RETRACTED: Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex

Zhang, Qinghong; Wang, Su Yan; Fleuriel, Capucine; Leprince, Dominique; Rocheleau, Jonathan V.; Piston, David W.; Goodman, Richard H.

doi:10.1073/pnas.0610590104

Cited by 159 publications

(149 citation statements)

References 52 publications

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“…S5 and data not shown). The reason for this lack of regulation remains unclear, and could be because there is no close C. elegans homologues of HIC-1, which was shown to be required for the transcription regulation of SIRT1 by CtBP (28). Together with the epistatic analysis, our results suggest that CTBP-1 does not regulate life span through up-regulation of SIR-2.1.…”

Section: Resultssupporting

confidence: 58%

“…Interestingly, previous studies show that a reduction in CtBP binding to the transcription repressor HIC-1 [hypermethylated in cancer (27)] results in an up-regulation of the human Sir2 homologue SIRT1 expression in primary fibroblasts (28), suggesting that SIRT1 may be a downstream target of CtBP. However, the expression of C. elegans sir-2.1 and other possible Sir2 homologues (sir-2.2, sir-2.3 and sir-2.4) was unaltered in the absence of a functional CTBP-1 in our study (Fig.…”

Section: Resultsmentioning

confidence: 99%

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The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span

Chen

Whetstine²,

Ghosh³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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CtBP (C-terminal binding protein) is an evolutionarily conserved NAD(H)-dependent transcriptional corepressor, whose activity has been shown to be regulated by the NAD/NADH ratio. Although recent studies have provided significant new insights into mechanisms by which CtBP regulates transcription, the biological function of CtBP remains incompletely understood. Here, we report that genetic inactivation of the Caenorhabditis elegans homolog, ctbp-1, results in life span extension, which is suppressed by reintroduction of the ctbp-1 genomic DNA encoding wild-type but not NAD(H)-binding defective CTBP-1 protein. We show that CTBP-1 possibly modulates aging through the insulin/IGF-1 signaling pathway, dependent on the forkhead transcription factor DAF-16, but independent of the NAD-dependent histone deacetylase SIR-2.1. Genome-wide microarray analysis identifies >200 potential CTBP-1 target genes. Importantly, RNAi inhibition of a putative triacylglycerol lipase gene lips-7(C09E8.2) but not another lipase suppresses the life span extension phenotype. Consistently, metabolic analysis shows that the triacylglycerol level is reduced in the ctbp-1 deletion mutant, which is restored to the wild-type level by RNAi inhibition of lips-7. Taken together, our data suggest that CTBP-1 controls life span probably through the regulation of lipid metabolism.aging ͉ CtBP ͉ transcription corepressor C tBP is a transcriptional corepressor that is evolutionarily conserved from Caenorhabditis elegans to human (1). CtBP shares sequence homology with the NAD/NADH-dependent 2-hydroxy acid dehydrogenases (2-Hacid DH) (2), and has been shown to exhibit dehydrogenase activity in vitro (3-5), although the physiological substrates and functional significance of this enzymatic activity remain unclear. CtBP binds NAD and NADH, and the NAD/NADH ratio appears to regulate the interactions of CtBP with DNA-binding transcription factors (6, 7), suggesting a potential role for CtBP as a sensor of cellular redox states. CtBP represses transcription by recruiting multiple histone modifying enzymes including the histone H3 lysine 9 (H3K9) methyltransferase G9a/HMTase1 and the histone H3 lysine 4 (H3K4) demethylase LSD1 (3,8). Previous studies suggest a role for CtBP in mouse development, apoptosis, and hypoxia-induced tumor migration (9-12). However, by and large, the biology of CtBP is still incompletely understood.Aging is a complex process regulated by an interacting network of factors. The insulin/insulin-like growth factor-1 (IGF-1) signaling pathway, the JNK anti-stress pathway and the mitochondria respiratory chain, have all been shown to regulate the aging process (13). Besides genetic factors, environmental conditions including stress and nutrient availability, have also been demonstrated to influence longevity (13-15). Transcription factors including DAF-16 and the NAD-dependent histone deacetylase SIR2 are at the converging points to integrate these different signals and regulate longevity through modulating gene transcription (13,15). Similar...

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Section: Resultssupporting

confidence: 58%

Section: Resultsmentioning

confidence: 99%

The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span

Chen

Whetstine²,

Ghosh³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…2B), recent reports revealed the existence of a nucleocytoplasmic shuttling mechanism for SIRT1 (24,50). Thus, our data strongly suggest that SIRT1 abundance and its localization, being sensitively influenced by ambient glucose levels, are also directly involved in the regulation of myogenesis as a prerequisite for regulating its enzymatic activity at suitable (55). These changes in SIRT1 abundance in skeletal muscle cells may contribute not only to myogenesis but also to metabolic adaptations during glucose deprivation, such as regulation of mitochondrial gene expression and fatty acid utilization (17,29).…”

Section: Discussionsupporting

confidence: 48%

Ambient glucose levels qualify the potency of insulin myogenic actions by regulating SIRT1 and FoxO3a in C₂C₁₂ myocytes

