Targeted Disruption of the Basic Krüppel-Like Factor Gene (<i>Klf3</i>) Reveals a Role in Adipogenesis

Sue, Nancy; Jack, Briony; Eaton, Sally A.; Pearson, Richard; Funnell, Alister P. W.; Turner, Jeremy; Czolij, R.; Denyer, Gareth; Bao, Shisan; Molero-Navajas, Juan Carlos; Perkins, Andrew C.; Fujiwara, Yuko; Orkin, Stuart H.; Bell-Anderson, Kim; Crossley, Merlin

doi:10.1128/mcb.01942-07

Cited by 172 publications

(174 citation statements)

References 38 publications

(65 reference statements)

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“…Our data also show that lipid metabolism is important in CTBP-1 regulation of life span. Consistent with our demonstration of CTBP-1's involvement in lipid regulation, recent publications have documented a role for mammalian CtBP in regulating lipid storage and adipogenesis in mammalian cells and mice (47)(48)(49) while this manuscript was under review. Accumulation of lipid has been associated with aging-related diseases such as obesity, type II diabetes, insulin resistance and cancer (50,51).…”

Section: Resultssupporting

confidence: 62%

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: 62%

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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“…The generation of a KLF3 knockout mouse has revealed a role for KLF3 in regulating adipogenesis (10). In this model, KLF3 expression was ablated by targeted deletion of a region within the C-terminal zinc finger DNA-binding domain.…”

Section: Klf3 and Adipogenesismentioning

confidence: 99%

“…In addition to the interaction with CtBP, full repression activity is dependent on sumoylation (6). Recent progress has begun to define the biology of KLF3, suggesting widespread roles in differentiation, including erythropoiesis, lymphopoiesis, and adipogenesis (7)(8)(9)(10). This review will describe the molecular structure of KLF3 in the context of the KLF family, the molecular mechanisms by which it regulates expression of its target genes and also the biological functions that have been recently attributed to this protein.…”

Section: Introductionmentioning

confidence: 99%

The mammalian zinc finger transcription factor Krüppel‐like factor 3 (KLF3/BKLF)

2011

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KLF3 is a member of the Krüppel‐like factor (KLF) family of transcription factors. These proteins are classified by the presence of three C‐terminal C2H2 zinc fingers that allow sequence‐specific binding to CACCC boxes and GC‐rich motifs found in the promoters, enhancers, and other control regions of target genes. KLFs have diverse biological roles, regulating proliferation, differentiation, and apoptosis in many tissues throughout development. KLF3 is a transcriptional repressor that binds the cofactor C‐terminal binding protein, which in turn recruits a large repressor complex to mediate transcriptional silencing. In addition to an understanding of the molecular mechanisms that allow KLF3 to regulate the expression of its target genes, the biological roles of this transcription factor are now being defined. In agreement with the widespread expression pattern of this transcription factor, it is becoming clear that KLF3 is an important regulator of several biological processes, including adipogenesis, erythropoiesis, and B cell development. © 2011 IUBMB IUBMB Life, 63(2): 86–93, 2011

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“…14 Previous reports showed that KLF proteins had different expression patterns during adipogenesis and several KLFs had been proved to either promote or inhibit this process. [15][16][17][18][19][20][21] Krü ppel-like factor 9 (KLF9), previously designated as basic transcription element-binding protein-1 (BTEB1), was initially isolated from a rat liver cDNA library. 22 KLF9 was further identified to be important for development and other physiological functions.…”

mentioning

confidence: 99%

Krüppel-like factor KLF9 regulates PPARγ transactivation at the middle stage of adipogenesis

et al. 2010

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Krü ppel-like factors (KLFs) as a family of zinc-finger transcription factors involve in the regulation of many physiological processes. In these studies, KLF9 was characterized for its role in adipogenesis. The expression of KLF9 was markedly upregulated during the middle stage of 3T3-L1 adipocyte differentiation, and inhibition of KLF9 by RNAi impaired adipogenesis. Using promoter deletion and mutation analysis, we identified two KLF9-binding sites within the 0.6-kb region of the PPARc2 proximal promoter, indicating that KLF9 interacts with the PPARc2 promoter. Furthermore, we found that KLF9 could synergistically activate PPARc2 promoter by directly interacting with C/EBPa. In addition, overexpression of PPARc2 rescued the impairment of adipocyte differentiation induced by KLF9 knockdown, which supports that PPARc2 is a downstream target of KLF9. Collectively, our results indicate KLF9 as a key pro-adipogenic transcription factor through regulation of PPARc2 expression with C/EBPa at the middle stage of adipogenesis.

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Targeted Disruption of the Basic Krüppel-Like Factor Gene (Klf3) Reveals a Role in Adipogenesis

Cited by 172 publications

References 38 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

The mammalian zinc finger transcription factor Krüppel‐like factor 3 (KLF3/BKLF)

Krüppel-like factor KLF9 regulates PPARγ transactivation at the middle stage of adipogenesis

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