SHP Represses Transcriptional Activity via Recruitment of Histone Deacetylases

Gobinet, Jérôme; Carascossa, Sophie; Cavaillès, Vincent; Vignon, Françoise; Nicolas, Jean‐Claude; Jalaguier, Stéphan

doi:10.1021/bi047308d

Cited by 49 publications

(42 citation statements)

References 44 publications

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“…However, recent studies have shown that SHP regulates a number of target genes through heterodimerization with other nuclear receptors, through effects on heterochromatin (14,15,34) and competition mechanisms (35). Although most FXR target genes evidence SHP-mediated repression (13)(14)(15), an interesting feature of the present study is the stimulatory effect of SHP on MMP-9 gene transcription. Indeed, a recent microarray-based analysis of a transgenic mouse constitutively expressing SHP revealed a surprisingly large number of genes that were up-regulated by SHP as well (13).…”

Section: Discussionmentioning

confidence: 53%

Disruption of an SP2/KLF6 Repression Complex by SHP Is Required for Farnesoid X Receptor-induced Endothelial Cell Migration

Das

Fernández-Zapico

Cao

et al. 2006

Journal of Biological Chemistry

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The farnesoid X receptor (FXR) signaling pathway regulates bile acid and cholesterol homeostasis. Here, we demonstrate, using a variety of gain-and loss-of-function approaches, a role of FXR in the process of cell motility, which involves the small heterodimeric partner (SHP)-dependent up-regulation of matrix metalloproteinase-9. We use this observation to reveal a transcriptional regulatory mechanism involving the SP/KLF transcription factors, SP2 and KLF6. Small interference RNA-based silencing studies in combination with promoter, gel shift, and chromatin immunoprecipitation assays indicate that SP2 and KLF6 bind to the matrix metalloproteinase-9 promoter and together function to maintain this gene in a silenced state. However, upon activation of FXR, SHP interacts with SP2 and KLF6, disrupting the SP2/KLF6 repressor complex. Thus, together, these studies identify a mechanism for antagonizing Sp/KLF protein repression function via SHP, with this process regulating endothelial cell motility. Farnesoid X Receptor (FXR)3 is a member of the nuclear receptor superfamily of transcription factors. In response to ligand binding, FXR regulates expression of genes involved in bile acid, cholesterol, and triglyceride metabolism (1-9). FXR heterodimerizes with the 9-cis-retinoic acid receptor ␣, which allows binding to a specific DNA sequence composed of two inverted hexamer repeats separated by one nucleotide (IR-1), thereby regulating target gene transcription (10 -12). An alternate mechanism of regulation occurs through FXR-dependent up-regulation of the atypical nuclear receptor, small heterodimeric partner (SHP). Although SHP lacks a DNA binding domain, it regulates transcription by several putative mechanisms that are not fully understood (13-15).Recent work has delineated a requisite role for Sp/KLF transcription factors for diverse biological functions (16 -19). The Sp/KLF family contains 24 identified members, including SP1-8 and KLF1-16, which bind with varying affinity to GCrich DNA sequences of target gene promoters (20). Interestingly, these proteins may function as transcriptional activators or repressors, although the mechanisms by which specificity of effect is achieved are not well defined.Because bile acids such as chenodeoxycholic acid (CDCA) are the natural ligands for FXR (21-23), prior investigations have largely been pursued in cells with active bile acid signaling, such as hepatocytes, cholangiocytes, and enterocytes (4,24,25). However, more recent work has expanded the scope of this nuclear receptor system into a diversity of cell types and functions, including vascular wall cells (26 -28), thereby suggesting potentially important and heretofore unrecognized actions that may be achieved by the FXR pathway. In this study, we delineate a signaling pathway by which FXR promotes endothelial cell motility through transcriptional activation of matrix metalloproteinase-9 (MMP-9). This pathway requires SHP inhibition of an SP2/KLF6 repressor complex. Thus, whereas SP2 and KLF6 repress MMP-9 promoter acti...

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Section: Discussionmentioning

confidence: 53%

Disruption of an SP2/KLF6 Repression Complex by SHP Is Required for Farnesoid X Receptor-induced Endothelial Cell Migration

Das

Fernández-Zapico

Cao

et al. 2006

Journal of Biological Chemistry

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“…Next, functional interactions of GPS2 and SHP with known corepressor complex components were investigated. Because SHP interacts with HDAC1 and HDAC3 (21,22), whereas GPS2 via N-CoR associates with HDAC3 (16), we investigated interactions with these HDACs in vitro. As expected, SHP interacted with both HDAC1 and HDAC3 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis

Sanyal

Båvner

Haroniti

et al. 2007

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

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Coordinated regulation of bile acid biosynthesis, the predominant pathway for hepatic cholesterol catabolism, is mediated by few key nuclear receptors including the orphan receptors liver receptor homolog 1 (LRH-1), hepatocyte nuclear factor 4␣ (HNF4␣), small heterodimer partner (SHP), and the bile acid receptor FXR (farnesoid X receptor). Activation of FXR initiates a feedback regulatory loop via induction of SHP, which suppresses LRH-1-and HNF4␣-dependent expression of cholesterol 7␣ hydroxylase (CYP7A1) and sterol 12␣ hydroxylase (CYP8B1), the two major pathway enzymes. Here we dissect the transcriptional network governing bile acid biosynthesis in human liver by identifying GPS2, a stoichiometric subunit of a conserved corepressor complex, as a differential coregulator of CYP7A1 and CYP8B1 expression. Direct interactions of GPS2 with SHP, LRH-1, HNF4␣, and FXR indicate alternative coregulator recruitment strategies to cause differential transcriptional outcomes. In addition, species-specific differences in the regulation of bile acid biosynthesis were uncovered by identifying human CYP8B1 as a direct FXR target gene, which has implications for therapeutic approaches in bile acid-related human disorders.cholesterol 7␣ hydroxylase ͉ sterol 12␣ hydroxylase ͉ farnesoid X receptor ͉ small heterodimer partner B ile acids (BAs) are cholesterol derivatives essential for absorption of dietary lipids and fat-soluble vitamins and maintenance of cholesterol BA homeostasis (1, 2). In humans the major BA biosynthetic pathway is initiated by cholesterol 7␣ hydroxylase (CYP7A1) to produce two primary BAs, cholic acid and chenodeoxycholic acid (CDCA). Sterol 12␣ hydroxylase (CYP8B1) catalyzes the synthesis of cholic acid and determines the ratio of cholic acid to CDCA in the bile (1). In addition to emulsification of dietary lipids, cholic acid and CDCA are ligands for farnesoid X receptor (FXR/NR1H4) (3-5). Ligandbound FXR regulates a number of target genes involving BA transport and metabolism (6). BAs also feedback-regulate BA biosynthesis, where activated FXR induces small heterodimer partner (SHP/NR0B2) gene expression, and SHP in turn inhibits liver receptor homolog 1 (LRH-1/NR5A2) or hepatocyte nuclear factor 4␣ (HNF4␣/NR2A1) activities on the BA response elements (BAREs) of CYP7A1 and CYP8B1 promoters (7-10). BAs can also act via FXR-independent pathways that use PKC (11) and JNK signaling (12, 13) to suppress HNF4␣-mediated expression of human CYP8B1 (hCYP8B1) (10,11,14). Although the physiological role of SHP in BA biosynthesis is well documented, mechanistic details of repression by SHP remain unclear. Recent studies indicate that SHP may repress its targets (i) via direct binding and blocking the coactivator interaction interface of its target nuclear receptors (NRs), (ii) by antagonizing CREB binding protein (CBP)/p300-dependent coactivator functions on NRs via recruitment of a coinhibitor protein like EID1, and (iii) by recruiting corepressor complexes that include histone deacetylases (HDAC) 1, 3, and 6, Sin3A...

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“…7B, left). This is somewhat unexpected, because the recruitment of HDAC1 has been implicated in SHP-mediated repression of androgen receptor (AR) and estrogen receptor ␣ transcriptional activity (34). We then investigated the ability of SHP WT and SHP K170N to recruit those repressors to the apoCIII promoter when they interact with SHP using chromatin immunoprecipitation assays.…”

Section: R38hmentioning

confidence: 99%

Novel Polymorphisms of Nuclear Receptor SHP Associated with Functional and Structural Changes

Zhou

Zhang

Macchiarulo

et al. 2010

Journal of Biological Chemistry

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We identified three heterozygous nonsynonymous single nucleotide polymorphisms in the small heterodimer partner (SHP, NROB2) gene in normal subjects and CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)-like patients, including two novel missense mutations (p.R38H, p.K170N) and one of the previously reported polymorphism (p.G171A). Four novel heterozygous mutations were also identified in the intron ( Intron 1265T3 A), 3-untranslated region ( 3-UTR 101C3 G, 3-UTR 186T3 C), and promoter ( Pro -423C3 T) of the SHP gene. The exonic R38H and K170N mutants exhibited impaired nuclear translocation. K170N made SHP more susceptible to ubiquitination mediated degradation and blocked SHP acetylation, which displayed lost repressive activity on its interacting partners ERR␥ and HNF4␣ but not LRH-1. In contrast, G171A increased SHP mRNA and protein expression and maintained normal function. In general, the interaction of SHP mutants with LRH-1 and EID1 was enhanced. K170N also markedly impaired the recruitment of SHP, HNF4␣, HDAC1, and HDAC3 to the apoCIII promoter. Molecular dynamics simulations of SHP showed that G171A stabilized the nuclear receptor boxes, whereas K170N promoted the conformational destabilization of all the structural elements of the receptor. This study suggests that genetic variations in SHP are common among human subjects and the Lys-170 residue plays a key role in controlling SHP ubiquitination and acetylation associated with SHP protein stability and repressive function.

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SHP Represses Transcriptional Activity via Recruitment of Histone Deacetylases

Cited by 49 publications

References 44 publications

Disruption of an SP2/KLF6 Repression Complex by SHP Is Required for Farnesoid X Receptor-induced Endothelial Cell Migration

Disruption of an SP2/KLF6 Repression Complex by SHP Is Required for Farnesoid X Receptor-induced Endothelial Cell Migration

Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis

Novel Polymorphisms of Nuclear Receptor SHP Associated with Functional and Structural Changes

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