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SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae))

Written2010-03Ruo-Chia Tseng, Yi-Ching Wan
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
Updated2014-12WenYong Chen
Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA

Abstract SIRT1 is a member of the mammalian sirtuin genes that encode for seven protein lysine modifiers with deacetylase, ADP-ribosyltransferase and other deacylase activities. SIRT1 plays diverse roles in regulating cell proliferation, differentiation, stress response, metabolism, energy homeostasis, aging and cancer. Besides deacetylating histone substrates, SIRT1 regulates functions of an array of non-histone proteins including transcriptional factors for gene regulation, DNA repair machinery elements for reducing catastrophic genome lesions, epigenetic factors for chromatin and gene regulation, nuclear receptors and circadian clock as well as related factors for metabolism, and other cell signaling molecules. SIRT1 is involved in many types of human cancer.

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Identity

Alias_namessirtuin (silent mating type information regulation 2, S. cerevisiae, homolog) 1
sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)
Alias_symbol (synonym)SIR2L1
Other aliasEC 3.5.1
hSIR2
hSIRT1
SIR2alpha
HGNC (Hugo) SIRT1
LocusID (NCBI) 23411
Atlas_Id 44006
Location 10q21.3  [Link to chromosome band 10q21]
Location_base_pair Starts at 67885181 and ends at 67918390 bp from pter ( according to hg19-Feb_2009)  [Mapping SIRT1.png]
Fusion genes
(updated 2016)
SIRT1 (10q21.3) / CELF2 (10p14)

DNA/RNA

 
  SIRT1 gene expression is modulated at both transcriptional and posttranscriptional levels.
Description The SIRT1 gene spans about 34 kb including nine exons. The SIRT1 promoter contains a CCAAT box and a number of NF-kappaB and GATA transcription factor binding sites in addition to a small 350-bp CpG island in the 5' flanking genomic region. The gene encodes a 747 amino acids protein with a predictive molecular weight of 81.7 kDa and an isoelectric point of 4.55 (Alcaín and Villalba, 2009).
Transcription SIRT1 transcription is under the control of at least two negative feedback loops that keep its induction tightly regulated under conditions of oxidative stress. SIRT1 promoter can be regulated by E2F1 and HIC1 during cellular stress. E2F1 directly binds to the SIRT1 promoter at a consensus site located at bp position -65 and appears to regulate the basal expression level of SIRT1. Such high levels of SIRT1 lead to a negative feedback loop where E2F1 activity is inhibited by SIRT1-mediated deacetylation. By contrast, the tumor suppressor HIC1 and SIRT1 form a transcriptional repression complex that directly binds SIRT1 promoter and represses SIRT1 transcription thereby inhibiting SIRT1-mediated p53 deacetylation and inactivation. Two HIC1 binding sites have been assigned to base pair positions -1116 and -1039 within the SIRT1 promoter (Chen et al., 2005). In addition, two functional p53 binding sites (-178 bp and -168 bp), which normally repress SIRT1 expression, have been identified. Furthermore, SIRT1 transcription is upregulated by MYC that binds at SIRT1 promoter position -80 and by STAT5 that binds at positions -2235 and -1838 in response to BCR-ABL oncogenic stress (Yuan et al., 2012).
SIRT1 expression is also regulated at the posttranscriptional level by HuR. It has been demonstrated that HuR, a ubiquitously expressed RNA binding protein, associates with the 3' UTR of the SIRT1 mRNA under physiological conditions and helps to stabilize the transcript. This interaction results in increased SIRT1 mRNA stability and thus in elevated protein levels. Conversely, the HuR-SIRT1 mRNA complex is being disrupted upon oxidative stress, which finally leads to decreased mRNA stability and therefore decreased SIRT protein levels. In addition, several microRNA (miR) species negatively regulate SIRT1 mRNA by targeting its 3' UTR, including miR-34a and miR-200a (reviewed in Roth and Chen, 2014).
Pseudogene None identified.

