Steroid receptor coactivators: servants and masters for control of systems metabolism

Stashi, Erin; York, Brian; O’Malley, Bert W.

doi:10.1016/j.tem.2014.05.004

Cited by 96 publications

(88 citation statements)

References 85 publications

(138 reference statements)

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“…Consistent with the classical definition of a transcriptional coactivator as an amplifier and stabilizer of coregulator complexes (2,9,10,14,15), loss of SRC-2 strikingly reduced the recruitment of metabolically responsive proteins to both Gck and G6pc promoters (Fig. 3C).…”

Section: Src-2 Recruits Distinct Coregulator Complexes To Regulate Gcsupporting

confidence: 83%

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SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis

Fleet

Zhang

Lin

et al. 2015

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

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Despite extensive efforts to understand the monogenic contributions to perturbed glucose homeostasis, the complexity of genetic events that fractionally contribute to the spectrum of this pathology remain poorly understood. Proper maintenance of glucose homeostasis is the central feature of a constellation of comorbidities that define the metabolic syndrome. The ability of the liver to balance carbohydrate uptake and release during the feeding-to-fasting transition is essential to the regulation of peripheral glucose availability. The liver coordinates the expression of gene programs that control glucose absorption, storage, and secretion. Herein, we demonstrate that Steroid Receptor Coactivator 2 (SRC-2) orchestrates a hierarchy of nutritionally responsive transcriptional complexes to precisely modulate plasma glucose availability. Using DNA pull-down technology coupled with mass spectrometry, we have identified SRC-2 as an indispensable integrator of transcriptional complexes that control the rate-limiting steps of hepatic glucose release and accretion. Collectively, these findings position SRC-2 as a major regulator of polygenic inputs to metabolic gene regulation and perhaps identify a previously unappreciated model that helps to explain the clinical spectrum of glucose dysregulation.

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Section: Src-2 Recruits Distinct Coregulator Complexes To Regulate Gcsupporting

confidence: 83%

“…Published studies from our laboratory, as well as others, have established Steroid Receptor Coactivator 2 (SRC-2) as a powerful pleiotropic metabolic modulator (2). In adipose tissue, SRC-2 is a key regulator of lipolytic (white fat) and thermogenic gene programs (brown fat) (3).…”

mentioning

confidence: 99%

SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis

Fleet

Zhang

Lin

et al. 2015

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

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“…Defective growth hormone signaling and estrogen production resulting in short stature and reduced female reproductive function were reported in Src3 −/− mice (Wang et al 2000, Xu et al 2000. These findings established that p160 co-regulators possess certain functional specificity in vivo (recently reviewed in , Stashi et al 2014b. Data obtained from these animal models pertinent to TH signaling and metabolic regulation is discussed below in the sections 'Roles of co-regulators in peripheral tissues' and 'Roles of co-regulators in the funtion of HPT axis and RTH'.…”

Section: Animal Models Of Co-regulator Functionmentioning

confidence: 77%

“…Mouse knockout models identified SRC co-activators as essential regulators of energy homeostasis as they modulate expression of multiple enzymes in different metabolic pathways and tissues , Stashi et al 2014b.…”

Section: Src1 Knockout Micementioning

confidence: 99%

Role of co-regulators in metabolic and transcriptional actions of thyroid hormone

Astapova¹

2016

Journal of Molecular Endocrinology

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Thyroid hormone (TH) controls a wide range of physiological processes through TH receptor (TR) isoforms. Classically, TRs are proposed to function as tri-iodothyronine (T 3 )-dependent transcription factors: on positively regulated target genes, unliganded TRs mediate transcriptional repression through recruitment of co-repressor complexes, while T 3 binding leads to dismissal of co-repressors and recruitment of co-activators to activate transcription. Co-repressors and co-activators were proposed to play opposite roles in the regulation of negative T 3 target genes and hypothalamic-pituitary-thyroid axis, but exact mechanisms of the negative regulation by TH have remained elusive. Important insights into the roles of co-repressors and co-activators in different physiological processes have been obtained using animal models with disrupted co-regulator function. At the same time, recent studies interrogating genome-wide TR binding have generated compelling new data regarding effects of T 3 , local chromatin structure, and specific response element configuration on TR recruitment and function leading to the proposal of new models of transcriptional regulation by TRs. This review discusses data obtained in various mouse models with manipulated function of nuclear receptor co-repressor (NCoR or NCOR1) and silencing mediator of retinoic acid receptor and thyroid hormone receptor (SMRT or NCOR2), and family of steroid receptor co-activators (SRCs also known as NCOAs) in the context of TH action, as well as insights into the function of co-regulators that may emerge from the genome-wide TR recruitment analysis.

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“…Similarly, expression of the gene encoding the estrogen receptor-α (ER-α) in medial preoptic neurons is essential for the performance of maternal behaviors (6). For behavior and other physiological functions, early papers reported that the first molecular event that leads to hormone-facilitated transcription, depends on the binding of ER-α to an estrogen response element (7), followed by the actions of coactivator proteins (8,9). Recent molecular endocrine papers are more ambiguous on the exact order of events (see Some Outstanding Questions, below) (10)(11)(12).…”

mentioning

confidence: 99%