Glucocorticoid receptor physiology

Heitzer, Marjet D.; Wolf, Irene M.; Sánchez, Edwin R.; Witchel, Selma F.; DeFranco, Donald B.

doi:10.1007/s11154-007-9059-8

Cited by 202 publications

(169 citation statements)

References 92 publications

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“…GC responses are mediated primarily by the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily of transcription factors (1,14), through the actions of two separate but interrelated mechanisms. In classical or genomic signaling, binding of ligand results in GR translocation to the nucleus, where it can either activate or repress the transcription of target genes (15). In contrast, rapid or nonclassical signaling involves a plasma membrane-associated GR that is capable of activating kinases, such as mitogen-activated protein kinase (MAPK).…”

mentioning

confidence: 99%

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Peffer

Chandran

Luthra

et al. 2014

Molecular and Cellular Biology

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While glucocorticoids (GCs) are used clinically to treat many conditions, their neonatal and prenatal usage is increasingly controversial due to reports of delayed adverse outcomes, especially their effects on brain development. Such alterations may reflect the impact of GCs on neural progenitor/stem cell (NPSC) function. We previously demonstrated that the lipid raft protein caveolin-1 (Cav-1) was required for rapid GC signaling in embryonic mouse NPSCs operating through plasma membranebound glucocorticoid receptors (GRs). We show here that genomic GR signaling in NPSCs requires Cav-1. Loss of Cav-1 impacts the transcriptional response of many GR target genes (e.g., the serum-and glucocorticoid-regulated kinase 1 gene) that are likely to mediate the antiproliferative effects of GCs. Microarray analysis of wild-type C57 or Cav-1-deficient NPSCs identified approximately 100 genes that are differentially regulated by GC treatment. These changes in hormone responsiveness in Cav-1 knockout NPSCs are associated with the loss of GC-regulated phosphorylation of GR at serine 211 but not at serine 226. Chromatin recruitment of total GR to regulatory regions of target genes such as Fkbp-5, RhoJ, and Sgk-1, as well as p211-GR recruitment to Sgk-1, are compromised in Cav-1 knockout NPSCs. Cav-1 is therefore a multifunctional regulator of GR in NPSCs influencing both rapid and genomic action of the receptor to impact cell proliferation.

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confidence: 99%

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Peffer

Chandran

Luthra

et al. 2014

Molecular and Cellular Biology

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“…Upon homologous recombination, exons 4-12 of the endogenous Ppp5 gene (PPP5 C) were replaced with DNA encoding exons 4-6, exon 7 (with the GCT codon) and exons [8][9][10][11][12]. C57BL/6 J genomic DNA was used for construction of the targeting vector, which was introduced into C57BL/6 N embryonic stem (ES) cells by electroporation.…”

Section: Generation and Maintenance Of Ppp5mentioning

confidence: 99%

“…Protein phosphatase 5 (Ppp5/PP5), which dephosphorylates serine and threonine residues in proteins [2,3], was identified as a component of GR-Hsp90 complexes [4,5] and shown to interact with Hsp90 and Hsp70 via its tetratricopeptide repeat (TPR) domain [6,7]. Three TPR-containing proteins, FK506 binding protein 51 (FKBP51), FKBP52 and Ppp5/PP5 are now known to separately associate with the mature GR through Hsp90, to form different GR complexes [8,9]. A further small protein termed p23 is an essential component of GR complexes [10].…”

Section: Introductionmentioning

confidence: 99%

Decreased adipogenesis and adipose tissue in mice with inactivated protein phosphatase 5

Jacob

Rosenzweig

Vázquez-Martin

et al. 2015

Biochemical Journal

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Glucocorticoids play an important role in the treatment of inflammation and immune disorders, despite side effects, which include metabolic derangements such as central adiposity. These studies examine the role of protein phosphatase 5 (Ppp5) in glucocorticoid receptor (GR) complexes which mediate response to glucocorticoids. Mice homozygous for inactivated Ppp5 (Ppp5 D274A/D274A ) exhibit decreased adipose tissue surrounding the gonads and kidneys compared with wild-type mice. Adipocyte size is smaller, more preadipocytes/stromal cell are present in their gonadal fat tissue and differentiation of preadipocytes to adipocytes is retarded. Glucocorticoid levels are raised and the GR is hyperphosphorylated in adipose tissue of Ppp5 D274A/D274A mice at Ser212 and Ser220 (orthologous to human Ser203 and Ser211) in the absence of glucocorticoids. Preadipocyte cultures from Ppp5 D274A/D274A mice show decreased down regulation of Delta-like protein-1/preadipocyte factor-1, hyperphosphorylation of extra-cellular signal regulated kinase 2 (ERK2) and increased concentration of (sex determining region Y)-box 9 (SOX9), changes in a pathway essential for preadipocyte differentiation, which leads to decreased concentrations of the transcription factors CEBPβ and CEBPα necessary for the later stages of adipogenesis. The data indicate that Ppp5 plays a crucial role in modifying GR-mediated initiation of adipose tissue differentiation, suggesting that inhibition of Ppp5 may potentially be beneficial to prevent obesity during glucocorticoid treatment.

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“…Furthermore, the circadian rhythm exhibits an ultradian pattern with rapid pulsatile secretions of glucocorticoids from the adrenal gland. 7 Once cortisol is released, it binds to glucocorticoid receptors on target cells, altering gene transcription [8][9][10] and regulating multiple physiological functions, including cellular metabolism of glucose, proteins, and lipids 11,12 for energy homeostasis, 13,14 salt and water balance, 15 blood pressure, 16,17 and functions of the immune system. 18,19 Abnormal activity of the adrenal cortex leads to hypercortisolism or 60% of Cushing's syndrome cases, characterized by excessive cortisol levels.…”

Section: Introductionmentioning

confidence: 99%

ACTH-Independent Hypercorticism in Adrenal Tumors and Adrenocortical Hyperplasia

Li¹,

Hanna²

2016

Cell Communication Insights

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Cortisol production is normally under the regulation of adrenocorticotropic hormone (ACTH). Hypercortisolism or Cushing's syndrome, characterized by excessive cortisol levels, may be caused by ACTH-independent mechanisms. The present work aims to review the current knowledge on ACTH-independent mechanisms through aberrant expression of hormone receptors in adrenal tumors and adrenocortical hyperplasia. In particular, the effects of epinephrine, norepinephrine, serotonin, arginine vasopressin, and gastric inhibitory polypeptide are discussed.KEY WORDS: hypercorticism, adrenal tumors, adrenocortical hyperplasia, Cushing's syndrome, ACTH-independent CITATION: liu and hanna. aCth-independent hypercorticism in adrenal tumors and adrenocortical hyperplasia.

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Glucocorticoid receptor physiology

Cited by 202 publications

References 92 publications

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Decreased adipogenesis and adipose tissue in mice with inactivated protein phosphatase 5

ACTH-Independent Hypercorticism in Adrenal Tumors and Adrenocortical Hyperplasia

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