Nuclear Receptor SHP, a Death Receptor That Targets Mitochondria, Induces Apoptosis and Inhibits Tumor Growth

Zhang, Yuxia; Soto, Jamie; Park, Kyungtae; Gunda, Viswanath; Kuwada, Scott K.; Abel, E. Dale; Wang, Li

doi:10.1128/mcb.01076-09

Cited by 90 publications

(144 citation statements)

References 46 publications

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“…For luciferase reporter assay, YY1 promoter reporter was used to determine SHP repression of ERR␥ transactivation using HeLa cells (11). SHP promoter was used to determine SHP repression of LRH-1 transactivation (8). ApoCIII and apoB promoters (21) from Dr. Frances Sladek were used to determine SHP repression of HNF4a transactivation.…”

Section: Methodsmentioning

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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Section: Methodsmentioning

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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“…SHP has been shown to be involved in BA synthesis, lipid and cholesterol metabolism, glucose homeostasis, apoptosis, and cell invasion 36, 37, 38, 39, 40, 41, 42, 43. SHP has also been identified as a mediating factor in the metabolic circadian clock 44, 45, 46, 47, 48.…”

Section: Nuclear Receptor Crosstalk With Noncoding Rnasmentioning

confidence: 99%

Nuclear receptors and liver disease: Summary of the 2017 basic research symposium

Tran

Liu

Huang

et al. 2018

Hepatology Communications

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The nuclear receptor superfamily contains important transcriptional regulators that play pleiotropic roles in cell differentiation, development, proliferation, and metabolic processes to govern liver physiology and pathology. Many nuclear receptors are ligand‐activated transcription factors that regulate the expression of their target genes by modulating transcriptional activities and epigenetic changes. Additionally, the protein complex associated with nuclear receptors consists of a multitude of coregulators, corepressors, and noncoding RNAs. Therefore, acquiring new information on nuclear receptors may provide invaluable insight into novel therapies and shed light on new interventions to reduce the burden and incidence of liver diseases. (Hepatology Communications 2018;2:765‐777)

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“…It appears to interfere with coregulator interaction in a similar manner to DAX1, but it can also inhibit NR binding to DNA (Zhang et al 2010). No human tissue expression data for SHP are available, but in vitro work suggests that SHP levels are higher in non-malignant prostate cell lines, and absent or low in prostate cancer cell lines, supporting a role in regulating proliferation and apoptosis (Dawson et al 2007, Xiao et al 2012.…”

Section: Short Heterodimeric Partner (Shp or Nr0b2)mentioning

confidence: 99%

WOMEN IN CANCER THEMATIC REVIEW: New roles for nuclear receptors in prostate cancer

Leach

Powell

Bevan

2016

Endocrine-Related Cancer

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Prostate cancer has, for decades, been treated by inhibiting androgen signalling. This is effective in the majority of patients, but inevitably resistance develops and patients progress to life-threatening metastatic disease -hence the quest for new effective therapies for 'castrate-resistant' prostate cancer (CRPC). Studies into what pathways can drive tumour recurrence under these conditions has identified several other nuclear receptor signalling pathways as potential drivers or modulators of CRPC. The nuclear receptors constitute a large (48 members) superfamily of transcription factors sharing a common modular functional structure. Many of them are activated by the binding of small lipophilic molecules, making them potentially druggable. Even those for which no ligand exists or has yet been identified may be tractable to activity modulation by small molecules. Moreover, genomic studies have shown that in models of CRPC, other nuclear receptors can potentially drive similar transcriptional responses to the androgen receptor, while analysis of expression and sequencing databases shows disproportionately high mutation and copy number variation rates among the superfamily. Hence, the nuclear receptor superfamily is of intense interest in the drive to understand how prostate cancer recurs and how we may best treat such recurrent disease. This review aims to provide a snapshot of the current knowledge of the roles of different nuclear receptors in prostate cancer -a rapidly evolving field of research.

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Nuclear Receptor SHP, a Death Receptor That Targets Mitochondria, Induces Apoptosis and Inhibits Tumor Growth

Cited by 90 publications

References 46 publications

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

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

Nuclear receptors and liver disease: Summary of the 2017 basic research symposium

WOMEN IN CANCER THEMATIC REVIEW: New roles for nuclear receptors in prostate cancer

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