DBC1 is a negative regulator of SIRT1

Ja Eun Kim; Junjie Chen; Zhenkun Lou

doi:10.1038/nature06500

DBC1 is a negative regulator of SIRT1

Ja Eun Kim, Junjie Chen, Zhenkun Lou

Oncology

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379 Scopus citations

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.

Original language	English (US)
Pages (from-to)	583-586
Number of pages	4
Journal	Nature
Volume	451
Issue number	7178
DOIs	https://doi.org/10.1038/nature06500
State	Published - Jan 31 2008

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title = "DBC1 is a negative regulator of SIRT1",

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.",

author = "Kim, {Ja Eun} and Junjie Chen and Zhenkun Lou",

note = "Funding Information: Acknowledgements We thank E. White for providing DBC1 expression constructs. We thank T. P. Yao, R. Janknecht, M. Huen and M. H. Sy for providing constructs encoding SIRT1, p300, p53 and Myc, respectively. This work was supported in part by grants from the National Institutes of Health (to J.C). Z.L was supported by a Susan G. Komen Breast Cancer Foundation Research Grant. J.C. is a recipient of an Era of Hope Scholars award from Department of Defense and a member of Mayo Clinic Breast SPORE program.",

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AU - Chen, Junjie

AU - Lou, Zhenkun

N1 - Funding Information: Acknowledgements We thank E. White for providing DBC1 expression constructs. We thank T. P. Yao, R. Janknecht, M. Huen and M. H. Sy for providing constructs encoding SIRT1, p300, p53 and Myc, respectively. This work was supported in part by grants from the National Institutes of Health (to J.C). Z.L was supported by a Susan G. Komen Breast Cancer Foundation Research Grant. J.C. is a recipient of an Era of Hope Scholars award from Department of Defense and a member of Mayo Clinic Breast SPORE program.

PY - 2008/1/31

Y1 - 2008/1/31

N2 - 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.

AB - 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.

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DBC1 is a negative regulator of SIRT1

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