Disease relevance of SIRT1

• Interestingly, the regulation of SIRT mRNAs was highly similar both in mouse Neuro-2a neuroblastoma cells and post-mitotic rat primary hippocampal and cerebellar granule neurons [1].
• SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling [2].
• Tat and SIRT1 coimmunoprecipitate and synergistically activate the HIV promoter [3].
• DHT-induced prostate cancer cellular contact-independent growth is also blocked by SIRT1, providing a direct functional link between the AR, which is a critical determinant of progression of human prostate cancer, and the sirtuins [4].
• We propose that low expression of SIRT1 and Foxo1 leads to impaired Foxo1-C/EBPalpha complex formation, which contributes to the diminished adiponectin expression in obesity and type 2 diabetes [5].
• In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival [6].
• HIC-1, which has been shown to regulate SIRT1 levels, was markedly reduced in the same tumors, suggesting that a reduction in HIC-1 may be in part responsible for the increased expression of SIRT1 in prostatic adenocarcinomas [7].
• Collectively, these findings identify SIRT1 as a corepressor of AR and elucidate a new molecular pathway relevant to prostate cancer growth and approaches to therapy [8].
• SIRT1 expression was also significantly correlated with tumor stage (P < 0.001), lymph node metastasis (P < 0.001), tumor invasion (P < 0.001), histologic types (P < 0.001), and p53 expression (P = 0.001) [9].

Psychiatry related information on SIRT1

• In a mouse model of Huntington's disease, resveratrol-induced SIRT1 was found to protect neurons against ployQ toxicity and in Wallerian degeneration slow mice, resveratrol was found to protect the degeneration of neurons from axotomy, suggesting that resveratrol may possess therapeutic value to neuronal degeneration [10].

High impact information on SIRT1

• Studies by and now show that resveratrol promotes longevity and improves glucose homeostasis in mice by stimulating the Sirt1-mediated deacetylation of the transcriptional coactivator PGC-1alpha [11].
• Inhibition of SIRT1 function in cells without HIC1 abolishes the resistance to apoptosis [12].
• Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses [12].
• Since aging increases promoter hypermethylation and epigenetic silencing of HIC1, we speculate that the resultant upregulation of SIRT1 may be a double-edged sword that both promotes survival of aging cells and increases cancer risk in mammals [12].
• SIRT1 might increase longevity by shifting FOXO dependent responses away from cell death and towards cell survival [13].

Chemical compound and disease context of SIRT1

• Roles of SIRT1 and phosphoinositide 3-OH kinase/protein kinase C pathways in evodiamine-induced human melanoma A375-S2 cell death [14].

Biological context of SIRT1

• Moreover, we show that SIRT1 and p53 co-localize in nuclear bodies upon PML upregulation [15].
• Taken together, our data establish the SIRT1 deacetylase as a novel negative regulator of p53 function capable of modulating cellular senescence [15].
• Consistent with the role of SIRT1 in promoting cell survival during stress, inhibition of SIRT1 activity with cambinol during genotoxic stress leads to hyperacetylation of key stress response proteins and promotes cell cycle arrest [16].
• Using this method, the kinetics of the reaction of the cosubstrate nicotinamide adenine dinucleotide and the competitive inhibitor nicotinamide with SIRT1 and SIRT2 has been analyzed [17].
• Differential responses in SIRT mRNA expression profiles indicate that the expression of the Sir2 family of genes is selectively regulated and dependent on histone/protein acetylation status [1].

Anatomical context of SIRT1

• These results show that, although SIRT1 deacetylates p53, this does not play a role in cell survival following DNA damage in certain cell lines and primary human mammary epithelial cells [18].
• Tat transactivation is defective in SIRT1-null mouse embryonic fibroblasts and can be rescued by expression of SIRT1 [3].
• Our work identifies SIRT1 as a novel target for selective killing of cancer versus noncancer epithelial cells [19].
• In PC12 cells, increased expression of the NAD-dependent deacetylase SIRT1 reduces cellular oxygen consumption by approximately 25% [20].
• In this study, we evaluated whether mammalian silent information regulator 2 (SIRT1), which has been recently identified as a cell survival factor countering various stressors, is a key regulator of oxidative stress-induced mesangial cell apoptosis [21].