Nedachi

Kadotani²,

Ariga³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Nedachi T, Kadotani A, Ariga M, Katagiri H, Kanzaki M. Ambient glucose levels qualify the potency of insulin myogenic actions by regulating SIRT1 and FoxO3a in C 2C12 myocytes. Am J Physiol Endocrinol Metab 294: E668-E678, 2008. First published January 29, 2008 doi:10.1152/ajpendo.00640.2007.-Nutrition availability is one of the major environmental signals influencing cell fate, such as proliferation, differentiation, and apoptosis, often functioning in concert with other humoral factors, including insulin. Herein, we show that low-serum-induced differentiation of C 2C12 myocytes is significantly hampered under low glucose (LG; 5 mM) compared with high glucose (HG; 22.5 mM) conditions, concurrently with nuclear accumulation of SIRT1, an NAD ϩ -dependent deacetylase, and FoxO3a, both of which are implicated in the negative regulation of myogenesis. Intriguingly, insulin appears to exert opposite actions, depending on glucose availability, with regard to the regulation of SIRT1 and FoxO3a abundance, which apparently contributes to modulating the potency of insulin's myogenic action. Namely, insulin exerts a potent myogenic effect in the presence of sufficient glucose, whereas insulin is unable to exert its myogenic action under LG conditions, since insulin evokes massive upregulation of both SIRT1 and FoxO3a in the absence of sufficient ambient glucose. In addition, the hampered differentiation state under LG is significantly restored by sirtinol, a SIRT1 inhibitor, whereas insulin abolished this sirtinoldependent restoration, indicating that insulin can function as a negative as well as a positive myogenic factor depending on glucose availability. Taken together, our data reveal the importance of ambient glucose levels in the regulation of myogenesis and also in the determination of insulin's myogenic potency, which is achieved, at least in part, through regulation of the cellular contents and localization of SIRT1 and FoxO3a in differentiating C 2C12 myocytes.forkhead box O; differentiation SKELETAL MUSCLE CELLS have provided a useful model for exploring the molecular mechanisms involved in cellular differentiation (13), and insulin and insulin-like growth factors (IGFs) have been implicated in the process of myogenesis by activating the IRS-PI 3-kinase signaling pathway (7,22,25,53) that also serves as a pivotal intracellular signal for exerting metabolic actions in mature skeletal muscle (9). However, despite our general understanding of the effects of ambient glucose levels on insulin responsiveness with regard to metabolic actions in skeletal muscle cells (37), the possible interrelationship between glucose and insulin acting on myogenesis remains to be clarified.Skeletal muscle differentiation is a well-organized process governed by muscle-specific transcription factors belonging to the MyoD family, such as MyoD and myogenin (42), and the myocyte enhancer factor-2 (MEF2) family, such as MEF2A and MEF2C (35). In addition to these muscle-specific transcription factors, positively regulating myogenesis, the f...

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“…Intriguingly, the repression of SIRT1 gene expression does not appear to be affected on the basis by functional HIC1 solely, but also by the availability of the redoxsensitive HIC1-corepressor CtBP and the concentration of NADH in the nucleus. The reduction of NADH results in impaired formation of HIC1-CtBP complexes, therefore leading to decreased HIC1-mediated repression, which is associated with increased SIRT1 gene expression independent of HIC1-status (Zhang et al, 2007). Moreover, previous studies reported an increase in SIRT1 protein in the liver of fasted mice while mRNA levels remained constant, suggesting that SIRT1 is regulated post-transcriptionally (Rodgers et al, 2005).…”

Section: Discussionmentioning

confidence: 94%

Detailed mapping of chromosome 17p deletions reveals HIC1 as a novel tumor suppressor gene candidate telomeric to TP53 in diffuse large B-cell lymphoma

et al. 2007

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Deletions in the short arm of chromosome 17 (17p) involving the tumor suppressor TP53 occur in up to 20% of diffuse large B-cell lymphomas (DLBCLs). Although inactivation of both alleles of a tumor suppressor gene is usually required for tumor development, the overlap between TP53 deletions and mutations is poorly understood in DLBCLs, suggesting the possible existence of additional tumor suppressor genes in 17p. Using a bacterial artificial chromosome (BAC) and Phage 1 artificial chromosome (PAC) contig, we here define a minimally deleted region in DLBCLs encompassing approximately 0.8 MB telomeric to the TP53 locus. This genomic region harbors the tumor suppressor Hypermethylated in Cancer 1 (HIC1). Methylation-specific PCR demonstrated hypermethylation of HIC1 exon 1a in a substantial subset of DLBCLs, which is accompanied by simultaneous HIC1 deletion of the second allele in 90% of cases. In contrast, HIC1 inactivation by hypermethylation was rarely encountered in DLBCLs without concomitant loss of the second allele. DLBCL patients with complete inactivation of both HIC1 and TP53 may be characterized by an even inferior clinical course than patients with inactivation of TP53 alone, suggesting a functional cooperation between these two proteins. These findings strongly imply HIC1 as a novel tumor suppressor in a subset of DLBCLs.

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RETRACTED: Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex

Cited by 159 publications

References 52 publications

The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span

The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span

Ambient glucose levels qualify the potency of insulin myogenic actions by regulating SIRT1 and FoxO3a in C₂C₁₂ myocytes

Detailed mapping of chromosome 17p deletions reveals HIC1 as a novel tumor suppressor gene candidate telomeric to TP53 in diffuse large B-cell lymphoma

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RETRACTED: Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex

Cited by 159 publications

References 52 publications

The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span

The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span

Ambient glucose levels qualify the potency of insulin myogenic actions by regulating SIRT1 and FoxO3a in C2C12 myocytes

Detailed mapping of chromosome 17p deletions reveals HIC1 as a novel tumor suppressor gene candidate telomeric to TP53 in diffuse large B-cell lymphoma

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Ambient glucose levels qualify the potency of insulin myogenic actions by regulating SIRT1 and FoxO3a in C₂C₁₂ myocytes