Protein

 
  SIRT1 deacetylase activity is modulated through protein-protein interaction and sumoylation at its three protein domains (Liu T et al., 2009).
Description Human SIRT1 encodes 747 amino acids protein with a nuclear localization signal (NLS) at the N-terminus (aa 41-46) and a sirtuin homology domain at the center (aa 261-447); this domain is a conserved catalytic domain for deacetylation. The catalytic activity of SIRT1 is dependent on the cofactor nicotinamide adenine dinucleotide (NAD+).
Expression Expression appears to be ubiquitous in adult tissues (although at different levels). Two proteins have been identified to regulate the SIRT1 activity both positively and negatively through complex formation in the context of the cellular stress response. The first identified direct regulator of SIRT1 was the active regulator of SIRT1 (AROS). The AROS protein is known to significantly enhance the activity of SIRT1 on acetylated p53 both in vitro and in cell lines thereby promoting the inhibitory effect of SIRT1 on p53-mediated transcriptional activity of pro-apoptotic genes (e.g. Bax and p21Waf-1) under conditions of DNA-damage. A negative regulator of SIRT1, DBC-1 (deleted in breast cancer-1), has recently been identified. DBC1 binds directly to the catalytic domain of SIRT1, preventing substrate binding to SIRT1 and inhibiting SIRT1 activity. Reduction of DBC1 inhibits p53-mediated apoptosis after induction of double-stranded DNA breaks owing to SIRT1-mediated p53 deacetylation. Both factors represent the first endogenous, direct regulators of SIRT1 function. SIRT1 activity is also regulated by cis-elements of its own peptides. The SIRT1 C-terminal region (aa 631-635) is a disordered domain, and it interacts with SIRT1 catalytic core domain by competing with DBC1 and activates SIRT1 activity (Kang et al., 2011). A small rigid region at the N-terminus (aa 190-244) of SIRT1 appears to mediates allosteric activators for the SIRT1 catalytic core function (Hubbard et al., 2013). In addition, SIRT1 activity is subjected to regulation by other posttranslational modifications such as sumoylation, phosphorylation and methylation in response to stress signaling and cell cycle changes (reviewed in Wang and Chen, 2013). As an NAD-dependent enzyme, SIRT1 activity is regulated by cellular NAD metabolism in which NAD salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) is often co-activated with SIRT1 to maintain the deacetylase activity (Wang et al., 2011; Menssen et al., 2012).
Localisation SIRT1 is predominately in the nucleus (although SIRT1 does have some important cytoplasmic functions as well). In addition to possessing two NLSs, SIRT1 contains two nuclear export signals. Thus, the exposure of nuclear localization signals versus nuclear export signals may dictate the cytosolic versus nuclear localization of SIRT1.
Function SIRT1 has been reported to play a key role in a variety of physiological processes such as metabolism, neurogenesis and cell survival due to its ability to deacetylate both histone and numerous nonhistone substrates.
(1) Lysines 9 and 14 in the amino-terminal tail of histone H3 and lysine 16 of histone H4 are deacetylated by yeast Sir2 and mammalian SIRT1 (Sir2alpha).
(2) Metabolic homeostasis is controlled by SIRT1-mediated deacetylation and thus activation of the peroxisome proliferation activating receptor (PPAR)-gamma co-activator-1a (PGC-1a), which stimulates mitochondrial activity and subsequently increases glucose metabolism, which in turn improves insulin sensitivity. SIRT1 represses PPAR-gamma, a key regulator of adipogenesis, by docking with its cofactors NCoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors). The upregulation of SIRT1 triggers lipolysis and loss of fat.
(3) The activation of SIRT1 appears to be neuroprotective in animal models for Alzheimer's disease and amyotrophic lateral sclerosis as well as optic neuritis mainly due to decreased deacetylation of the tumor suppressor p53 and PGC-1a.
(4) SIRT1 represses p53-dependent apoptosis in response to DNA damage and oxidative stress and promotes cell survival under cellular stress induced by etoposide treatment or irradiation.
(5) SIRT1 activates FOXO1 and FOXO4, which promote cell-cycle arrest by inducing p27kip1; SIRT1 also induces cellular resistance to oxidative stress by increasing the levels of manganese superoxide dismutase and GADD45 (growth arrest and DNA damage-inducible protein 45).
(6) SIRT1 inhibits the transcriptional activity of NF-kappaB by deacetylating NF-kappaB's subunit, RelA/p65, at lysine 310. Thus, although SIRT1 is capable of protecting cells from p53-induced apoptosis, it may augment apoptosis by repressing NF-kappaB. SIRT1 is reported to bind CTIP2 (BCL11B B-cell CLL/lymphoma 11B) and accelerate the transcriptional repression by this molecule. CTIP2 represses the transcription of its target genes and is implicated in hematopoietic cell development.
(7) SIRT1 deacetylates and activates functions of several DNA repair factors, including KU70, NBS1, APE1, XPA/C and WRN for multiple DNA damage repair pathways to cope with genotoxic stress. Stimulated repair may help cells avoid catastrophic genomic events and survive the damage.
(8) SIRT1 is involved in epigenetic regulation of genes and chromatin. SIRT1 deacetylates several histone tail lysines: histone H4 lysine 16 (H4K16), histone H3 K9 and K14, and histone H1 K26. These modifications of histone tails are closely related to gene silencing and heterochromatin formation that may underlie certain biological processes. SIRT1 can deacetylate DNA methyltransferase 1 (DNMT1) and can either enhance or hinder its methyltransferase activity, thus indirectly affecting global or local DNA methylation patterns. SIRT1 is a component of the polycomb repressor complex (PRC) that is involved in silencing genes during normal development. SIRT1 directly complexes with EZH2, a H3K27 methyltransferase within PRC II complex, and is an integral part of the PRC's silencing functions. A SIRT1-containing PRC complex, termed PRC4, is specifically found in transformed cells and embryonic stem cells. In addition, SIRT1 interacts and deacetylates the SUV39H1 methyltransferase, promoting histone H3 methylation and fostering heterochromatin formation, and repressing rRNA transcription to protect cells from energy deprivation-dependent apoptosis (reviewed in Roth and Chen, 2014).
Homology SIRT1 is the mammalian homologue closest to yeast NAD+-dependent deacetylase Sir2 (silent information regulation 2). It was originally identified as a lifespan extending gene when over-expressed in budding yeast, Caenorhabditis elegans, and Drosophila melanogaster. The SIR2 gene is broadly conserved in organisms ranging from bacteria to humans. The accession numbers for the amino acid sequences used are as follows: yeast Sir2 (CAA25667), mouse Sir2alpha (AAF24983), human Sirt1 (AAD40849). All of the sirtuin proteins contain the ~275 residue sirtuin homology domain. In many instances a highly conserved protein domain represents a conserved functional binding site for a metabolite or biomolecule and such conserved binding site domains are often found within enzymatic catalytic domains.

Mutations

Germinal A germ line mutation L107P of SIRT1 was found in a family with type I diabetes. Expression of this mutant SIRT1 in insulin-producing cells stimulated production of nitric oxide, cytokines and chemokines, and decreased anti-inflammatory activity of pancreatic beta cells (Biason-Lauber et al., 2013).
Somatic A small number of SIRT1 somatic mutations were registered in human cancer databases but the mutation rate is typically very low (<0.5%) and their effect on SIRT1 function is unknown. Both gene amplification and deletion are found in human cancers depending on cancer types (reviewed in Roth and Chen, 2014).

Implicated in

Note
  
Entity Chronic myelogenous leukemia
Note SIRT1 plays an important role in drug resistance of chronic myelogenous leukemia (CML).
Disease CML is a lethal malignant disease of hematopoietic stem cells. It is caused by reciprocal translocation of chromosomes 9 and 22, producing BCR-ABL fusion gene. BCR-ABL protein has aberrant tyrosine kinase activity and predominantly resides in the cytoplasm in contrast to predominantly nuclear localization of ABL protein. CML progresses from chronic phase to accelerated phase and blast crisis with increasing numbers of blast cells in bone marrow and blood. SIRT1 is activated by BCR-ABL oncogenic transformation in human CML stem/progenitor cells (Yuan et al., 2012; Li et al., 2012).
Prognosis CML in chronic phase can be effectively treated tyrosine kinase inhibitors such as first-line drug imatinib, and second-line drugs nilotinb and dasatinib, which results in the five-year survival rate over 85%. However, the residual disease persists as these drugs do not eradicate CML leukemic stem cells, and the disease relapses if the drug is ceased. CML in advanced phases has much poorer prognosis and the disease typically relapses quickly on tyrosine kinase inhibitor treatment since the cells acquire BCR-ABL mutations that block the binding of the drugs to BCR-ABL.
Cytogenetics Philadelphia chromosome, t(9;22) translocation.
Abnormal Protein BCR-ABL fusion protein with aberrant tyrosine kinase activity.
Oncogenesis BCR-ABL transformation activates SIRT1 gene expression in both tyrosine kinase-dependent and independent manners, with the former mediating via STAT5 that binds on the SIRT1 promoter to stimulate the transcription. The mechanism for the kinase-independent SIRT1 activation is unknown. SIRT1 knockout significantly blocks BCR-ABL mediated leukemogenesis in a mouse model study (Yuan et al., 2012). Since blocking BCR-ABL kinase activity only partially reduces SIRT1 expression and the pathway remains active, SIRT1 inhibition sensitizes human CML leukemia stem cells to tyrosine kinase inhibitors and helps eradicate these cells by increasing p53 acetylation and activating p53 downstream target gene expression (Li et al., 2012). In addition, SIRT1 promotes acquisition of resistant BCR-ABL mutations for disease relapse in association with its ability to deacetylate and activate KU70 for increased error-prone DNA damage repair in blast crisis CML cells (Wang et al., 2013). Targeting SIRT1 may have clinical implication to improve CML treatment.
  
