Pharmacological inhibition of SIRT1 limits the growth of ovarian granulosa cell tumors in vitro and in preclinical mouse models
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE252773 | GEO | 2024/12/31
REPOSITORIES: GEO
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Project description:Pharmacological inhibition of SIRT1 limits the growth of ovarian granulosa cell tumors in vitro and in preclinical mouse models
| PRJNA1062422 | ENA
Project description:Sirtuin-1 (Sirt1), a class III histone/protein deacetylase is central to cellular metabolism, stress responses and aging, but its contributions to various host immune functions have been little investigated. To study the role of Sirt1 in T-cell functions, we undertook targeted deletions by mating mice with a floxed Sirt1 gene to mice expressing CD4-cre or Foxp3-cre recombinase, respectively. We found that Sirt1 deletion left conventional T-effector cell activation, proliferation and cytokine production largely unaltered. However, Sirt1 targeting promoted the expression and acetylation of Foxp3, a key transcription factor in T-regulatory (Treg) cells, and increased Treg suppressive functions in vitro and in vivo. Consistent with these data, mice with targeted deletions of Sirt1 in either CD4+ T-cells or Foxp3+ Treg cells exhibited prolonged survival of MHC-mismatched cardiac allografts. Allografts in Sirt1 targeted recipients showed long-term preservation of myocardial histology and infiltration by Foxp3+ Treg cells. Comparable results were seen in wild-type allograft recipients treated with Sirt1 inhibitors, such as EX-527 and splitomicin. Hence, Sirt1 may inhibit Treg functions and its targeting may have therapeutic value in autoimmunity and transplantation.
2011-01-05 | GSE26425 | GEO
Project description:Sirtuin-1 (Sirt1), a class III histone/protein deacetylase is central to cellular metabolism, stress responses and aging, but its contributions to various host immune functions have been little investigated. To study the role of Sirt1 in T-cell functions, we undertook targeted deletions by mating mice with a floxed Sirt1 gene to mice expressing CD4-cre or Foxp3-cre recombinase, respectively. We found that Sirt1 deletion left conventional T-effector cell activation, proliferation and cytokine production largely unaltered. However, Sirt1 targeting promoted the expression and acetylation of Foxp3, a key transcription factor in T-regulatory (Treg) cells, and increased Treg suppressive functions in vitro and in vivo. Consistent with these data, mice with targeted deletions of Sirt1 in either CD4+ T-cells or Foxp3+ Treg cells exhibited prolonged survival of MHC-mismatched cardiac allografts. Allografts in Sirt1 targeted recipients showed long-term preservation of myocardial histology and infiltration by Foxp3+ Treg cells. Comparable results were seen in wild-type allograft recipients treated with Sirt1 inhibitors, such as EX-527 and splitomicin. Hence, Sirt1 may inhibit Treg functions and its targeting may have therapeutic value in autoimmunity and transplantation. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of Sirt1 knock out, compared to wild type (C57BL6) control
2011-01-05 | E-GEOD-26425 | biostudies-arrayexpress
Project description:NAD+ levels decline with age and in certain disease conditions. NAD+ precursors have been shown to stimulate NAD+ biosynthesis and ameliorate various age-associated diseases in mouse models. However, NAD+ metabolism is complicated in cancer and its role in triple-negative breast cancer (TNBC) remains elusive. Here, we show that NAD+ supplement suppresses tumor metastasis in a TNBC orthotopic patient-derived xenograft (PDX) model. Sirtuin1 lysine deacetylase (SIRT1) is required for the effects since SIRT1 knockdown blocks NAD+-suppressed tumor metastasis. Overexpression of SIRT1 effectively impairs the metastatic potential of TNBC. Importantly, the interaction between SIRT1 and p66Shc causes the deacetylation and functional inactivation of p66Shc, which inhibits epithelial-mesenchymal transition (EMT). Overall, we demonstrate that NAD+ supplementation executes its anti-tumor function via activating the SIRT1-p66Shc axis, which highlights the preventive and therapeutic potential of SIRT1 activators as effective interventions for TNBC.
