Negative regulation of the deacetylase SIRT1 by DBC1. Nature

Institute for Cancer Genetics, and Department of Pathology College of Physicians and Surgeons, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA.
Nature (Impact Factor: 41.46). 02/2008; 451(7178):587-90. DOI: 10.1038/nature06515
Source: PubMed


SIRT1 is an NAD-dependent deacetylase critically involved in stress responses, cellular metabolism and, possibly, ageing. The tumour suppressor p53 represents the first non-histone substrate functionally regulated by acetylation and deacetylation; we and others previously found that SIRT1 promotes cell survival by deacetylating p53 (refs 4-6). These results were further supported by the fact that p53 hyperacetylation and increased radiation-induced apoptosis were observed in Sirt1-deficient mice. Nevertheless, SIRT1-mediated deacetylase function is also implicated in p53-independent pathways under different cellular contexts, and its effects on transcriptional factors such as members of the FOXO family and PGC-1alpha directly modulate metabolic responses. These studies validate the importance of the deacetylase activity of SIRT1, but how SIRT1 activity is regulated in vivo is not well understood. Here we show that DBC1 (deleted in breast cancer 1) acts as a native inhibitor of SIRT1 in human cells. DBC1-mediated repression of SIRT1 leads to increasing levels of p53 acetylation and upregulation of p53-mediated function. In contrast, depletion of endogenous DBC1 by RNA interference (RNAi) stimulates SIRT1-mediated deacetylation of p53 and inhibits p53-dependent apoptosis. Notably, these effects can be reversed in cells by concomitant knockdown of endogenous SIRT1. Our study demonstrates that DBC1 promotes p53-mediated apoptosis through specific inhibition of SIRT1.

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Available from: Jun Qin, Oct 09, 2015
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    • "Additionally, the NTERM domain interacts with DBC1, a negative regulator of SIRT1 activity (Kang et al., 2011; Kim et al., 2008; Zhao et al., 2008). The binding of DBC1 to the NTERM domain may additionally contribute to enhanced SIRT1 deacetylase activity. "
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    ABSTRACT: The NAD(+)-dependent protein deacetylase SIRT1 regulates energy metabolism, responses to stress, and aging by deacetylating many different proteins, including histones and transcription factors. The mechanisms controlling SIRT1 enzymatic activity are complex and incompletely characterized, yet essential for understanding how to develop therapeutics that target SIRT1. Here, we demonstrate that the N-terminal domain of SIRT1 (NTERM) can trans-activate deacetylation activity by physically interacting with endogenous SIRT1 and promoting its association with the deacetylation substrate NF-κB p65. Two motifs within the NTERM domain contribute to activation of SIRT1-dependent activities, and expression of one of these motifs in mice is sufficient to lower fasting glucose levels and improve glucose tolerance in a manner similar to overexpression of SIRT1. Our results provide insights into the regulation of SIRT1 activity and a rationale for pharmacological control of SIRT1-dependent activities. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(10). DOI:10.1016/j.celrep.2015.02.036 · 8.36 Impact Factor
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    • "For instance, DBC1 activates retinoic acid receptor a and androgen receptor and represses transcription activity of estrogen receptor b (Fu et al., 2009; Garapaty et al., 2009; Koyama et al., 2010). Furthermore, we and others have found that DBC1 negatively regulates SIRT1 activity through binding to its active site (Kim et al., 2008; Zhao et al., 2008). DNA damage and oxidative stress increase the DBC1-SIRT1 interaction, whereas PKA and AMPK induce dissociation of SIRT1 from DBC1 (Yuan et al., 2012; Nin et al., 2012). "
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    ABSTRACT: DBC1 (deleted in breast cancer 1), also known as CCAR2 or KIAA1967, is an important negative regulator of SIRT1 and cellular stress response. Although the Dbc1 gene localizes at a region that is homozygously deleted in breast cancer, its role in tumorigenesis remains unclear. It has been suggested to be either a tumor suppressor or an oncogene. Therefore, the function of DBC1 in cancer needs to be further explored. Here, we report that Dbc1 knockout mice are tumor prone, suggesting that DBC1 functions as a tumor suppressor in vivo. Our data suggest that the increased tumor incidence in Dbc1 knockout mice is independent of Sirt1. Instead, we found that DBC1 loss results in less p53 protein in vitro and in vivo. DBC1 directly binds p53 and stabilizes it through competition with MDM2. These studies reveal that DBC1 plays an important role in tumor suppression through p53 regulation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 02/2015; 7(8). DOI:10.1016/j.celrep.2015.01.066 · 8.36 Impact Factor
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    • "SIRT1 can also be regulated through protein–protein interactions occurring at the N-and C-terminal regulatory regions or directly at the catalytic domain. An example of the latter is interaction with DBC1 (Deleted in breast cancer-1) protein, which inhibits the activity of SIRT1 and promotes p53- mediated apoptosis [25] [26]. Active regulator of SIRT1 (AROS) is the only SIRT1 interaction partner which has been reported to directly increase its catalytic activity. "
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    ABSTRACT: The modulation of protein deacetylase SIRT1 has a vast therapeutic potential in treatment of several aging-associated diseases. Active regulator of SIRT1 (AROS) is a small endogenous protein which was originally reported to activate SIRT1 through a direct interaction in cancer cells. We show that the interaction between the two proteins is weak and does not alter the activity of SIRT1 in non-cancerous human cells. The results of different in vitro SIRT1 activity assays disclosed AROS as an inhibitor of SIRT1. The functional relationship between AROS and SIRT1 proved to be dependent on the biological context and experimental setting.
    FEBS letters 03/2014; 588(9). DOI:10.1016/j.febslet.2014.03.020 · 3.17 Impact Factor
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