BET Inhibition Upregulates SIRT1 and Alleviates Inflammatory Responses

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Control of histone acetylation is a part of the epigenetic mechanism that regulates gene expression and chromatin architecture. The members of the bromodomain and extra terminal domain (BET) protein family are a group of epigenetic readers that recognize histone acetylation, whereas histone deacetyl- ases such as sirtuin 1 (SIRT1) function as epigenetic erasers. We observed that BET inhibition by the specific inhibitor JQ1 upregulated SIRT1 expression and activated SIRT1. Moreover, we observed that BET inhibition functionally reversed the pro-inflammatory effect of SIRT1 inhibition in a cellular lung disease model. SIRT1 activation is desirable in many age-related, metabolic and inflammatory diseases; our results suggest that BET protein inhibition would be beneficial in treatment of those conditions. Most importantly, our findings demonstrate a novel mechanism of SIRT1 activation by inhibition of the BET proteins.

Related collections

Most cited references 24

Record: found
Abstract: found
Article: found

Is Open Access

Rapid planetesimal formation in turbulent circumstellar discs

Anders Johansen, Jeffrey S. Oishi, Mordecai-Mark Mac Low … (2007)

The initial stages of planet formation in circumstellar gas discs proceed via dust grains that collide and build up larger and larger bodies (Safronov 1969). How this process continues from metre-sized boulders to kilometre-scale planetesimals is a major unsolved problem (Dominik et al. 2007): boulders stick together poorly (Benz 2000), and spiral into the protostar in a few hundred orbits due to a head wind from the slower rotating gas (Weidenschilling 1977). Gravitational collapse of the solid component has been suggested to overcome this barrier (Safronov 1969, Goldreich & Ward 1973, Youdin & Shu 2002). Even low levels of turbulence, however, inhibit sedimentation of solids to a sufficiently dense midplane layer (Weidenschilling & Cuzzi 1993, Dominik et al. 2007), but turbulence must be present to explain observed gas accretion in protostellar discs (Hartmann 1998). Here we report the discovery of efficient gravitational collapse of boulders in locally overdense regions in the midplane. The boulders concentrate initially in transient high pressures in the turbulent gas (Johansen, Klahr, & Henning 2006), and these concentrations are augmented a further order of magnitude by a streaming instability (Youdin & Goodman 2005, Johansen, Henning, & Klahr 2006, Johansen & Youdin 2007) driven by the relative flow of gas and solids. We find that gravitationally bound clusters form with masses comparable to dwarf planets and containing a distribution of boulder sizes. Gravitational collapse happens much faster than radial drift, offering a possible path to planetesimal formation in accreting circumstellar discs.

0 comments Cited 2503 times – based on 0 reviews

Preprint

     Review now

Bookmark

Record: found
Abstract: found
Article: not found

SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.

Michelle Pacholec, John Bleasdale, Boris Chrunyk … (2010)

Sirtuins catalyze NAD(+)-dependent protein deacetylation and are critical regulators of transcription, apoptosis, metabolism, and aging. There are seven human sirtuins (SIRT1-7), and SIRT1 has been implicated as a key mediator of the pathways downstream of calorie restriction that have been shown to delay the onset and reduce the incidence of age-related diseases such as type 2 diabetes. Increasing SIRT1 activity, either by transgenic overexpression of the Sirt1 gene in mice or by pharmacological activation by small molecule activators resveratrol and SRT1720, has shown beneficial effects in rodent models of type 2 diabetes, indicating that SIRT1 may represent an attractive therapeutic target. Herein, we have assessed purported SIRT1 activators by employing biochemical assays utilizing native substrates, including a p53-derived peptide substrate lacking a fluorophore as well as the purified native full-length protein substrates p53 and acetyl-CoA synthetase1. SRT1720, its structurally related compounds SRT2183 and SRT1460, and resveratrol do not lead to apparent activation of SIRT1 with native peptide or full-length protein substrates, whereas they do activate SIRT1 with peptide substrate containing a covalently attached fluorophore. Employing NMR, surface plasmon resonance, and isothermal calorimetry techniques, we provide evidence that these compounds directly interact with fluorophore-containing peptide substrates. Furthermore, we demonstrate that SRT1720 neither lowers plasma glucose nor improves mitochondrial capacity in mice fed a high fat diet. SRT1720, SRT2183, SRT1460, and resveratrol exhibit multiple off-target activities against receptors, enzymes, transporters, and ion channels. Taken together, we conclude that SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.

0 comments Cited 246 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Substrate-specific activation of sirtuins by resveratrol.

Matt Kaeberlein, Thomas McDonagh, Birgit Heltweg … (2005)

Resveratrol, a small molecule found in red wine, is reported to slow aging in simple eukaryotes and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to act as a sirtuin activator, and this property has been proposed to account for its anti-aging effects. We show here that resveratrol is a substrate-specific activator of yeast Sir2 and human SirT1. In particular, we observed that, in vitro, resveratrol enhances binding and deacetylation of peptide substrates that contain Fluor de Lys, a non-physiological fluorescent moiety, but has no effect on binding and deacetylation of acetylated peptides lacking the fluorophore. Consistent with these biochemical data we found that in three different yeast strain backgrounds, resveratrol has no detectable effect on Sir2 activity in vivo, as measured by rDNA recombination, transcriptional silencing near telomeres, and life span. In light of these findings, the mechanism accounting for putative longevity effects of resveratrol should be reexamined.

0 comments Cited 180 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Chembiochem

Journal ID (iso-abbrev): Chembiochem

Journal ID (publisher-id): cbic

Title: Chembiochem

Publisher: Blackwell Publishing Ltd (Oxford, UK )

ISSN (Print): 1439-4227

ISSN (Electronic): 1439-7633

Publication date (Print): September 2015

Publication date (Electronic): 13 August 2015

Volume: 16

Issue: 14

Pages: 1997-2001

Affiliations

[[a] ]School of Pharmacy, University of Eastern Finland Yliopistonranta 1C, 70211, Kuopio, Finland E-mail: tarja.kokkola@ 123456uef.fi

[[b] ]Institute of Clinical Medicine, University of Eastern Finland Yliopistonranta 1C, 70211, Kuopio, Finland

[[c] ]Structural Genomics Consortium, University of Oxford Roosevelt Drive, Oxford, OX3 7DQ, UK

Author notes

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cbic.201500272.

Article

DOI: 10.1002/cbic.201500272

PMC ID: 4600234

PubMed ID: 26212199

SO-VID: e62524bb-7c2b-428d-ae50-5a5a577c83a7

License:

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

BET Inhibition Upregulates SIRT1 and Alleviates Inflammatory Responses

Read this article at

Abstract

Related collections

Journal of Circulating Biomarkers

Most cited references 24

Rapid planetesimal formation in turbulent circumstellar discs

SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.

Substrate-specific activation of sirtuins by resveratrol.

Author and article information

Journal

Affiliations

Author notes

Article

History

Categories

Comments

Comment on this article

Similar content 733

Cited by 10

Most referenced authors 786