  
Entity Acute myeloid leukemia
Note SIRT1 plays an important role in drug resistance of acute myeloid leukemia (AML) with FLT-ITD mutation.
Disease AML is a group of highly heterogenous myeloid leukemia with distinct oncogenic events including various chromosomal aberrations and mutations. AML is generally derived from myeloid progenitor cells. SIRT1 protein expression is more consistently increased in AML samples, particularly those harboring FLT-ITD alteration. The change of SIRT1 mRNA is less consistent in certain AML subcategories from one to another study (Sasca et al., 2014; Li et al., 2014).
Prognosis AML with FLT-ITD mutation has poor prognosis.
Abnormal Protein FLT-ITD has constitutively activated tyrosine kinase activity.
Oncogenesis Similar to BCR-ABL transformation of hematopoietic stem cells, SIRT1 expression change in AML cells is likely a result of cellular response to oncogenic stress. However, protein regulation of SIRT1 appears more important in the AML setting. SIRT1 protein is stabilized by USP22, a deubiquitinase that is induced by c-MYC in FLT-ITD AML cells (Li et al., 2014). In addition, SIRT1 activity is further regulated by ATM-DBC1 in a FLT-ITD dependent manner (Sasca et al., 2014). Inhibition of SIRT1 sensitizes FLT-ITD AML stem/progenitor cells to tyrosine kinase inhibitor treatment, and may help improve management of this category of AML.
  
  
Entity Lymphoma
Note In large B-cell lymphoma patients, positive expression of SIRT1 protein was seen in 74% of patients, and significantly associated with shorter overall survival. Inhibition of SIRT1/2 by Cambinol induces apoptosis in Burkitt lymphoma cells (reviewed in Yuan et al., 2013).
Prognosis Large B-cell lymphoma with SIRT1 upregulation showed poor prognosis.
  
  
Entity Lung cancer
Note Distinct status of p53 acetylation/deacetylation and HIC1 alteration mechanism result from different SIRT1-DBC1 (deleted in breast cancer 1) control and epigenetic alteration in lung squamous cell carcinoma and lung adenocarcinoma. The lung squamous cell carcinoma patients with low p53 acetylation and SIRT1 expression mostly showed low HIC1 expression, confirming deregulation HIC1-SIRT1-p53 circular loop in clinical model. Expression of DBC1, which blocks the interaction between SIRT1 deacetylase and p53, led to acetylated p53 in lung adenocarcinoma patients.
Prognosis Lung cancer patients with altered HIC1-SIRT1-p53 circular regulation showed poor prognosis.
  
  
Entity Breast cancer
Note The breast cancer associated protein, BCA3, when neddylated (modified by NEDD8) interacts with SIRT1 and suppresses NF-kB-dependent transcription, also sensitizes human breast cancer cells (such as MCF7) to TNF-a-induced apoptosis. In addition, it has been shown recently that SIRT7 levels of expression increase significantly in breast cancer, and that SIRT7 and SIRT3 both are highly transcribed in lymph-node positive breast biopsies, a stage in which the tumour size is at least 2 mm and the cancer has already spread to the lymph nodes. SIRT1 up-regulation is also associated with decreased miR-200a in breast cancer samples, which targets the 3'UTR of SIRT1 mRNA and promotes epithelial-mesenchymal transition (EMT)-like transformation in mammary epithelial cells. SIRT1 is essential for oncogenic signaling of estrogen/estrogen receptor α (ERα) in breast cancer. SIRT1 inactivation suppresses estrogen/ERα-induced cell growth and tumor development, and induces apoptosis. SIRT1 is found to be significantly up-regulated in the invasive ductal carcinoma, and positively regulates the expression of aromatase, an enzyme responsible for a key step in the biosynthesis of estrogen in breast cancer. However, in HMLER breast cancer cells, SIRT1 was found to suppress EMT, and reduced SIRT1 expression increases metastasis of these cells in nude mice (reviewed in Yuan et al., 2013).
  
  
Entity Prostate cancer
Note SIRT1 is significantly overexpressed in primary human prostate cancer tissues and cell lines. SIRT1 inhibition via nicotinamide, sirtinol, short hairpin RNAs or mutation of the 25 amino acid C-terminal SIRT1 activator sequence, results in a significant inhibition of prostate cancer cell growth, viability and chemoresistance. SIRT1 is highly expressed in advanced prostate cancer tissues and promotes prostate cancer cell invasion, migration and metastasis through MMP2, EMT inducing transcription factor ZEB1, and cortactin. Concomitant with SIRT1 activation, NAMPT is over-expressed in prostate cancer, likely enabling supply of NAD+ for SIRT1 functions. In the transgenic mouse model, SIRT1 expression promotes murine prostate carcinogenesis initiated by Pten-deficiency (reviewed in Yuan et al., 2013).
  
  
Entity Liver cancer
Note SIRT1 expression is significantly elevated in hepatocellular carcinoma (HCC) tissues, and the expression levels correlate with tumor grades and predict poor prognosis. SIRT1 expression also positively correlates with c-MYC levels in HCC. SIRT1 and c-MYC regulate each other via a positive feedback loop and act synergistically to promote cell proliferation of both mouse and human liver tumor cells. SIRT1 promotes tumorigenesis and chemoresistance in HCC, and inhibition of SIRT1 suppresses the proliferation of HCC cells in vitro or in vivo via the induction of cellular senescence or apoptosis. Accordingly, expression of miRNA-34a is reduced in HCC, and the reduced expression of miRNA-34a is associated with worse outcome of HCC patients. Treatment of established HCC xenograft with miR-34a-expressing adenovirus in a mouse model results in complete tumor regression without recurrence (reviewed in Yuan et al., 2013).
  
  
Entity Gastric cancer
Note SIRT1 protein expression in gastric cardiac carcinoma is significantly higher than that in normal gastric tissues and is associated with lymphatic metastasis, TNM [the extent of tumor (T), the extent of spread to lymph nodes (N), and the presence of distant metastasis (M)] stage, survival rate and mean survival time. In another study, positive expression of SIRT1 was seen in 73% of gastric cancer patients. SIRT1 expression is also significantly associated with shorter overall survival and relapse-free survival. SIRT1 is required for activating transcription factor 4 (ATF4)-induced multidrug resistance in gastric cancer cells. ATF4 facilitates multidrug resistance in gastric cancer cells through direct binding to SIRT1 promoter and activating SIRT1 expression. Significantly, inhibition of SIRT1 by RNAi or a specific inhibitor (EX-527) sensitizes gastric cancer cells to therapeutic treatment (reviewed in Yuan et al., 2013).
  
  
Entity Pancreatic cancer
Note SIRT1 overexpression was observed in pancreatic cancer tissues at both mRNA and protein levels. Increased SIRT1 positivity is associated with patients' age (over 60 years old), larger tumor size (larger than 4 cm), and higher TNM stage. SIRT1 knockdown induces apoptosis and senescence, inhibits invasion and enhances chemosensitivity in pancreatic cancer cells. In pancreatic cancer, SIRT1 regulates ADM (acinar-to-ductal metaplasia) and supports cancer cell viability through deacetylating pancreatic transcription factor-1a and β-catenin. Inhibition of SIRT1 is effective in suppression of ADM and in reducing cell viability in established pancreatic ductal adenocarcinoma. In addition, SIRT1 promotes EMT ability as well as invasion of pancreatic cancer cell by forming a complex with Twist and MBD1 thus suppressing E-cadherin transcription activity. However, one study showed that SIRT1 inhibits proliferation of pancreatic cancer cells expressing oncogenic pancreatic adenocarcinoma up-regulated factor (PAUF), by suppression of β-catenin and cyclin-D1 (reviewed in Yuan et al., 2013).
  
