DBC1 Is a Negative Regulator of SIRT1

Nature. 2008 Jan 31;451(7178):583-6. doi: 10.1038/nature06500.

Abstract

The NAD-dependent protein deacetylase Sir2 (silent information regulator 2) regulates lifespan in several organisms. SIRT1, the mammalian orthologue of yeast Sir2, participates in various cellular functions and possibly tumorigenesis. Whereas the cellular functions of SIRT1 have been extensively investigated, less is known about the regulation of SIRT1 activity. Here we show that Deleted in Breast Cancer-1 (DBC1), initially cloned from a region (8p21) homozygously deleted in breast cancers, forms a stable complex with SIRT1. DBC1 directly interacts with SIRT1 and inhibits SIRT1 activity in vitro and in vivo. Downregulation of DBC1 expression potentiates SIRT1-dependent inhibition of apoptosis induced by genotoxic stress. Our results shed new light on the regulation of SIRT1 and have important implications in understanding the molecular mechanism of ageing and cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Aging
  • Apoptosis / drug effects
  • Catalytic Domain
  • Cell Line
  • Down-Regulation
  • Etoposide / pharmacology
  • Humans
  • Immunoprecipitation
  • Leucine Zippers
  • Mutagens / pharmacology
  • Protein Binding
  • Protein Interaction Mapping
  • Sirtuin 1
  • Sirtuins / antagonists & inhibitors*
  • Sirtuins / chemistry
  • Sirtuins / genetics
  • Sirtuins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • CCAR2 protein, human
  • Mutagens
  • Etoposide
  • SIRT1 protein, human
  • Sirtuin 1
  • Sirtuins