to be sufficient to affect its biological functions, this mouse should be helpful in establishing the causal relationships between SIRT1 and the diseases and processes it affects.
authors.affiliation: Program in Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Katherine V
authors.initials: KV
authors.lastname: Clark-Knowles
authors.affiliation: Program in Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: He
authors.affiliation: Program in Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Jardine
authors.affiliation: Program in Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Josée
authors.initials: J
authors.lastname: Coulombe
authors.affiliation: Program in Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Danielle
authors.initials: D
authors.lastname: Dewar-Darch
authors.affiliation: Program in Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Annabelle Z
authors.initials: AZ
authors.lastname: Caron
authors.affiliation: Program in Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.
authors.forename: Douglas A
authors.identifier: http://orcid.org/0000-0002-8634-4984
authors.initials: DA
authors.lastname: Gray
authors.affiliation: Program in Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.|Department of Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Michael W
authors.identifier: http://orcid.org/0000-0001-6096-3659
authors.initials: MW
authors.lastname: McBurney
mesh_terms: D000483:Alleles; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002384:Catalysis; D002460:Cell Line; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D005838:Genotype; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D013629:Tamoxifen; D056564:Sirtuin 1