  
Entity Thyroid cancer
Note SIRT1 is overexpressed in human thyroid cancers and it is positively correlated with c-MYC protein levels. Transgenic SIRT1 expression promotes murine thyroid carcinogenesis initiated by Pten-deficiency. SIRT1 increases c-MYC transcription and stabilizes c-MYC protein in thyroid cancers from SIRT1 transgenic mice or cultured thyroid cancer cells (reviewed in Yuan et al., 2013).
  
  
Entity Colon cancer
Note Highly-expressed c-MYC correlates with increased SIRT1 protein level in colorectal cancer. In 121 colorectal serrated lesions, the higher expression of c-MYC and SIRT1 protein is strongly associated with higher grades of malignancy. In another study with a total of 485 colorectal cancer patients, SIRT1 overexpression was detected in 180 (37%) tumors. SIRT1 expression is associated with microsatellite instability and CpG island methylator phenotype, although not patient prognosis. Reduced expression of miR-34a, a negative regulator of SIRT1 mRNA, is observed in drug-resistant DLD-1 colon cancer cells, and introduction of miR-34a induces apoptosis by downregulating SIRT1. However, one study showed that in colorectal adenocarcinoma, SIRT1 overexpression was observed in approximately 25% of stage I/II/III tumors but rarely in advanced stage IV tumors. Approximately 30% of carcinomas showed lower SIRT1 expression than normal tissues. In another clinical observation, SIRT1 protein expression is gradually decreased during the normal-adenoma-adenocarcinoma-metastasis stage in colorectal cancers, with the positivity 100%, 80.8%, 41.9%, and 35.7%, respectively (reviewed in Yuan et al., 2013).
  
  
Entity Ovarian cancer
Note Expression of SIRT1 protein is significantly increased in malignant ovarian epithelial tumors compared to that in benign and borderline epithelial tumors. High proportion (86%) of serous ovarian cancer expressed SIRT1. Interestingly, increased SIRT1 protein in serous ovarian epithelial cancer was associated with increased overall survival (Jang et al., 2009).
  
  
Entity Brain tumor
Note In glioblastoma, SIRT1 is highly expressed in tumor-derived CD133+ progenitor cells compared to CD133-cells and knockdown of SIRT1 expression enhances the radio-sensitivity and radiation-induced apoptosis in the CD133+ cells. SIRT1 is also frequently expressed in human medulloblastomas relative to surrounding noncancerous cerebellar tissues and its expression is correlated with the formation and prognosis of medulloblastomas. SIRT1 and N-MYC form a positive feedback regulation loop during the tumorigenesis of neuroblastoma, and preventive treatment with the SIRT1 inhibitor Cambinol significantly reduces tumorigenesis in N-MYC transgenic mice (reviewed in Yuan et al., 2013).
  
  
Entity Soft tissue sarcoma
Note SIRT1 is frequently over-expressed in soft tissue neoplasms with myoid differentiation including angiomyolipoma (4 out of 4 patients), glomus tumor (5 out of 5 patients), leiomyoma (9 out of 10 patients), leiomyosarcoma (76.5% of 51 patients), and rhabdomyosarcoma (87% of 24 patients), and thus could be a potential immunohistochemical marker and therapeutic target in these tumors (reviewed in Yuan et al., 2013).
  
  
Entity Kidney diseases
Note SIRT1 attenuates TGF-beta (transforming growth factor-beta) apoptotic signaling that is mediated by the effector molecule Smad7. SIRT1-dependent deacetylation of Smad7 at Lys60 and Lys70 enhances its ubiquitin-dependent proteasomal degradation via Smurf1 (Smad ubiquitination regulatory factor 1), thus protecting glomerular mesangial cells from TGF-beta-dependent apoptosis. As a result, SIRT1 expression tends to have protective roles in diabetic kidney disease and excessive inflammatory response triggered by bacterial endotoxins. However, SIRT1 inhibition was found to delay kidney cyst formation in autosomal-dominant polycystic kidney disease through regulating Rb and p53 in cystic renal epithelial cells (Zhou et al., 2013).
  
  
Entity Cardiac hypertrophy
Note Decreasing hypertrophy or apoptosis in cardiac myocytes can ameliorate the disease, and there is reason to suspect that SIRT1 activation may be useful in this regard. SIRT1 protects primary cultured myocytes from programmed cell death induced by serum starvation or by the activation of PARP-1 [poly(ADP-ribose) polymerase-1] in a p53-dependent manner. SIRT1 also deacetylates Lys115 and Lys121 of the histone variant H2A.Z, a factor known to promote cardiac hypertrophy. In doing so, SIRT1 promotes the ubiquitination and proteosome-dependent degradation of H2A.Z, which may help to protect against heart failure. However, in mouse models it was found that SIRT1 haploinsufficiency attenuates pressure overload-induced cardiac hypertrophy and heart failure (Oka et al., 2011). Contributing to this effect, SIRT1, coordinated by PPARα, suppresses genes involved in mitochondrial functions. In a separate study, cardiac hypertrophy is reduced in Sirt1 deficient mice in response to physical exercise and angiotensin II due to impaired Akt activation as a result of its acetylation (Sundaresan et al., 2011).
  

Breakpoints

Note No breakpoints are associated with SIRT1.

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Holloway KR, Barbieri A, Malyarchuk S, Saxena M, Nedeljkovic-Kurepa A, Cameron Mehl M, Wang A, Gu X, Pruitt K.
Mol Endocrinol. 2013 Mar;27(3):480-90. Epub 2013 Jan 22.
PMID 23340254
 
Evidence for a common mechanism of SIRT1 regulation by allosteric activators.
Hubbard BP, Gomes AP, Dai H, Li J, Case AW, Considine T, Riera TV, Lee JE, E SY, Lamming DW, Pentelute BL, Schuman ER, Stevens LA, Ling AJ, Armour SM, Michan S, Zhao H, Jiang Y, Sweitzer SM, Blum CA, Disch JS, Ng PY, Howitz KT, Rolo AP, Hamuro Y, Moss J, Perni RB, Ellis JL, Vlasuk GP, Sinclair DA.
Science. 2013;339(6124):1216-9.
PMID 23471411
 
SIRT1 is significantly elevated in mouse and human prostate cancer.
Huffman DM, Grizzle WE, Bamman MM, Kim JS, Eltoum IA, Elgavish A, Nagy TR.
Cancer Res. 2007 Jul 15;67(14):6612-8.
PMID 17638871
 
Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase.
Imai S, Armstrong CM, Kaeberlein M, Guarente L.
Nature. 2000 Feb 17;403(6771):795-800.
PMID 10693811
 
SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress.
Inoue T, Hiratsuka M, Osaki M, Yamada H, Kishimoto I, Yamaguchi S, Nakano S, Katoh M, Ito H, Oshimura M.
Oncogene. 2007 Feb 15;26(7):945-57. Epub 2006 Aug 14.
PMID 16909107
 
Expression and prognostic significance of SIRT1 in ovarian epithelial tumours.
Jang KY, Kim KS, Hwang SH, Kwon KS, Kim KR, Park HS, Park BH, Chung MJ, Kang MJ, Lee DG, Moon WS.
Pathology. 2009;41(4):366-71.
PMID 19404850
 
