Gan, L. et al. FoxO-dependent and -independent mechanisms mediate SIRT1 effects on IGFBP-1 gene expression. Biochem. Biophys. Res. Commun. 337, 1092-1096

Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montreal, Que., Canada H4H 1R3.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 01/2006; 337(4):1092-6. DOI: 10.1016/j.bbrc.2005.09.169
Source: PubMed


Sirtuin 1 (SirT1), an NAD-dependent deacetylase that is important for promoting longevity during caloric restriction, can deacetylate and enhance the function of forkhead box transcription factors, O subfamily (FoxO). We examined the effect of SirT1 on the regulation of insulin-like growth factor-binding protein 1 (IGFBP-1), a known target of FoxO proteins that is increased in fasting. Co-transfection with a SirT1 expression vector dose-dependently stimulated IGFBP-1 promoter activity and a heterologous reporter gene construct containing three FoxO-binding sites linked to a minimal promoter. This effect is mimicked by 20muM resveratrol, a potent SirT1 activator, and immunoprecipitation and Western blotting confirm that SirT1 and FoxO1 interact in cells. Interestingly, mutation of FoxO-binding sites in the IGFBP-1 promoter reduces, but does not completely disrupt, the stimulatory effect of SirT1 on promoter activity. We found that overexpression of SirT1 is accompanied by enhanced mitogen-activated protein kinase (MAPK) activation. Treatment of SirT1-cotransfected cells with PD98059, which inhibits MAPK activation, decreased IGFBP-1 promoter activity by approximately 50%, in a FoxO-binding site-independent manner, and disrupts the residual effect of SirT1. These results indicate that SirT1 stimulates IGFBP-1 promoter activity through FoxO-dependent and -independent mechanisms, and provides the first evidence that activation of MAPK contributes to effects of SirT1 on gene expression.

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    • "FoxO1-mediated inhibition of GHR expression in the liver attenuates GH-mediated synthesis and secretion of hepatic IGF-1, the main source of IGF-1 in the systemic circulation 10. Furthermore, FoxO1 induces hepatic expression of circulating IGFBP-1, thereby reducing the bioavailability of free IGF-1 10,51,52. Reduced levels of IGF-1 attenuate both general growth and SG growth and lipid synthesis 13–17. "
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    ABSTRACT: Acne in adolescents of developed countries is an epidemic skin disease and has currently been linked to the Western diet (WD). It is the intention of this viewpoint to discuss the possible impact of WD-mediated nutrient signalling in the pathogenesis of acne. High glycaemic load and dairy protein consumption both increase insulin/insulin-like growth factor-1 (IGF-1) signalling (IIS) that is superimposed on elevated IGF-1 signalling of puberty. The cell's nutritional status is primarily sensed by the forkhead box transcription factor O1 (FoxO1) and the serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1). Increased IIS extrudes FoxO1 into the cytoplasm, whereas nuclear FoxO1 suppresses hepatic IGF-1 synthesis and thus impairs somatic growth. FoxO1 attenuates androgen signalling, interacts with regulatory proteins important for sebaceous lipogenesis, regulates the activity of innate and adaptive immunity, antagonizes oxidative stress and most importantly functions as a rheostat of mTORC1, the master regulator of cell growth, proliferation and metabolic homoeostasis. Thus, FoxO1 links nutrient availability to mTORC1-driven processes: increased protein and lipid synthesis, cell proliferation, cell differentiation including hyperproliferation of acroinfundibular keratinocytes, sebaceous gland hyperplasia, increased sebaceous lipogenesis, insulin resistance and increased body mass index. Enhanced androgen, TNF-α and IGF-1 signalling due to genetic polymorphisms promoting the risk of acne all converge in mTORC1 activation, which is further enhanced by nutrient signalling of WD. Deeper insights into the molecular interplay of FoxO1/mTORC1-mediated nutrient signalling are thus of critical importance to understand the impact of WD on the promotion of epidemic acne and more serious mTORC1-driven diseases of civilization.
    Experimental Dermatology 05/2013; 22(5):311-5. DOI:10.1111/exd.12142 · 3.76 Impact Factor
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    • ". Using an inducible FoxO3 consisting of a fusion between constitutively active FoxO3a and the ligand-binding domain of the estrogen receptor, SIRT1 increased expression of FoxO targets p27 and GADD45 but appeared to diminish expression of pro-apoptotic BIM [16]. In addition, we and others demonstrated that SIRT1 stimulates expression of MnSOD, IGFBP-1, and GADD45 [5] [21] [22]. Taken together, these findings suggest that gene-specific contexts could determine the effects of FoxO acetylation/ deacetylation on FoxO-induced gene expression. "
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    ABSTRACT: The forkhead box O transcription factors convert a variety of external stimuli, including growth factors, nutrients, and oxidative stress, into diverse biological responses through modulation of specific gene expression. Forkhead box O regulation is principally achieved by two distinct mechanisms: post-translational modifications and protein-protein interactions. Among several modifications of forkhead box O factors, we focus on reversible acetylation, describing past research and current advances. In the latter part of this review, we also provide an overview of forkhead box O-binding partners that control the transcriptional activity of forkhead box O factors. These two layers of regulation mostly overlap and thereby enable a more precise fine-tuning of forkhead box O functions involved in metabolism, longevity, and tumor suppression. This article is part of a Special Issue entitled: PI3K-AKT-FoxO axis in cancer and aging.
    Biochimica et Biophysica Acta 03/2011; 1813(11):1954-60. DOI:10.1016/j.bbamcr.2011.03.001 · 4.66 Impact Factor
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    • "The induction of BCL6 accounts for part of the apoptotic mechanism mediated by AFXα. FOXO dependent expression of IGFBP-1 [17], FasL [18], [19] and Bim [20]–[23] have also been shown to promote apoptosis. Direct FOXO binding activity has been demonstrated in the FasL promoter (GTAAATAAATA) and the Bim promoter (GTAAACAC). "
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    ABSTRACT: Loss-of-function in the apoptosis-inducing genes is known to facilitate tumorigenesis. AFX (FOXO4), a member of forkhead transcription factors functions as a tumor suppressor and has 2 isoforms, AFXalpha (505 a.a.) and AFXzeta (450 a.a.). In human cancer cells, we identified an N-terminally deleted form of AFXalpha (alpha198-505), translated from a downstream start and 2 short N-terminal AFX proteins (90, and 101 a.a.) produced by aberrant splicing. We investigated the expression and role of these AFX variants. Cell transduction study revealed that short N-terminal AFX proteins were not stable. Though alpha(198-505) protein expression was detected in the cytoplasm and nucleus, alpha(198-505) expressing cells did not show a nucleocytoplasmic shuttling mediated by PI3 kinase signaling. Whereas, we observed this shuttling in cells expressing either AFXalpha or AFXzeta protein. AFXzeta and alpha(198-505) lost the ability to transactivate BCL6 or suppress cyclin D2 gene expression. These variants did not induce cancer cell death whereas AFXalpha resulted in apoptosis. We found that AFXzeta and alpha(198-505) suppress the AFXalpha stimulation of BCL6 promoter in a dose dependent manner, indicating dominant negative activity. These variants also inhibited AFXalpha induction of apoptosis. Loss of function by aberrant splicing and the dominant negative activity of AFX variants may provide a mechanism for enhanced survival of neoplastic cells.
    PLoS ONE 07/2008; 3(7):e2743. DOI:10.1371/journal.pone.0002743 · 3.23 Impact Factor
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