Transcription of Human Resistin Gene Involves an Interaction of Sp1 with Peroxisome Proliferator-Activating Receptor Gamma (PPARγ)

Abstract

BackgroundResistin is a cysteine rich protein, mainly expressed and secreted by circulating human mononuclear cells. While several factors responsible for transcription of mouse resistin gene have been identified, not much is known about the factors responsible for the differential expression of human resistin.Methodology/Principal FindingWe show that the minimal promoter of human resistin lies within ∼80 bp sequence upstream of the transcriptional start site (−240) whereas binding sites for cRel, CCAAT enhancer binding protein α (C/EBP-α), activating transcription factor 2 (ATF-2) and activator protein 1 (AP-1) transcription factors, important for induced expression, are present within sequences up to −619. Specificity Protein 1(Sp1) binding site (−276 to −295) is also present and an interaction of Sp1 with peroxisome proliferator activating receptor gamma (PPARγ) is necessary for constitutive expression in U937 cells. Indeed co-immunoprecipitation assay demonstrated a direct physical interaction of Sp1 with PPARγ in whole cell extracts of U937 cells. Phorbol myristate acetate (PMA) upregulated the expression of resistin mRNA in U937 cells by increasing the recruitment of Sp1, ATF-2 and PPARγ on the resistin gene promoter. Furthermore, PMA stimulation of U937 cells resulted in the disruption of Sp1 and PPARγ interaction. Chromatin immunoprecipitation (ChIP) assay confirmed the recruitment of transcription factors phospho ATF-2, Sp1, Sp3, PPARγ, chromatin modifier histone deacetylase 1 (HDAC1) and the acetylated form of histone H3 but not cRel, C/EBP-α and phospho c-Jun during resistin gene transcription.ConclusionOur findings suggest a complex interplay of Sp1 and PPARγ along with other transcription factors that drives the expression of resistin in human monocytic U937 cells.

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

“…One study showed that PPARγ mediated the anti-proliferative effect of cladosporol A, a secondary metabolite from cladosporium tenuissimum, through interacting with Sp1, followed by stimulating expression of cyclin-dependent kinase p21 (Waf1/Cip 1) in colorectal cancer cells [55]. Also, the interaction between Sp1 and PPARγ along or with other transcription factors, such as CCAAT enhancer binding protein alpha (C/EBP-alpha), activating transcription factor 2 (ATF-2) and activator protein 1 (AP-1), could trigger the expression of resistin gene in human monocytic cells [56]. Moreover, one report demonstrated that reduction of Sp1 mediated the anti-tumor effect of emodin and other extracts of polygonum cuspidatum root in oral cancer cells via inhibiting survivin, one of downstream targets of Sp1 [57].…”

Epigenome-wide association study suggests that SNPs in the promoter region of RETN influence plasma resistin level via effects on DNA methylation at neighbouring sites

“…The region including DNAm sites cg02346997, cg21777015 and cg22322184 as well as SNPs rs34861192 and rs3219175 overlaps with a region characterised by DNase I hypersensitivity [34] and a high level of histone modification (H3K4m1/2/3, H3K27ac), which are indicators of a potential regulatory region. Binding sites for the transcription factors c-Rel, CCAAT/enhancer binding protein α (C/EBPα), activating transcription factor 2 (ATF2) and activator protein (AP1) have been identified within a 619 bp region upstream of the translation start site of RETN [35]. The DNAm site cg02346997 is located within this region.…”

“…The DNAm site cg02346997 is located within this region. The transcription factor Sp1 was also found to play an important role in RETN transcription, with a predicted Sp1 binding site also being located near cg02346997 [35]. It is thus possible that DNAm at cg02346997 regulates RETN transcription by preventing the binding of these transcription factors to DNA.…”

In vitro interaction between resistin and peroxisome proliferator-activated receptor γ in porcine ovarian follicles

“…Furthermore, several studies have indicated the involvement of PPARg in the regulation of resistin gene transcription (Hartman et al 2002;Song et al 2002;Zhou et al 2006). PPARg regulates the C/EBP-a binding site, which is necessary and sufficient for transcription from the resistin gene promoter (Singh et al 2010). However, the precise molecular mechanism by which PPARg downregulates ovarian resistin expression remains unclear.…”

“…For example, overexpression of PPARg reduces resistin expression in 3T3-L1 adipocytes (Song et al 2002) and the PPARginduced reduction in resistin expression reached 80% after exposure to rosiglitazone, a selective PPARg agonist (Patel et al 2003). Moreover, expression of PPARg mRNA is involved in the regulation of resistin gene transcription (Singh et al 2010). Both resistin and PPARg have been suggested to have important roles in ovarian function; thus, we hypothesised that resistin and PPARg expression interact in the ovary.…”