The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms.
Kaeberlein M, McVey M, Guarente L.
Genes Dev. 1999 Oct 1;13(19):2570-80.
PMID 10521401
 
Peptide switch is essential for Sirt1 deacetylase activity.
Kang H, Suh JY, Jung YS, Jung JW, Kim MK, Chung JH.
Mol Cell. 2011; 44:203-13.
PMID 22017869
 
SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis.
Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH.
EMBO J. 2007 Jul 11;26(13):3169-79. Epub 2007 Jun 21.
PMID 17581637
 
Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity.
Kim EJ, Kho JH, Kang MR, Um SJ.
Mol Cell. 2007 Oct 26;28(2):277-90.
PMID 17964266
 
DBC1 is a negative regulator of SIRT1.
Kim JE, Chen J, Lou Z.
Nature. 2008;451(7178):583-6.
PMID 18235501
 
SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress.
Kobayashi Y, Furukawa-Hibi Y, Chen C, Horio Y, Isobe K, Ikeda K, Motoyama N.
Int J Mol Med. 2005 Aug;16(2):237-43.
PMID 16012755
 
SIRT1 inhibits transforming growth factor beta-induced apoptosis in glomerular mesangial cells via Smad7 deacetylation.
Kume S, Haneda M, Kanasaki K, Sugimoto T, Araki S, Isshiki K, Isono M, Uzu T, Guarente L, Kashiwagi A, Koya D.
J Biol Chem. 2007 Jan 5;282(1):151-8. Epub 2006 Nov 10.
PMID 17098745
 
SIRT1 Activation by a c-MYC Oncogenic Network Promotes the Maintenance and Drug Resistance of Human FLT3-ITD Acute Myeloid Leukemia Stem Cells.
Li L, Osdal T, Ho Y, Chun S, McDonald T, Agarwal P, Lin A, Chu S, Qi J, Li L, Hsieh YT, Dos Santos C, Yuan H, Ha TQ, Popa M, Hovland R, Bruserud O, Gjertsen BT, Kuo YH, Chen W, Lain S, McCormack E, Bhatia R.
Cell Stem Cell. 2014;15:431-46.
PMID 25280219
 
Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with Imatinib.
Li L, Wang L, Li L, McDonald T, Ho Y, Holyoake T, Chen WY, Bhatia R.
Cancer Cell 2012; 21: 266-281.
PMID 22340598
 
The critical role of the class III histone deacetylase SIRT1 in cancer.
Liu T, Liu PY, Marshall GM.
Cancer Res. 2009 Mar 1;69(5):1702-5. Epub 2009 Feb 24. (REVIEW)
PMID 19244112
 
Negative control of p53 by Sir2alpha promotes cell survival under stress.
Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W.
Cell. 2001 Oct 19;107(2):137-48.
PMID 11672522
 
SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability.
Marshall GM, Liu PY, Gherardi S, Scarlett CJ, Bedalov A, Xu N, Iraci N, Valli E, Ling D, Thomas W, van Bekkum M, Sekyere E, Jankowski K, Trahair T, Mackenzie KL, Haber M, Norris MD, Biankin AV, Perini G, Liu T.
PLoS Genet. 2011 Jun;7(6):e1002135. Epub 2011 Jun 16.
PMID 21698133
 
The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop.
Menssen A, Hydbring P, Kapelle K, Vervoorts J, Diebold J, Lüscher B, Larsson LG, Hermeking H.
Proc Natl Acad Sci U S A. 2012;109:E187-96.
PMID 22190494
 
Sirtuins in mammals: insights into their biological function.
Michan S, Sinclair D.
Biochem J. 2007 May 15;404(1):1-13. (REVIEW)
PMID 17447894
 
Epigenetic control of rDNA loci in response to intracellular energy status.
Murayama A, Ohmori K, Fujimura A, Minami H, Yasuzawa-Tanaka K, Kuroda T, Oie S, Daitoku H, Okuwaki M, Nagata K, Fukamizu A, Kimura K, Shimizu T, Yanagisawa J.
Cell. 2008;133:627-39.
PMID 18485871
 
PPARa-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway.
Oka S, Alcendor R, Zhai P, Park JY, Shao D, Cho J, Yamamoto T, Tian B, Sadoshima J.
Cell Metab. 2011 Nov 2;14(5):598-611. doi: 10.1016/j.cmet.2011.10.001.
PMID 22055503
 
SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities.
Peng L, Yuan Z, Ling H, Fukasawa K, Robertson K, Olashaw N, Koomen J, Chen J, Lane WS, Seto E.
Mol Cell Biol. 2011;31:4720-34.
PMID 21947282
 
Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma.
Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, Leid M, McBurney MW, Guarente L.
Nature. 2004 Jun 17;429(6993):771-6. Epub 2004 Jun 2.
PMID 15175761
 
Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2alpha deacetylase activity.
Pillai JB, Isbatan A, Imai S, Gupta MP.
J Biol Chem. 2005 Dec 30;280(52):43121-30. Epub 2005 Oct 5.
PMID 16207712
 
Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.
Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P.
Nature. 2005 Mar 3;434(7029):113-8.
PMID 15744310
 
Sorting out functions of sirtuins in cancer.
Roth M, Chen WY.
Oncogene. 2014; 33(13):1609-20. (REVIEW)
PMID 23604120
 
SIRT1 prevents genotoxic stress-induced p53 activation in acute myeloid leukemia.
Sasca D, Hahnel PS, Szybinski J, Khawaja K, Kriege O, Pante SV, Bullinger L, Strand S, Strand D, Theobald M, Kindler T.
Blood. 2014; 124:121-33.
PMID 24855208
 
The biochemistry of sirtuins.
Sauve AA, Wolberger C, Schramm VL, Boeke JD.
Annu Rev Biochem. 2006;75:435-65. (REVIEW)
PMID 16756498
 
Involvement of the histone deacetylase SIRT1 in chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2-mediated transcriptional repression.
Senawong T, Peterson VJ, Avram D, Shepherd DM, Frye RA, Minucci S, Leid M.
J Biol Chem. 2003 Oct 31;278(44):43041-50. Epub 2003 Aug 19.
PMID 12930829
 
SIRT1 activation confers neuroprotection in experimental optic neuritis.
Shindler KS, Ventura E, Rex TS, Elliott P, Rostami A.
Invest Ophthalmol Vis Sci. 2007 Aug;48(8):3602-9.
PMID 17652729
 
An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity.
Stankovic-Valentin N, Deltour S, Seeler J, Pinte S, Vergoten G, Guerardel C, Dejean A, Leprince D.
Mol Cell Biol. 2007 Apr;27(7):2661-75. Epub 2007 Feb 5.
PMID 17283066
 
The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy.
Sundaresan NR, Pillai VB, Wolfgeher D, Samant S, Vasudevan P, Parekh V, Raghuraman H, Cunningham JM, Gupta M, Gupta MP.
Sci Signal. 2011 Jul 19;4(182):ra46. doi: 10.1126/scisignal.2001465.
PMID 21775285
 
Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1.
Tanno M, Sakamoto J, Miura T, Shimamoto K, Horio Y.
J Biol Chem. 2007 Mar 2;282(9):6823-32. Epub 2006 Dec 30.
PMID 17197703
 
Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients.
Tseng RC, Lee CC, Hsu HS, Tzao C, Wang YC.
Neoplasia. 2009 Aug;11(8):763-70.
PMID 19649206
 
SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation.
Vaquero A, Scher M, Erdjument-Bromage H, Tempst P, Serrano L, Reinberg D.
Nature. 2007; 450:440-4.
PMID 18004385
 
hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.
Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, Guarente L, Weinberg RA.
Cell. 2001 Oct 19;107(2):149-59.
PMID 11672523
 
Cloning, chromosomal characterization and mapping of the NAD-dependent histone deacetylases gene sirtuin 1.
Voelter-Mahlknecht S, Mahlknecht U.
Int J Mol Med. 2006 Jan;17(1):59-67. (REVIEW)
PMID 16328012
 
NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response.
Wang B, Hasan MK, Alvarado E, Yuan H, Wu H, Chen WY.
Oncogene. 2011;30(8):907-21.
PMID 20956937
 
Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage.
Wang C, Chen L, Hou X, Li Z, Kabra N, Ma Y, Nemoto S, Finkel T, Gu W, Cress WD, Chen J.
Nat Cell Biol. 2006 Sep;8(9):1025-31. Epub 2006 Aug 6.
PMID 16892051
 
Emerging Roles of SIRT1 in Cancer Drug Resistance.
Wang Z, Chen WY.
Genes Cancer. 2013 Mar;4(3-4):82-90. doi: 10.1177/1947601912473826. (REVIEW)
PMID 24019998
 
SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells.
Wang Z, Yuan H, Roth M, Stark J, Bhatia R, Chen WY.
Oncogene 2013; 32: 589-598.
PMID 22410779
 
miR-34a repression of SIRT1 regulates apoptosis.
Yamakuchi M, Ferlito M, Lowenstein CJ.
Proc Natl Acad Sci U S A. 2008;105(36):13421-6.
PMID 18755897
 
SIRT1 sumoylation regulates its deacetylase activity and cellular response to genotoxic stress.
Yang Y, Fu W, Chen J, Olashaw N, Zhang X, Nicosia SV, Bhalla K, Bai W.
Nat Cell Biol. 2007;9(11):1253-62.
PMID 17934453
 
Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase.
Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW.
EMBO J. 2004 Jun 16;23(12):2369-80. Epub 2004 May 20.
PMID 15152190
 
The emerging and diverse roles of sirtuins in cancer: a clinical perspective.
Yuan H, Su L, Chen WY.
Onco Targets Ther. 2013 Oct 8;6:1399-416. doi: 10.2147/OTT.S37750. (REVIEW)
PMID 24133372
 
Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis.
Yuan H, Wang Z, Li L, Zhang H, Modi H, Horne D, Stark J, Bhatia R, Chen WY.
Blood 2012; 119: 1904-1914.
PMID 22207735
 
Negative regulation of the deacetylase SIRT1 by DBC1.
Zhao W, Kruse JP, Tang Y, Jung SY, Qin J, Gu W.
Nature. 2008 Jan 31;451(7178):587-90.
PMID 18235502
 
Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease.
Zhou X, Fan LX, Sweeney WE Jr, Denu JM, Avner ED, Li X.
J Clin Invest. 2013 Jul 1;123(7):3084-98.
PMID 23778143
 
SIRTUIN 1: regulating the regulator.
Zschoernig B, Mahlknecht U.
Biochem Biophys Res Commun. 2008 Nov 14;376(2):251-5. Epub 2008 Sep 5.
PMID 18774777
 
FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1).
van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH, Burgering BM.
J Biol Chem. 2004 Jul 9;279(28):28873-9. Epub 2004 May 4.
PMID 15126506
 

Citation

This paper should be referenced as such :
Chen WY
SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae));
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/SIRT1ID44006ch10q21.html
History of this paper:
Tseng, RC ; Wang, YC. SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)). Atlas Genet Cytogenet Oncol Haematol. 2010;14(12):1152-1156.
http://documents.irevues.inist.fr/bitstream/handle/2042/44919/03-2010-SIRT1ID44006ch10q21.pdf


