Abstract
BackgroundThe NAD-dependent protein deacetylase SIRT1 has a wide range of different targets, which may be regulated either directly through deacetylation and thus potentially altering their activity or localization or indirectly by deacetylation of histones, which in turn alters their transcription rate and availability. SIRT1 is therefore involved in the regulation of many different and fundamental cellular processes such as apoptosis, metabolism, differentiation and cell cycle arrest. It is also involved in the regulation of resistance of cells against oxidative stress and longevity under conditions of caloric restriction. Even though the targets and role of SIRT1 have been studied quite intensively, only little is known about the mechanisms affecting SIRT1 transcriptional regulation. The nuclear factor NFκB is a well-studied and widely known transcription factor, which is involved in the regulation of many important cellular activities. The regulation of NFκB by SIRT1 has been reported recently, but it is, however, still unknown whether a feedback mechanism affects the regulation of SIRT1 too, particularly in view of the fact that putative NFκB binding sites within the SIRT1 promoter suggest just that.ResultsIn the study presented herein we show that there is activation of the SIRT1 promoter by overexpression of different NFκB subunits. Direct binding of NFκB to the SIRT1 promoter can be demonstrated by an electrophoretic mobility shift assay. Further investigations indicated enhanced expression of SIRT1 on the mRNA levels in cells overexpressing NFκB. A functional assay showed that acetylation of one of the main target proteins of SIRT1 is reduced in these cells.ConclusionsThese finding together indicate SIRT1 expression to be regulated in a positive feedback loop by NFκB. The putative binding sites for NFκB found within the SIRT1 promoter appears to be functional and several NFκB subunits are able to enhance the expression of SIRT1 if they are overexpressed.
Highlights
The NAD-dependent protein deacetylase SIRT1 has a wide range of different targets, which may be regulated either directly through deacetylation and potentially altering their activity or localization or indirectly by deacetylation of histones, which in turn alters their transcription rate and availability
Histone deacetylases are divided into four different classes: three groups of classical HDACs known as class I, class II and class IV HDACs and a fourth class, being referred to as the ‘sirtuins’ [3]
Human SIRT1 gene promoter analysis Alterations in the SIRT1 expression rate are associated with changes in cell metabolism, differentiation, proliferation and many other fundamental cell features and affect many diseases such as diabetes, cancer or arteriosclerosis
Summary
The NAD-dependent protein deacetylase SIRT1 has a wide range of different targets, which may be regulated either directly through deacetylation and potentially altering their activity or localization or indirectly by deacetylation of histones, which in turn alters their transcription rate and availability. SIRT1 is involved in the regulation of many different and fundamental cellular processes such as apoptosis, metabolism, differentiation and cell cycle arrest. The regulation of activity, cellular localization and stability of most proteins depends on post-transcriptional and/or post-translational modifications. Such modifications are being carried out by a diversity of chemical reactions including (de)phosphorylation, (de)acetylation or ubiquitination and many others. SIR2 is responsible for the transcriptional silencing of silent mating loci, telomeres and ribosomal DNA in yeast. High levels of NAD+ go along with high sirtuins activity [9]
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