Cellular Regulation of SIRT1

The intersection between regulatory pathways responsive to metabolic fluctuation on one hand, and to cellular stress on the other, is a fascinating area within which NAD/NADH responsive proteins play a major role [ 1, 2]. A key player amongst these is SIRT1, a member of the mammalian sirtuin family (SIRT1-7). SIRT1 is an NAD-dependent deacetylase with critical functions in the maintenance of homeostasis and cell survival. In this review I shall focus upon (i) the cellular regulation of SIRT1 expression and (ii) the cellular regulation of SIRT1 activity. In addition the distinction between basal and stress-induced functions will be addressed: do they simply reflect a sliding scale of response, or are they mechanistically distinct? Elevated levels of SIRT1 are evident in cancer and SIRT1 can function as a cancer-specific survival factor in human cell lines. However, in a mouse model SIRT1 is reported to function as a tumour suppressor. Possible explanations for this apparent discrepancy will be considered. Given the high profile of SIRT1 as a potential therapeutic target it is clearly important to clarify its basal functioning in relation to differentiation, cell type, intercellular communication, and to age-related disease states including neurodegeneration and cancer.