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.
Highlights
The proteins encoded by the sir2 genes in yeast, C. elegans, D. melanogaster, and mouse have been reported to prolong lifespan and increase organismal resistance to stress [1,2,3,4]
RNA isolated from clones of embryonic stem (ES) cells carrying one sirt1ER allele showed that the mRNA encoding SIRT1-estrogen receptor ligand-binding domain (ER) was present at higher levels than the mRNA encoding the wild type SIRT1 protein (Fig 1B)
We found that sirt1ER/ER fed a high fat diet developed much reduced fat depots when the chow contained tamoxifen; similar effects were seen in wild type mice so the reduced fat accumulation in the sirt1ER/ER was likely a result of the effects of tamoxifen on fat metabolism rather than on the induction of SIRT1-ER
Summary
The proteins encoded by the sir genes in yeast, C. elegans, D. melanogaster, and mouse have been reported to prolong lifespan and increase organismal resistance to stress [1,2,3,4]. The number of documented acetylated protein substrates of SIRT1 exceeds 100 [8], and there is evidence that the SIRT1 protein has functions not dependent on its catalytic activity [9,10,11,12,13,14,15]. SIRT1 has been reported to have effects on a wide variety of cellular functions yet there is a remarkable amount of controversy because many of the reports are contradictory. This is PLOS ONE | DOI:10.1371/journal.pone.0173002 March 8, 2017
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