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(9;17)(p13;p12) PAX5/NCOR1


External links

Nomenclature
HGNC (Hugo)SIRT1   14929
Cards
AtlasSIRT1ID44006ch10q21
Entrez_Gene (NCBI)SIRT1  23411  sirtuin 1
AliasesSIR2; SIR2L1; SIR2alpha
GeneCards (Weizmann)SIRT1
Ensembl hg19 (Hinxton)ENSG00000096717 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000096717 [Gene_View]  chr10:67885181-67918390 [Contig_View]  SIRT1 [Vega]
ICGC DataPortalENSG00000096717
TCGA cBioPortalSIRT1
AceView (NCBI)SIRT1
Genatlas (Paris)SIRT1
WikiGenes23411
SOURCE (Princeton)SIRT1
Genetics Home Reference (NIH)SIRT1
Genomic and cartography
GoldenPath hg38 (UCSC)SIRT1  -     chr10:67885181-67918390 +  10q21.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SIRT1  -     10q21.3   [Description]    (hg19-Feb_2009)
EnsemblSIRT1 - 10q21.3 [CytoView hg19]  SIRT1 - 10q21.3 [CytoView hg38]
Mapping of homologs : NCBISIRT1 [Mapview hg19]  SIRT1 [Mapview hg38]
OMIM604479   
Gene and transcription
Genbank (Entrez)AA452304 AF083106 AF235040 AK027686 AK074805
RefSeq transcript (Entrez)NM_001142498 NM_001314049 NM_012238
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)SIRT1
Cluster EST : UnigeneHs.369779 [ NCBI ]
CGAP (NCI)Hs.369779
Alternative Splicing GalleryENSG00000096717
Gene ExpressionSIRT1 [ NCBI-GEO ]   SIRT1 [ EBI - ARRAY_EXPRESS ]   SIRT1 [ SEEK ]   SIRT1 [ MEM ]
Gene Expression Viewer (FireBrowse)SIRT1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)23411
GTEX Portal (Tissue expression)SIRT1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ96EB6   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ96EB6  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ96EB6
Splice isoforms : SwissVarQ96EB6
Catalytic activity : Enzyme3.5.1.- [ Enzyme-Expasy ]   3.5.1.-3.5.1.- [ IntEnz-EBI ]   3.5.1.- [ BRENDA ]   3.5.1.- [ KEGG ]   
PhosPhoSitePlusQ96EB6
Domaine pattern : Prosite (Expaxy)SIRTUIN (PS50305)   
Domains : Interpro (EBI)DHS-like_NAD/FAD-binding_dom    Sirtuin    Sirtuin_cat_small_dom    Ssirtuin_cat_dom   
Domain families : Pfam (Sanger)SIR2 (PF02146)   
Domain families : Pfam (NCBI)pfam02146   
Conserved Domain (NCBI)SIRT1
DMDM Disease mutations23411
Blocks (Seattle)SIRT1
PDB (SRS)4I5I    4IF6    4IG9    4KXQ    4ZZH    4ZZI    4ZZJ    5BTR   
PDB (PDBSum)4I5I    4IF6    4IG9    4KXQ    4ZZH    4ZZI    4ZZJ    5BTR   
PDB (IMB)4I5I    4IF6    4IG9    4KXQ    4ZZH    4ZZI    4ZZJ    5BTR   
PDB (RSDB)4I5I    4IF6    4IG9    4KXQ    4ZZH    4ZZI    4ZZJ    5BTR   
Structural Biology KnowledgeBase4I5I    4IF6    4IG9    4KXQ    4ZZH    4ZZI    4ZZJ    5BTR   
SCOP (Structural Classification of Proteins)4I5I    4IF6    4IG9    4KXQ    4ZZH    4ZZI    4ZZJ    5BTR   
CATH (Classification of proteins structures)4I5I    4IF6    4IG9    4KXQ    4ZZH    4ZZI    4ZZJ    5BTR   
SuperfamilyQ96EB6
Human Protein AtlasENSG00000096717
Peptide AtlasQ96EB6
HPRD08381
IPIIPI00016802   IPI00879854   IPI01010716   
Protein Interaction databases
DIP (DOE-UCLA)Q96EB6
IntAct (EBI)Q96EB6
FunCoupENSG00000096717
BioGRIDSIRT1
STRING (EMBL)SIRT1
ZODIACSIRT1
Ontologies - Pathways
QuickGOQ96EB6
Ontology : AmiGOsingle strand break repair  negative regulation of transcription from RNA polymerase II promoter  negative regulation of transcription from RNA polymerase II promoter  chromatin silencing at rDNA  chromatin silencing at rDNA  pyrimidine dimer repair by nucleotide-excision repair  DNA synthesis involved in DNA repair  nuclear chromatin  core promoter sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  angiogenesis  ovulation from ovarian follicle  cellular glucose homeostasis  positive regulation of protein phosphorylation  positive regulation of endothelial cell proliferation  p53 binding  positive regulation of adaptive immune response  transcription corepressor activity  transcription corepressor activity  NAD+ ADP-ribosyltransferase activity  histone deacetylase activity  histone deacetylase activity  protein binding  nucleus  nuclear envelope  nuclear inner membrane  nucleoplasm  nucleoplasm  chromatin silencing complex  nuclear euchromatin  nuclear heterochromatin  nucleolus  nucleolus  cytoplasm  cytoplasm  mitochondrion  cytosol  DNA replication  DNA repair  chromatin organization  chromatin silencing  establishment of chromatin silencing  maintenance of chromatin silencing  methylation-dependent chromatin silencing  rRNA processing  transcription from RNA polymerase II promoter  protein ADP-ribosylation  protein deacetylation  protein deacetylation  triglyceride mobilization  cellular response to DNA damage stimulus  response to oxidative stress  spermatogenesis  regulation of mitotic cell cycle  muscle organ development  cell aging  protein C-terminus binding  transcription factor binding  positive regulation of cell proliferation  cellular response to starvation  negative regulation of gene expression  positive regulation of cholesterol efflux  regulation of lipid storage  regulation of glucose metabolic process  macrophage cytokine production  positive regulation of phosphatidylinositol 3-kinase signaling  viral process  positive regulation of macroautophagy  protein ubiquitination  protein ubiquitination  histone deacetylation  PML body  NAD-dependent histone deacetylase activity  peptidyl-lysine acetylation  deacetylase activity  enzyme binding  macrophage differentiation  negative regulation of cell growth  negative regulation of transforming growth factor beta receptor signaling pathway  negative regulation of prostaglandin biosynthetic process  protein destabilization  protein destabilization  positive regulation of chromatin silencing  negative regulation of TOR signaling  regulation of endodeoxyribonuclease activity  negative regulation of NF-kappaB transcription factor activity  response to insulin  circadian regulation of gene expression  circadian regulation of gene expression  regulation of protein import into nucleus, translocation  leptin-mediated signaling pathway  rDNA heterochromatin  protein deacetylase activity  protein deacetylase activity  regulation of smooth muscle cell apoptotic process  NAD-dependent protein deacetylase activity  NAD-dependent protein deacetylase activity  NAD-dependent protein deacetylase activity  peptidyl-lysine deacetylation  ESC/E(Z) complex  nuclear hormone receptor binding  cellular triglyceride homeostasis  regulation of peroxisome proliferator activated receptor signaling pathway  regulation of cell proliferation  negative regulation of phosphorylation  histone binding  response to hydrogen peroxide  behavioral response to starvation  cholesterol homeostasis  intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  identical protein binding  positive regulation of apoptotic process  positive regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of I-kappaB kinase/NF-kappaB signaling  proteasome-mediated ubiquitin-dependent protein catabolic process  positive regulation of cysteine-type endopeptidase activity involved in apoptotic process  HLH domain binding  bHLH transcription factor binding  negative regulation of sequence-specific DNA binding transcription factor activity  negative regulation of sequence-specific DNA binding transcription factor activity  negative regulation of DNA damage response, signal transduction by p53 class mediator  response to leptin  positive regulation of MHC class II biosynthetic process  negative regulation of fat cell differentiation  positive regulation of DNA repair  positive regulation of angiogenesis  negative regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of insulin receptor signaling pathway  metal ion binding  NAD-dependent histone deacetylase activity (H3-K9 specific)  white fat cell differentiation  mitogen-activated protein kinase binding  negative regulation of helicase activity  positive regulation of smooth muscle cell differentiation  positive regulation of histone H3-K9 methylation  negative regulation of protein kinase B signaling  fatty acid homeostasis  negative regulation of androgen receptor signaling pathway  histone H3-K9 modification  cellular response to hydrogen peroxide  NAD+ binding  regulation of bile acid biosynthetic process  UV-damage excision repair  histone H3 deacetylation  histone H3 deacetylation  cellular response to tumor necrosis factor  negative regulation of histone H3-K14 acetylation  cellular response to hypoxia  cellular response to ionizing radiation  regulation of protein serine/threonine kinase activity  regulation of brown fat cell differentiation  stress-induced premature senescence  regulation of cellular response to heat  negative regulation of histone H3-K9 trimethylation  negative regulation of neuron death  negative regulation of protein acetylation  negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway  positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway  positive regulation of adipose tissue development  keratin filament binding  histone H3-K9 deacetylation  positive regulation of macrophage apoptotic process  negative regulation of cAMP-dependent protein kinase activity  positive regulation of cAMP-dependent protein kinase activity  negative regulation of histone H4-K16 acetylation  negative regulation of cellular response to testosterone stimulus  negative regulation of peptidyl-lysine acetylation  negative regulation of cellular senescence  positive regulation of cellular senescence  
