Nuclear Trapping May Help Avoid Aging

Science's STKE  31 May 2005:
Vol. 2005, Issue 286, pp. tw207
DOI: 10.1126/stke.2862005tw207

In the worm, at least, increased expression of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase Sir2.1 can prolong life span. Thus, the biochemical effects of such enzymes, known as Sirtuins, are of particular interest. Frescas et al. explored the effects of mammalian Sirtuins on deacetylation of the transcription factor FoxO1. They expressed a FoxO1 molecule modified by fusion with green fluorescent protein (GFP) in cultured cells and monitored its movement to the nucleus and its mobility in FLIP (fluorescence loss in photobleaching) and FRAP (fluorescence recovery after photobleaching) experiments. Their results show that treatment of cells with a Sirtuin activator, resveratrol, or promotion of oxidative stress by treatment of cells with hydrogen peroxide promoted nuclear translocation of FoxO1. The FRAP studies showed that after deacetylation by Sirtuins, FoxO1 remains bound in a particular nuclear compartment. The nuclear sequestration of FoxO1 is correlated with increased expression of FoxO1 target genes. Control of localization is not the whole story, however, as expression of a constitutively nuclear form of FoxO1 was not sufficient to stimulate FoxO1-dependent transcription. Thus, other signals must also modulate FoxO1 activity. Genes regulated by FoxO1 include hepatic enzymes that control gluconeogenesis; better understanding of these regulatory interactions may be useful in achieving therapeutic control of metabolic disorders.

D. Frescas, L. Valenti, D. Accili, Nuclear trapping of the Forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J. Biol. Chem. 280, 20589-20595 (2005). [Abstract] [Full Text]