Cellular Processing of the Glucocorticoid Receptor Gene and Protein: New Mechanisms for Generating Tissue-specific Actions of Glucocorticoids

Oakley, Robert H.; Cidlowski, John A.

doi:10.1074/jbc.r110.179325

Cited by 315 publications

(306 citation statements)

References 92 publications

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“…47 Consequently, the finding that the various cell types exhibit differing transcriptional responses to DEX (as shown here for the first time with CNS glia) is not without precedent. However, elucidation of the factors accounting for the intercellular differences, and limited glucocorticoid sensitivity of oligodendroglia, in particular, will require extensive further study.…”

Section: ■ Results and Discussionmentioning

confidence: 75%

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Jenkins

Pickard

Khong

et al. 2013

ACS Chem. Neurosci.

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Corticosteroid (CS) therapy is used widely in the treatment of a range of pathologies, but can delay production of myelin, the insulating sheath around central nervous system nerve fibers. The cellular targets of CS action are not fully understood, that is, "direct" action on cells involved in myelin genesis [oligodendrocytes and their progenitors the oligodendrocyte precursor cells (OPCs)] versus "indirect" action on other neural cells. We evaluated the effects of the widely used CS dexamethasone (DEX) on purified OPCs and oligodendrocytes, employing complementary histological and transcriptional analyses. Histological assessments showed no DEX effects on OPC proliferation or oligodendrocyte genesis/maturation (key processes underpinning myelin genesis). Immunostaining and RT-PCR analyses show that both cell types express glucocorticoid receptor (GR; the target for DEX action), ruling out receptor expression as a causal factor in the lack of DEX-responsiveness. GRs function as ligand-activated transcription factors, so we simultaneously analyzed DEX-induced transcriptional responses using microarray analyses; these substantiated the histological findings, with limited gene expression changes in DEX-treated OPCs and oligodendrocytes. With identical treatment, microglial cells showed profound and global changes post-DEX addition; an unexpected finding was the identification of the transcription factor Olig1, a master regulator of myelination, as a DEX responsive gene in microglia. Our data indicate that CS-induced myelination delays are unlikely to be due to direct drug action on OPCs or oligodendrocytes, and may occur secondary to alterations in other neural cells, such as the immune component. To the best of our knowledge, this is the first comparative molecular and cellular analysis of CS effects in glial cells, to investigate the targets of this major class of anti-inflammatory drugs as a basis for myelination deficits.

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Section: ■ Results and Discussionmentioning

confidence: 75%

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Jenkins

Pickard

Khong

et al. 2013

ACS Chem. Neurosci.

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“…4A). Glucocorticoid receptor (GR), which is ubiquitously expressed in many types of cells, mediates most of the effects of glucocorticoids (14). RU486, a GR antagonist, was used to determine whether cortisol decreases p53 protein levels through GR signaling.…”

Section: Glucocorticoids Decrease P53 Protein Levels and Function In mentioning

confidence: 99%

Chronic restraint stress attenuates p53 function and promotes tumorigenesis

Feng

Liu²,

Zhang³

et al. 2012

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

167

138

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Epidemiological studies strongly suggest that chronic psychological stress promotes tumorigenesis. However, its direct link in vivo and the underlying mechanisms that cause this remain unclear. This study provides direct evidence that chronic stress promotes tumorigenesis in vivo; chronic restraint, a well-established mouse model to induce chronic stress, greatly promotes ionizing radiation (IR)-induced tumorigenesis in p53 +/− mice. The tumor suppressor protein p53 plays a central role in tumor prevention. Loss or attenuation of p53 function contriubutes greatly to tumorigenesis. We found that chronic restraint decreases the levels and function of p53 in mice, and furthermore, promotes the growth of human xenograft tumors in a largely p53-dependent manner. Our results show that glucocorticoids elevated during chronic restraint mediate the effect of chronic restraint on p53 through the induction of serum-and glucocorticoid-induced protein kinase (SGK1), which in turn increases MDM2 activity and decreases p53 function. Taken together, this study demonstrates that chronic stress promotes tumorigenesis in mice, and the attenuation of p53 function is an important part of the underlying mechanism, which can be mediated by glucocortcoids elevated during chronic restraint.

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“…Binding of the drug to the receptor causes conformational changes, phosphorylation, and activation of receptor, resulting in the formation of a homodimer of the drug receptor complex (Oakley and Cidlowski, 2011;Schaaf and Cidlowski, 2002). This activated complex translocates into the nucleus and binds to regulator sites, glucocorticoid regulatory elements (GREs) in the DNA, resulting in the regulation of transcription rate.…”

Section: Introductionmentioning

confidence: 99%

Tandem Analysis of Transcriptome and Proteome Changes after a Single Dose of Corticosteroid: A Systems Approach to Liver Function in Pharmacogenomics

Kamisoglu

Sukumaran

Nouri-Nigjeh

et al. 2015

OMICS: A Journal of Integrative Biology

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Corticosteroids (CS) such as methylprednisolone (MPL) affect almost all liver functions through multiple mechanisms of action, and long-term use results in dysregulation causing diverse side effects. The complexity of involved molecular mechanisms necessitates a systems approach. Integration of information from the transcriptomic and proteomic responses has potential to provide deeper insights into CS actions. The present report describes the tandem analysis of rich time-series transcriptomic and proteomic data in rat liver after a single dose of MPL. Hierarchical clustering of the common genes represented in both mRNA and protein datasets displayed two dominant patterns. One of these patterns exhibited complementary mRNA and protein expression profiles indicating that MPL affected the regulation of these genes at the transcriptional level. Some of the classic pharmacodynamic markers for CS actions, including tyrosine aminotransferase (TAT), were among this group, together with genes encoding urea cycle enzymes and ribosomal proteins. The other pattern was rather unexpected. For this group of genes, MPL had distinctly observable effects at the protein expression level, although a change in the reverse direction occurred at the transcriptional level. These genes were functionally associated with metabolic processes that might be essential to elucidate side effects of MPL on liver, most importantly including modulation of oxidative stress, fatty acid oxidation, and bile acid biosynthesis. Furthermore, profiling of gene and protein expression data was also done independently of one another by a two-way sequential approach. Prominent temporal shifts in expression and relevant cellular functions were described together with the assessment of changes in the complementary side.

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Cellular Processing of the Glucocorticoid Receptor Gene and Protein: New Mechanisms for Generating Tissue-specific Actions of Glucocorticoids

Cited by 315 publications

References 92 publications

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Chronic restraint stress attenuates p53 function and promotes tumorigenesis

Tandem Analysis of Transcriptome and Proteome Changes after a Single Dose of Corticosteroid: A Systems Approach to Liver Function in Pharmacogenomics

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