Regulation of SIRT6 protein levels by nutrient availability

Kanfi, Yariv; Shalman, Ronnie; Peshti, Victoria; Pilosof, Shmuel N.; Gozlan, Yosi M.; Pearson, Kevin J.; Lerrer, Batia; Moazed, Danesh; Marine, Jean–Christophe; Cabo, Rafael de; Cohen, Haim Y.

doi:10.1016/j.febslet.2008.01.019

Cited by 159 publications

(148 citation statements)

References 19 publications

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“…Furthermore, SIRT6-mediated autophagy is crucial for determination of CSE-induced HBEC senescence. Consistent with recent findings regarding SIRT1, CSE reduced SIRT6 expression at the protein level without apparent changes in the amount of SIRT6 mRNA, suggesting that CSE-induced protein modification may lead to proteasomal degradation of SIRT6 (27). Although the involvement of SIRT6 in COPD pathogenesis has been proposed without detailed mechanisms (28), our findings of decreased expression levels of SIRT6 in lung homogenates from COPD patients may support the notion that reduced SIRT6 is associated with COPD development through the enhancement of cellular senescence created by insufficient autophagy during CS exposure.…”

Section: Discussionsupporting

confidence: 78%

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

Takasaka

Araya

Hara

et al. 2014

The Journal of Immunology

162

145

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Cigarette smoke (CS)–induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is negatively regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-associated β-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 s/forced vital capacity. CS extract (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.

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Section: Discussionsupporting

confidence: 78%

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

Takasaka

Araya

Hara

et al. 2014

The Journal of Immunology

162

145

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“…In addition, it has been shown that SIRT6 is stabilized by nutrient deprivation and CR in cultured cells and rats, respectively [29]. While the details of the molecular interaction between SIRT6 and DNA repair are not clear, it is speculated that CR can regulate the SIRT6-mediated stability of WRN and that other sirtuins may also be implicated in this regulation.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin‐mediated deacetylation pathway stabilizes Werner syndrome protein

et al. 2008

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Caloric restriction (CR) is known to promote longevity in various species. Sirtuin-mediated deacetylation has been shown to be related to the promotion of longevity in some species. Here, we show that CR of rats led to an increase in the level of Werner syndrome protein (WRN), a recognized DNA repair protein. In addition, CR simultaneously increased the level of SIRT1, a mammalian sirtuin. In HEK293T cells, sirtuin inhibitors decreased the WRN level, and this effect was suppressed by proteasomal inhibitors. Furthermore, we found a decrease in the WRN level in Sirt1-deficient mice. These results indicate that sirtuin-mediated deacetylation stabilizes WRN. Structured summary:MINT-6603869: ubiquitin (uniprotkb:P62988) physically interacts (MI:0218) with WRN (uniprotkb:Q14191) by pull down (MI:0096)

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“…In fact, Drosophila dSir2 has been functionally linked to CR-dependent life span through a mechanism linked to the HDAC Rpd1 (Rogina and Helfand 2004), but C. elegans Sir-2.1 increases life span through a CR-independent mechanism linked to the IIS pathway (Tissenbaum and Guarente 2001). Nevertheless, there is no doubt that Sirtuins are functionally linked to the CR response in mammals, since CR up-regulates SirT1, SirT2, SirT3, and SirT6 and down-regulates SirT4 Shi et al 2005;Wang et al 2007;Kanfi et al 2008). In fact, recent and controversial data have suggested that CR might not induce SirT1 up-regulation, but its down-regulation in liver (Chen et al 2008a).…”

Section: The Exertion Of Sirtuinsmentioning

confidence: 99%

Calorie restriction and the exercise of chromatin

Vaquero¹,

Reinberg²

2009

Genes Dev.

136

140

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Since the earliest stages of evolution, organisms have faced the challenge of sensing and adapting to environmental changes for their survival under compromising conditions such as food depletion or stress. Implicit in these responses are mechanisms developed during evolution that include the targeting of chromatin to allow or prevent expression of fundamental genes and to protect genome integrity. Among the different approaches to study these mechanisms, the analysis of the response to a moderate reduction of energy intake, also known as calorie restriction (CR), has become one of the best sources of information regarding the factors and pathways involved in metabolic adaptation from lower to higher eukaryotes. Furthermore, responses to CR are involved in life span regulation—conserved from yeast to mammals—and therefore have garnered major research interest. Herein we review current knowledge of responses to CR at the molecular level and their functional link to chromatin.

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Regulation of SIRT6 protein levels by nutrient availability

Cited by 159 publications

References 19 publications

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

Sirtuin‐mediated deacetylation pathway stabilizes Werner syndrome protein

Calorie restriction and the exercise of chromatin

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