Ontology : EGO-EBIsingle strand break repair  negative regulation of transcription from RNA polymerase II promoter  negative regulation of transcription from RNA polymerase II promoter  chromatin silencing at rDNA  chromatin silencing at rDNA  pyrimidine dimer repair by nucleotide-excision repair  DNA synthesis involved in DNA repair  nuclear chromatin  core promoter sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  angiogenesis  ovulation from ovarian follicle  cellular glucose homeostasis  positive regulation of protein phosphorylation  positive regulation of endothelial cell proliferation  p53 binding  positive regulation of adaptive immune response  transcription corepressor activity  transcription corepressor activity  NAD+ ADP-ribosyltransferase activity  histone deacetylase activity  histone deacetylase activity  protein binding  nucleus  nuclear envelope  nuclear inner membrane  nucleoplasm  nucleoplasm  chromatin silencing complex  nuclear euchromatin  nuclear heterochromatin  nucleolus  nucleolus  cytoplasm  cytoplasm  mitochondrion  cytosol  DNA replication  DNA repair  chromatin organization  chromatin silencing  establishment of chromatin silencing  maintenance of chromatin silencing  methylation-dependent chromatin silencing  rRNA processing  transcription from RNA polymerase II promoter  protein ADP-ribosylation  protein deacetylation  protein deacetylation  triglyceride mobilization  cellular response to DNA damage stimulus  response to oxidative stress  spermatogenesis  regulation of mitotic cell cycle  muscle organ development  cell aging  protein C-terminus binding  transcription factor binding  positive regulation of cell proliferation  cellular response to starvation  negative regulation of gene expression  positive regulation of cholesterol efflux  regulation of lipid storage  regulation of glucose metabolic process  macrophage cytokine production  positive regulation of phosphatidylinositol 3-kinase signaling  viral process  positive regulation of macroautophagy  protein ubiquitination  protein ubiquitination  histone deacetylation  PML body  NAD-dependent histone deacetylase activity  peptidyl-lysine acetylation  deacetylase activity  enzyme binding  macrophage differentiation  negative regulation of cell growth  negative regulation of transforming growth factor beta receptor signaling pathway  negative regulation of prostaglandin biosynthetic process  protein destabilization  protein destabilization  positive regulation of chromatin silencing  negative regulation of TOR signaling  regulation of endodeoxyribonuclease activity  negative regulation of NF-kappaB transcription factor activity  response to insulin  circadian regulation of gene expression  circadian regulation of gene expression  regulation of protein import into nucleus, translocation  leptin-mediated signaling pathway  rDNA heterochromatin  protein deacetylase activity  protein deacetylase activity  regulation of smooth muscle cell apoptotic process  NAD-dependent protein deacetylase activity  NAD-dependent protein deacetylase activity  NAD-dependent protein deacetylase activity  peptidyl-lysine deacetylation  ESC/E(Z) complex  nuclear hormone receptor binding  cellular triglyceride homeostasis  regulation of peroxisome proliferator activated receptor signaling pathway  regulation of cell proliferation  negative regulation of phosphorylation  histone binding  response to hydrogen peroxide  behavioral response to starvation  cholesterol homeostasis  intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  identical protein binding  positive regulation of apoptotic process  positive regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of I-kappaB kinase/NF-kappaB signaling  proteasome-mediated ubiquitin-dependent protein catabolic process  positive regulation of cysteine-type endopeptidase activity involved in apoptotic process  HLH domain binding  bHLH transcription factor binding  negative regulation of sequence-specific DNA binding transcription factor activity  negative regulation of sequence-specific DNA binding transcription factor activity  negative regulation of DNA damage response, signal transduction by p53 class mediator  response to leptin  positive regulation of MHC class II biosynthetic process  negative regulation of fat cell differentiation  positive regulation of DNA repair  positive regulation of angiogenesis  negative regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of insulin receptor signaling pathway  metal ion binding  NAD-dependent histone deacetylase activity (H3-K9 specific)  white fat cell differentiation  mitogen-activated protein kinase binding  negative regulation of helicase activity  positive regulation of smooth muscle cell differentiation  positive regulation of histone H3-K9 methylation  negative regulation of protein kinase B signaling  fatty acid homeostasis  negative regulation of androgen receptor signaling pathway  histone H3-K9 modification  cellular response to hydrogen peroxide  NAD+ binding  regulation of bile acid biosynthetic process  UV-damage excision repair  histone H3 deacetylation  histone H3 deacetylation  cellular response to tumor necrosis factor  negative regulation of histone H3-K14 acetylation  cellular response to hypoxia  cellular response to ionizing radiation  regulation of protein serine/threonine kinase activity  regulation of brown fat cell differentiation  stress-induced premature senescence  regulation of cellular response to heat  negative regulation of histone H3-K9 trimethylation  negative regulation of neuron death  negative regulation of protein acetylation  negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway  positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway  positive regulation of adipose tissue development  keratin filament binding  histone H3-K9 deacetylation  positive regulation of macrophage apoptotic process  negative regulation of cAMP-dependent protein kinase activity  positive regulation of cAMP-dependent protein kinase activity  negative regulation of histone H4-K16 acetylation  negative regulation of cellular response to testosterone stimulus  negative regulation of peptidyl-lysine acetylation  negative regulation of cellular senescence  positive regulation of cellular senescence  
Pathways : BIOCARTARegulation of transcriptional activity by PML [Genes]   
Pathways : KEGGFoxO signaling pathway    Amphetamine addiction    MicroRNAs in cancer   
REACTOMEQ96EB6 [protein]
REACTOME PathwaysR-HSA-427359 [pathway]   
NDEx NetworkSIRT1
Atlas of Cancer Signalling NetworkSIRT1
Wikipedia pathwaysSIRT1
Orthology - Evolution
OrthoDB23411
GeneTree (enSembl)ENSG00000096717
Phylogenetic Trees/Animal Genes : TreeFamSIRT1
HOVERGENQ96EB6
HOGENOMQ96EB6
Homologs : HomoloGeneSIRT1
Homology/Alignments : Family Browser (UCSC)SIRT1
Gene fusions - Rearrangements
Fusion : MitelmanSIRT1/CELF2 [10q21.3/10p14]  
Fusion: TCGASIRT1 10q21.3 CELF2 10p14 LUAD
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSIRT1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SIRT1
dbVarSIRT1
ClinVarSIRT1
1000_GenomesSIRT1 
Exome Variant ServerSIRT1
ExAC (Exome Aggregation Consortium)SIRT1 (select the gene name)
Genetic variants : HAPMAP23411
Genomic Variants (DGV)SIRT1 [DGVbeta]
DECIPHERSIRT1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSIRT1 
Mutations
ICGC Data PortalSIRT1 
TCGA Data PortalSIRT1 
Broad Tumor PortalSIRT1
OASIS PortalSIRT1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSIRT1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSIRT1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch SIRT1
DgiDB (Drug Gene Interaction Database)SIRT1
DoCM (Curated mutations)SIRT1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SIRT1 (select a term)
intoGenSIRT1
NCG5 (London)SIRT1
Cancer3DSIRT1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM604479   
Orphanet
MedgenSIRT1
Genetic Testing Registry SIRT1
NextProtQ96EB6 [Medical]
TSGene23411
GENETestsSIRT1
Target ValidationSIRT1
Huge Navigator SIRT1 [HugePedia]
snp3D : Map Gene to Disease23411
BioCentury BCIQSIRT1
ClinGenSIRT1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD23411
Chemical/Pharm GKB GenePA37935
Clinical trialSIRT1
Miscellaneous
canSAR (ICR)SIRT1 (select the gene name)
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSIRT1
EVEXSIRT1
GoPubMedSIRT1
iHOPSIRT1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Jun 7 12:14:43 CEST 2017

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