Abstract

In mammals, the Sirtuins are composed of seven Sir2 orthologues (Sirt1-7) with a conserved deacetylase core that utilizes NAD+ as a cofactor. Sirtuins play an important role in energy metabolism and regulating Sirtuin activity may be useful for controlling fat accumulation. Interestingly, the deacetylase core of Sirt1 by itself has no catalytic activity. We found within the C-terminal domain a 25 a.a. sequence that is essential for Sirt1 activity (ESA). Our results indicate that the ESA region interacts with and functions as an on switch for the deacetylase core. The endogenous Sirt1 inhibitor DBC1, which also binds to the deacetylase core, competes with and inhibits the ESA region from interacting with the deacetylase core. We discovered an ESA mutant peptide that can bind to the deacetylase core and inhibit Sirt1 in trans. By using this mutant peptide, we were able to inhibit Sirt1 activity and to increase the chemosensitivity of androgen-refractory prostate cancer cells. Therefore, the ESA region is a potential target for development of therapies to regulate Sirt1.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAHL006118-01
Application #
8344913
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2011
Total Cost
$858,640
Indirect Cost

  Institution

Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Kang, Hyeog; Oka, Shinichi; Lee, Duck-Yeon et al. (2017) Sirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins. Nat Commun 8:15560
Park, Sung-Jun; Ahmad, Faiyaz; Um, Jee-Hyun et al. (2017) Specific Sirt1 Activator-mediated Improvement in Glucose Homeostasis Requires Sirt1-Independent Activation of AMPK. EBioMedicine 18:128-138
Bitterman, Jacob L; Chung, Jay H (2015) Metabolic effects of resveratrol: addressing the controversies. Cell Mol Life Sci 72:1473-88
Mishra, Amarjit; Brown, Alexandra L; Yao, Xianglan et al. (2015) Dendritic cells induce Th2-mediated airway inflammatory responses to house dust mite via DNA-dependent protein kinase. Nat Commun 6:6224
Park, Jun Hong; Kang, Hong-Jun; Lee, Yun Kyung et al. (2015) Inactivation of EWS reduces PGC-1? protein stability and mitochondrial homeostasis. Proc Natl Acad Sci U S A 112:6074-9
Maurice, Donald H; Ke, Hengming; Ahmad, Faiyaz et al. (2014) Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov 13:290-314
Um, Jee-Hyun; Brown, Alexandra L; Singh, Samarendra K et al. (2013) Metabolic sensor AMPK directly phosphorylates RAG1 protein and regulates V(D)J recombination. Proc Natl Acad Sci U S A 110:9873-8
Pullikotil, Philomena; Chen, Hui; Muniyappa, Ranganath et al. (2012) Epigallocatechin gallate induces expression of heme oxygenase-1 in endothelial cells via p38 MAPK and Nrf-2 that suppresses proinflammatory actions of TNF-?. J Nutr Biochem 23:1134-45
Chung, Jay H; Manganiello, Vincent; Dyck, Jason R B (2012) Resveratrol as a calorie restriction mimetic: therapeutic implications. Trends Cell Biol 22:546-54
Chung, Jay H (2012) Metabolic benefits of inhibiting cAMP-PDEs with resveratrol. Adipocyte 1:256-258

Showing the most recent 10 out of 15 publications