2023-01-23 | GSE220683 | GEO
Project description:SIRT1 chromatin interactome analysis was performed to identify SIRT1 molecular targets involved in replication initiation from cells containing either WT or H363Y SIRT1. Co-IP-MS of pT530 SIRT1 from chromatin extracts was performed. Files are: 1422 WT SIRT1 untreated U2OS; 1423 WT SIRT1 H2O2 treated, U2OS; 1424 H363Y SIRT1 untreated U2OS; 1425 H363Y SIRT1 H2O2 U2OS; 1426 KO SIRT1 untreated U2OS; 1427 KO SIRT1 H2O2 U2OS; 1428 WT SIRT1 untreated HEK; 1429 WT SIRT1 H2O2 HEK; 1430 WT SIRT1 untreated HCT116; 1431 WT SIRT1 H2O2 HCT116; 1432 WT SIRT1 untreated K562; 1433 WT SIRT1 H2O2 K562. Each sample has 9 fractions.
| MSV000088103 | MassIVE
Project description:Sirt1, a NAD-dependent deacetylase, has been shown involved in many complex biological functions. We previously demonstrated that Sirt-1 gain of function is neuroprotective in a model of neurodegenenration. We recently found that Sirt1 loss of function (Sirt1Δ mouse) impairs learning, memory, and synaptic plasticity. We used microarray screening to identify potential miRNAs that may be regulated by Sirt1 and ivolved in learning and memory. Total RNA from the hippocampus of SIRT1Δ and control mice was extracted and used for microRNA expression level evaluation.
2010-06-24 | GSE22530 | GEO
Project description:The goal of this project is to investigate the role of SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, in the regulation of heart development. SIRT1 is important for heart development and functions. However, the underlying molecular mechanisms remain undefined. In this study, we analyzed the gene expression profiles in E18.5 WT and SIRT1 KO mouse hearts.
2021-08-23 | GSE86835 | GEO
Project description:Sirt1, a NAD-dependent deacetylase, has been shown involved in many complex biological functions. We previously demonstrated that Sirt-1 gain of function is neuroprotective in a model of neurodegenenration. We recently found that Sirt1 loss of function (Sirt1Î mouse) impairs learning, memory, and synaptic plasticity. We used microarray screening to identify potential miRNAs that may be regulated by Sirt1 and ivolved in learning and memory. Total RNA from the hippocampus of SIRT1Î and control mice was extracted and used for microRNA expression level evaluation. Two group experiment, in duplicates. Each sample is compared to a common reference sample, comprised of an equal mixture of all 4 experimental samples.
2010-07-29 | E-GEOD-22530 | biostudies-arrayexpress
Project description:Sirtuin-1 (Sirt1), a NAD+-dependent histone deacetylase, exhibits several properties of a versatile driver of maternal-zygotic transition, due to its epigenetic and non-epigenetic substrates. The study was aimed at the dynamics of Sirt1 in early embryos and the contribution to maternal-zygotic transition. A conditional Sirt1-deficient knock-out mouse model was used. Females were hormonally stimulated and used as oocyte donors. oocytes were parthenogenetically activated and Sirt1-/- two-cell embryos were used for transcriptomic analysis.
2024-07-06 | E-MTAB-13483 | biostudies-arrayexpress
Project description:Intestinal epithelial homeostasis is maintained by a complex interplay between different epithelial cells, gut microorganisms, and immune cells. Disruption of this interplay contributes to inflammatory and immune diseases associated with gut microbiome dysbiosis. A genetic factor that modulates the interactions between gut epithelium, microbiota and immune cells is sirtuin 1 (SIRT1), the most conserved mammalian NAD+-dependent protein deacetylase. We and others have shown that deficiency of intestinal epithelial SIRT1 leads to intestinal inflammation, disruption of gut microbial composition, and altered susceptibility to environmentally induced colitis. Recently we generated a Paneth-cell specific SIRT1 KO mouse model (SIRT1 PKO). Similar to mice with SIRT1 deficiency in whole intestinal epithelium, SIRT1 PKO mice had increased abundance as well as hyperactivation of Paneth cells in vivo and in cultured intestinal organoids. Single-cell RNA-seq of whole intestinal cell populations confirmed that deletion of Paneth cell SIRT1 significantly increases the abundance of Paneth cells. This increase was accompanied with an elevated abundance of intestinal stem cells, transition amplifying cells, and enterocytes. Consistently, SIRT1 PKO mice were able to better maintain their intestinal epithelial integrity during aging and were protected from chemically induced colitis compared to control mice. Deletion of SIRT1 in Paneth cells further induced profound alterations in gut microbiota. Using microbiota-depleted mice and fecal transplantation, we demonstrate that Paneth cell SIRT1 deficiency ameliorates colitis through the gut microbiota. Collectively, our findings uncover an unanticipated function of Paneth cell SIRT1 in conferring sensitivity of the gut epithelium to stress.
2026-01-20 | GSE261216 | GEO