Disease relevance of NR0B2

• Several recently described SHP mutations associated with moderate obesity in humans block the inhibition of ERRgamma activity [1].
• Finally, we found that a four-nucleotide deletion (-195CT-GAdel) in the hSHP promoter, which is reported to be associated with altered body weight and insulin secretion in human, coincides with the SRE1 [2].
• In transient transfection assays, SHP inhibited 4-OHT-stimulated reporter gene activity from an estrogen response element (ERE) in ER-positive RL95-2 but not in HEC-1A human endometrial carcinoma cells transfected with ER(alpha) or ERbeta [3].
• We examined the relation between genetic variation in SHP and birth weight, adiposity, and insulin levels in three independent populations [4].
• In this paper, we summarize recent studies on the expression and regulation of SHP-1 protein and its pathological function in the development of lymphoma, leukemia and other cancers [5].

High impact information on NR0B2

• Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes [6].
• These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese [6].
• FcalphaRI-mediated apoptosis signals were blocked by treatment with the pan-caspase inhibitor zVAD-fmk, involved proteolysis of procaspase-3, and correlated negatively with SHP-1 concentration [7].
• Our results suggest that SHP mediates recruitment of mSin3A-Swi/Snf to the CYP7A1 promoter, resulting in chromatin remodeling and gene repression, which may also be a mechanism for the repression by SHP of genes activated by many nuclear receptors [8].
• Bile acid-induced recruitment of mSin3A/Brm, chromatin remodeling, and concomitant repression of endogenous CYP7A1 expression were impaired when SHP expression was inhibited by SHP small interfering RNA [8].

Chemical compound and disease context of NR0B2

• SHP-1 has been proposed as a candidate tumor suppressor gene in lymphoma, leukemia and other cancers, as it functions as an antagonist to the growth-promoting and oncogenic potentials of tyrosine kinase [5].
• The aim of this prospective, follow-up study was to examine the influence of overt hypothyroidism (OHP) and subclinical (SHP), before and during thyroxine (T4) treatment, on lipoprotein(a) [Lp(a)], other lipoproteins, and apolipoproteins [9].
• Treatment of calcitriol has a beneficial effect on renal anemia in ESRD patients with SHP [10].

Biological context of NR0B2

• Small heterodimer partner (SHP, NR0B2) is an atypical orphan nuclear receptor that inhibits transcriptional activation by several other nuclear receptors [11].
• Overall, these results identify a new autoregulatory loop controlling SHP gene expression and significantly extend the potential functional roles of the three ERRs [1].
• In transfection assays, SHP inhibits the expression of an artificial reporter driven by an LXR-response element and represses the transcriptional activation by LXR of the human ATP-binding cassette transporter 1 (ABCA1) promoter [12].
• The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c [13].
• While the mechanistic basis of these interactions has remained enigmatic, SHP has been suggested to inhibit nuclear receptor activation by at least three alternatives; inhibition of DNA binding via dimerization, direct antagonism of coactivator function via competition, and possibly transrepression via recruitment of putative corepressors [14].

Anatomical context of NR0B2

• SHP and ERRgamma mRNAs are coexpressed in several tissues, including pancreas, kidney, and heart, confirming the potential relevance of this transactivation [1].
• Treatment of Caco-2 cells with bile acids, which activate farnesoid X receptor and subsequently induce SHP, leads to the repression of the human ABCG1 gene, an established LXR target gene [12].
• In mouse AML-12 hepatocytes, chenodeoxycholic acid (CDCA) or androsterone induced SHP expression with a similar kinetic pattern [15].
• Chenodeoxycholate activated endogenous FXR in gallbladder epithelial cells, as ascertained by electromobility shift assay and upregulation of the FXR target gene, small heterodimer partner [16].
• The orphan nuclear receptor small heterodimer partner as a novel coregulator of nuclear factor-kappa b in oxidized low density lipoprotein-treated macrophage cell line RAW 264.7 [17].

Associations of NR0B2 with chemical compounds

• As with other SHP targets, this interaction is dependent on the AF-2 coactivator-binding site of ERRgamma and the previously described N-terminal receptor interaction domain of SHP [1].
• Overexpression of the farnesoid X receptor-inducible transcriptional repressor small heterodimer partner also suppressed the GR/dexamethasone-activation of the hNTCP promoter [18].
• The FXR antagonist guggulsterone blocked the induction of SHP by androsterone in AML-12 cells [15].
• We now show that SHP binds directly to estrogen receptors via LXXLL-related motifs [14].
• Although no conventional receptor function has yet been identified, SHP has been proposed to act as a negative regulator of nuclear receptor signaling pathways, because it interacts with and inhibits DNA binding and transcriptional activity of various nonsteroid receptors, including thyroid hormone and retinoid receptors [19].

Physical interactions of NR0B2

• The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity [12].
• We present the crystal structure at a resolution of 1.9 A of the ligand-binding domain of hLRH-1 in complex with the NR box 1 motif of human SHP, which we find contacts the AF-2 region of hLRH-1 using selective structural motifs [20].
• In contrast, SHP interacts with ERbeta independent of ligand and reduces its ability to activate transcription by only 50% [21].
• SHP specifically targets the ligand-regulated activation domain AF-2 and competes for binding of coactivators such as TIF2 [19].
• Interestingly, yeast two-hybrid and glutathione-S-transferase pull-down assays demonstrated that wild-type and SHP Delta128-139 have similar abilities to interact with estrogen receptor-related receptor-gamma, hepatocyte nuclear factor 4alpha, and constitutive androstane receptor [22].

Regulatory relationships of NR0B2

• We have found that the SHP promoter is also activated by the estrogen receptor-related receptor gamma (ERRgamma) but not the related ERRalpha and ERRbeta isoforms [1].
• A negative nuclear receptor, small heterodimer partner markedly inhibited transactivation of CYP8B1 by HNF4alpha [23].
• We demonstrated that SHP inhibited up to 97% of AR-induced activity [24].
• Instead, SHP may either inhibit recruitment of other coactivators by GRIP1 or actively recruit corepressors directly to the CAR/RXR/PBRU complex [25].
• Thus, SHP appears to be an important modulatory component to regulate the transcriptional activities of NF kappa B in oxLDL-treated, resting macrophage cells [17].

Other interactions of NR0B2

• Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP [20].
• The human Na+-taurocholate cotransporting polypeptide gene is activated by glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and suppressed by bile acids via a small heterodimer partner-dependent mechanism [18].
• However, small heterodimer partner (SHP) and bile salt export pump were normally expressed [26].
• Bile acids repress human CYP8B1 transcription by reducing the transactivation activity of HNF4alpha through interaction of HNF4alpha with SHP and reduction of HNF4alpha expression in the liver [23].
• Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner) [21].

Analytical, diagnostic and therapeutic context of NR0B2

• DNase I footprinting, gel shift assays, and chromatin immunoprecipitation assays demonstrated that SREBP-1 binds directly to the hSHP promoter [2].
• Mammalian two-hybrid assay confirmed that HNF4alpha interacted with small heterodimer partner [23].
• Electrophoretic mobility shift assays using oligonucleotides derived from the SHP promoter reveal that c-Jun exhibit TPA-induced DNA binding, providing a mechanism for the transcriptional activation of SHP gene expression [27].
• Using combined SSCP and heteroduplex analysis, we analyzed the entire coding region of SHP for variants in a cohort of 750 Danish men with early-onset obesity and genotyped a cohort of 795 nonobese control subjects using PCR-RFLP [28].
• LSTRA cells were shown to express SHP protein by immunoprecipitation, thus demonstrating a potential physiological interaction [29].

References