Associations of SIRT1 with chemical compounds

• Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications [22].
• We propose that binding of resveratrol to SIRT1 promotes a conformational change that better accommodates the attached coumarin group [23].
• The upregulation of SIRT mRNAs was inhibited by actinomycin D [1].
• Studies involving cobB, a bacterial SIR2-like gene, have suggested it could encode a pyridine nucleotide transferase [24].
• Our results indicate that hepatic SIRT1 is an important factor in the regulation of glucose and lipid metabolism in response to nutrient deprivation [25].
• AMPK activation by SIRT1 also protects against FAS induction and lipid accumulation caused by high glucose [26].
• In the mitochondrial fraction, SIRT1 inhibition by siRNA for SIRT1 increased the amount of Bax but reduced the amount of Bcl-2, while resveratrol reduced the amount of Bax but increased the amount of Bcl-2 [27].

Physical interactions of SIRT1

• SIRT1 was found to interact directly with BCL11A and was recruited to the promoter template in a BCL11A-dependent manner leading to transcriptional repression [28].
• Using available crystal structures, a model of SIRT1 bound to p53-AMC peptide was constructed [23].
• SIRT1 binds and deacetylates the AR at a conserved lysine motif [4].
• In contrast, mammalian SIRT1 was found to bind to FOXO4, catalyze its deacetylation in an NAD-dependent manner, and thereby increase its transactivation activity [29].
• AROS was unable to cooperate in p53 inactivation in an AROS-binding-defective SIRT1 mutant [30].
• SIRT1 interacts with LXR and promotes deacetylation and subsequent ubiquitination [31].

Regulatory relationships of SIRT1

• Furthermore, NDRG1 expression was regulated by the activity of SIRT1 (Sir2-like protein 1), which promotes cell survival [32].
• Instead, the NAD+-dependent deacetylase SIRT1 can potently induce MEF2 deacetylation [22].
• EX-527 and TSA acted synergistically to increase acetyl-p53 levels, confirming that p53 acetylation is regulated by both SIRT1 and HDACs [18].
• Overexpression of SIRT1 deacetylase and the addition of the SIRT1 agonist resveratrol markedly reduced NF-kappaB signaling stimulated by Abeta and had strong neuroprotective effects [2].
• We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity [33].

Other interactions of SIRT1

• Hereby, we describe the identification of a compound we named cambinol that inhibits NAD-dependent deacetylase activity of human SIRT1 and SIRT2 [16].
• These findings define a role for SIRT1 in transcriptional repression mediated by BCL11A in mammalian cells [28].
• Here we demonstrate that the human Sir2 homologue, SIRT1, also physically associates with the human bHLH repressor proteins, hHES1 and hHEY2, both in vitro and in vivo [34].
• Interestingly, SIRT1, a mammalian homolog of yeast Sir2, bound to and deacetylated FOXO1 and inhibited its transcriptional activity [35].
• Without resveratrol, the coumarin of p53-AMC peptide is solvent-exposed and makes no significant contacts with SIRT1 [23].
• Our results provide a possible molecular mechanism connecting the effects of CR on the endothelium and vascular tone to SIRT1-mediated deacetylation of eNOS [36].

Analytical, diagnostic and therapeutic context of SIRT1

• Beads preferentially deacetylated by SIRT1 were biotinylated and labeled with streptavidin-coated quantum dots [37].
• Caloric restriction delays ageing by activating Sir 2 deacetylase in yeast, and expression of Sir 2 (SIRT1) in human cells [38].
• After treatment with evodiamine for the indicated time periods, anti-apoptotic protein SIRT1 expression was decreased; p53 expression and its phosphorylation were both enhanced, whereas transient induction of downstream p21 was not enough to promote cell cycle arrest [14].
• Fluorescence in situ hybridization analysis localized the human Sirt1 gene to chromosome 10q21.3 [39].
• The lung uptake of thallium-201 (201Tl) in planar imaging was evaluated in 384 patients enrolled in the SIRT study (Italian Multicentre Study on Thallium Reinjection) [40].

References