Role of Deleted in Breast Cancer 1 (DBC1) protein in SIRT1 deacetylase activation induced by protein kinase A and AMP-activated protein kinase

Veronica Nin, Carlos Escande, Claudia C. Chini, Shailendra Giri, Juliana Camacho-Pereira, Jonathan Matalonga, Zhenkun Lou, Eduardo Nunes Chini

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

The NAD+-dependent deacetylase SIRT1 is a key regulator of several aspects of metabolism and aging. SIRT1 activation is beneficial for several human diseases, including metabolic syndrome, diabetes, obesity, liver steatosis, and Alzheimer disease. We have recently shown that the protein deleted in breast cancer 1 (DBC1) is a key regulator of SIRT1 activity in vivo. Furthermore, SIRT1 and DBC1 form a dynamic complex that is regulated by the energetic state of the organism. Understanding how the interaction between SIRT1 and DBC1 is regulated is therefore essential to design strategies aimed to activate SIRT1. Here, we investigated which pathways can lead to the dissociation of SIRT1 and DBC1 and consequently to SIRT1 activation. We observed that PKA activation leads to a fast and transient activation of SIRT1 that is DBC1-dependent. In fact, an increase in cAMP/PKA activity resulted in the dissociation of SIRT1 and DBC1 in an AMP-activated protein kinase (AMPK)-dependent manner. Pharmacological AMPK activation led to SIRT1 activation by a DBC1-dependent mechanism. Indeed, we found that AMPK activators promote SIRT1-DBC1 dissociation in cells, resulting in an increase in SIRT1 activity. In addition, we observed that the SIRT1 activation promoted by PKA and AMPK occurs without changes in the intracellular levels of NAD+. We propose that PKA and AMPK can acutely activate SIRT1 by inducing dissociation of SIRT1 from its endogenous inhibitor DBC1. Our experiments provide new insight on the in vivo mechanism of SIRT1 regulation and a new avenue for the development of pharmacological SIRT1 activators targeted at the dissociation of the SIRT1-DBC1 complex.

Original languageEnglish (US)
Pages (from-to)23489-23501
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number28
DOIs
StatePublished - Jul 6 2012

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BRCA1 Protein
AMP-Activated Protein Kinases
Cyclic AMP-Dependent Protein Kinases
Chemical activation
Breast Neoplasms
NAD
Medical problems
AMP-activated protein kinase kinase
Pharmacology
Metabolism
Liver
Metabolic Diseases
Aging of materials
Fatty Liver
Liver Diseases
Alzheimer Disease
Obesity

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Role of Deleted in Breast Cancer 1 (DBC1) protein in SIRT1 deacetylase activation induced by protein kinase A and AMP-activated protein kinase. / Nin, Veronica; Escande, Carlos; Chini, Claudia C.; Giri, Shailendra; Camacho-Pereira, Juliana; Matalonga, Jonathan; Lou, Zhenkun; Chini, Eduardo Nunes.

In: Journal of Biological Chemistry, Vol. 287, No. 28, 06.07.2012, p. 23489-23501.

Research output: Contribution to journalArticle

Nin, Veronica ; Escande, Carlos ; Chini, Claudia C. ; Giri, Shailendra ; Camacho-Pereira, Juliana ; Matalonga, Jonathan ; Lou, Zhenkun ; Chini, Eduardo Nunes. / Role of Deleted in Breast Cancer 1 (DBC1) protein in SIRT1 deacetylase activation induced by protein kinase A and AMP-activated protein kinase. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 28. pp. 23489-23501.
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AU - Escande, Carlos

AU - Chini, Claudia C.

AU - Giri, Shailendra

AU - Camacho-Pereira, Juliana

AU - Matalonga, Jonathan

AU - Lou, Zhenkun

AU - Chini, Eduardo Nunes

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AB - The NAD+-dependent deacetylase SIRT1 is a key regulator of several aspects of metabolism and aging. SIRT1 activation is beneficial for several human diseases, including metabolic syndrome, diabetes, obesity, liver steatosis, and Alzheimer disease. We have recently shown that the protein deleted in breast cancer 1 (DBC1) is a key regulator of SIRT1 activity in vivo. Furthermore, SIRT1 and DBC1 form a dynamic complex that is regulated by the energetic state of the organism. Understanding how the interaction between SIRT1 and DBC1 is regulated is therefore essential to design strategies aimed to activate SIRT1. Here, we investigated which pathways can lead to the dissociation of SIRT1 and DBC1 and consequently to SIRT1 activation. We observed that PKA activation leads to a fast and transient activation of SIRT1 that is DBC1-dependent. In fact, an increase in cAMP/PKA activity resulted in the dissociation of SIRT1 and DBC1 in an AMP-activated protein kinase (AMPK)-dependent manner. Pharmacological AMPK activation led to SIRT1 activation by a DBC1-dependent mechanism. Indeed, we found that AMPK activators promote SIRT1-DBC1 dissociation in cells, resulting in an increase in SIRT1 activity. In addition, we observed that the SIRT1 activation promoted by PKA and AMPK occurs without changes in the intracellular levels of NAD+. We propose that PKA and AMPK can acutely activate SIRT1 by inducing dissociation of SIRT1 from its endogenous inhibitor DBC1. Our experiments provide new insight on the in vivo mechanism of SIRT1 regulation and a new avenue for the development of pharmacological SIRT1 activators targeted at the dissociation of the SIRT1-DBC1 complex.

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