Inhibition of Estrogen Receptor Action by the Orphan Receptor SHP (Short Heterodimer Partner)

Seol, W.

doi:10.1210/me.12.10.1551

Cited by 59 publications

(38 citation statements)

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“…Notable examples included the expression of SHP in SCLC and also PPAR γ in NSCLC. SHP is an atypical nuclear receptor that is known for its role in enterohepatic lipid metabolism in which it interacts and negatively regulates the activity of other transcription factors, including many NRs (44, 45). The expression of a potent transcriptional repressor like SHP in a cell type in which it is not normally expressed may be expected to have significant pathological effects on cell function, and this finding provides a rationale for further mechanistic studies.…”

Section: Discussionmentioning

confidence: 99%

Research Resource: Diagnostic and Therapeutic Potential of Nuclear Receptor Expression in Lung Cancer

Jeong

Xie

Lee

et al. 2012

Molecular Endocrinology

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Lung cancer is the leading cause of cancer-related death. Despite a number of studies that have provided prognostic biomarkers for lung cancer, a paucity of reliable markers and therapeutic targets exist to diagnose and treat this aggressive disease. In this study we investigated the potential of nuclear receptors (NRs), many of which are well-established drug targets, as therapeutic markers in lung cancer. Using quantitative real-time PCR, we analyzed the expression of the 48 members of the NR superfamily in a human panel of 55 normal and lung cancer cell lines. Unsupervised cluster analysis of the NR expression profile segregated normal from tumor cell lines and grouped lung cancers according to type (i.e. small vs. non-small cell lung cancers). Moreover, we found that the NR signature was 79% accurate in diagnosing lung cancer incidence in smokers (n = 129). Finally, the evaluation of a subset of NRs (androgen receptor, estrogen receptor, vitamin D receptor, and peroxisome proliferator-activated receptor-γ) demonstrated the therapeutic potential of using NR expression to predict ligand-dependent growth responses in individual lung cancer cells. Preclinical evaluation of one of these receptors (peroxisome proliferator activated receptor-γ) in mouse xenografts confirmed that ligand-dependent inhibitory growth responses in lung cancer can be predicted based on a tumor's receptor expression status. Taken together, this study establishes NRs as theragnostic markers for predicting lung cancer incidence and further strengthens their potential as therapeutic targets for individualized treatment.

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Section: Discussionmentioning

confidence: 99%

Research Resource: Diagnostic and Therapeutic Potential of Nuclear Receptor Expression in Lung Cancer

Jeong

Xie

Lee

et al. 2012

Molecular Endocrinology

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“…Approximately 70% of breast cancers are ER positive, and adjuvant anti-estrogen therapy plays an important role in treatment. Previous studies have reported links between SHP and estrogen signaling, such as the direct interaction of SHP with ERs [151], inhibition ER-mediated transcriptional activation by SHP [41] and ER-dependent transcriptional regulation of SHP in a feedback loop [23]. In postmenopausal women with breast cancer the source of estrogen driving tumor growth is produced locally within the tumor and in the surrounding adipose tissue and is due to activity of aromatase CYP19 [152].…”

Section: Shp In Cancermentioning

confidence: 99%

Role of nuclear receptor SHP in metabolism and cancer

Zhang

Hagedorn

Wang

2011

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

220

205

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Small heterodimer partner (SHP, NR0B2) is a unique member of the nuclear receptor (NR) superfamily that contains the dimerization and ligand-binding domain found in other family members, but lacks the conserved DNA binding domain. The ability of SHP to bind directly to multiple NRs is crucial for its physiological function as a transcriptional inhibitor of gene expression. A wide variety of interacting partners for SHP have been identified, indicating the potential for SHP to regulate an array of genes in different biological pathways. In this review, we summarize studies concerning the structure and target genes of SHP and discuss recent progress in understanding the function of SHP in bile acid, cholesterol, triglyceride, glucose, and drug metabolism. In addition, we review the regulatory role of SHP in microRNA (miRNA) regulation, liver fibrosis and cancer progression. The fact that SHP controls a complex set of genes in multiple metabolic pathways suggests the intriguing possibility of developing new therapeutics for metabolic diseases, including fatty liver, dyslipidemia and obesity, by regulating SHP with small molecules. To achieve this goal, more progress regarding SHP ligands and protein structure will be required. Besides its metabolic regulatory function, studies by us and other groups provide strong evidence that SHP plays a critical role in the development of cancer, particularly liver and breast cancer. An increased understanding of the fundamental mechanisms by which SHP regulates the development of cancers will be critical in applying knowledge of SHP in diagnostic, therapeutic or preventive strategies for specific cancers.

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“…Other ER co-activators include RIP140 (Cavailles et al, 1995). Co-repressors of ER have also been described, including SHP (Seol et al, 1998; Johansson et al, 1999), NcoR (Lavinsky et al, 1998), and SMRT (Misiti et al, 1998). …”

Section: The Classical Er Signaling Pathwaymentioning

confidence: 99%

Estrogenic Regulation of the GnRH Neuron

Radovick

Levine

Wolfe³

2012

Front. Endocrin.

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Reproductive function is regulated by the secretion of luteinizing hormone (LH) and follicle-stimulating hormone from the pituitary and the steroid hormones from the gonads. The dynamic changes in the levels of the reproductive hormones regulate secondary sex characteristics, gametogenesis, cellular function, and behavior. Hypothalamic GnRH neurons, with cell bodies located in the basal hypothalamus, represent the final common pathway for neuronally derived signals to the pituitary. As such, they serve as integrators of a dizzying array of signals including sensory inputs mediating information about circadian, seasonal, behavioral, pheromonal, and emotional cues. Additionally, information about peripheral physiological function may also be included in the integrative signal to the GnRH neuron. These signals may communicate information about metabolic status, disease, or infection. Gonadal steroid hormones arguably exert the most important effects on GnRH neuronal function. In both males and females, the gonadal steroid hormones exert negative feedback regulation on axis activity at both the level of the pituitary and the hypothalamus. These negative feedback loops regulate homeostasis of steroid hormone levels. In females, a cyclic reversal of estrogen feedback produces a positive feedback loop at both the hypothalamic and pituitary levels. Central positive feedback results in a dramatic increase in GnRH secretion (Moenter et al., 1992; Xia et al., 1992; Clarke, 1993; Sisk et al., 2001). This is coupled with an increase in pituitary sensitivity to GnRH (Savoy-Moore et al., 1980; Turzillo et al., 1995), which produces the massive surge in secretion of LH that triggers ovulation. While feedback regulation of the axis in males is in part mediated by estrogen receptors (ER), there is not a clear consensus as to the relative role of ER versus AR signaling in males (Lindzey et al., 1998; Wersinger et al., 1999). Therefore, this review will focus on estrogenic signaling in the female.

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Inhibition of Estrogen Receptor Action by the Orphan Receptor SHP (Short Heterodimer Partner)

Cited by 59 publications

References 0 publications

Research Resource: Diagnostic and Therapeutic Potential of Nuclear Receptor Expression in Lung Cancer

Research Resource: Diagnostic and Therapeutic Potential of Nuclear Receptor Expression in Lung Cancer

Role of nuclear receptor SHP in metabolism and cancer

Estrogenic Regulation of the GnRH Neuron

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