Cellular receptor levels and glucocorticoid responsiveness of lymphoma cells

Gehring, Ulrich; Mugele, K.; Ulrich, Jürgen

doi:10.1016/0303-7207(84)90089-3

Cited by 68 publications

(20 citation statements)

References 28 publications

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“…Many studies investigating GR numbers have been performed, on the basis of the hypothesis that receptor down-regulation might be an additional form of negative feedback, protecting against the continued signal elicited by ligand in cases of hypercorticolism or other forms of GC excess (6). In several studies, a direct correlation between GR number and the cell's sensitivity to GCs was found (11,12). Furthermore, a receptor down-regulation in reaction to GC therapy was demonstrated in cell cultures and animals, including humans…”

Section: Discussionmentioning

confidence: 99%

Decreased ligand affinity rather than glucocorticoid receptor down-regulation in patients with endogenous Cushing's syndrome

Huizenga¹,

Herder²,

Koper³

et al. 2000

European Journal of Endocrinology

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Objective: Glucocorticoids (GCs) serve a variety of important functions throughout the body. The synthesis and secretion of GCs are under the strict influence of the hypothalamo-pituitary-adrenal axis. The mechanisms of action of GCs are mediated by the intracellular glucocorticoid receptor (GR). Over the years, many studies have been performed concerning the regulation of GR expression by GC concentrations. Methods: In the present study, we determined the characteristics of the GR in peripheral mononuclear blood leukocytes (PBML) from thirteen patients with endogenous Cushing's syndrome and fifteen control subjects, using a whole cell dexamethasone binding assay. Furthermore, cortisol concentrations were determined in order to investigate a possible relationship between serum cortisol levels and receptor characteristics. Results: There were no differences in mean receptor number between patients and controls. On the other hand, a significantly lower ligand affinity was identified in cells from patients with Cushing's syndrome compared with controls. A complete normalisation of the ligand affinity was observed after treatment in the only patient tested in this respect, whereas the receptor number was not affected. In patients, there was a statistically significant negative correlation between cortisol concentrations and ligand affinity, which was not found in controls. Conclusion: Receptor down-regulation does not occur in PBML from patients with endogenous Cushing's syndrome. On the other hand, there seems to be a diminished ligand affinity which possibly reflects receptor modification in response to exposure to the continuously high cortisol levels in patients with Cushing's syndrome. This assumption is substantiated by the fact that in one patient a normalisation of the ligand affinity after complete remission of the disease was seen.

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Section: Discussionmentioning

confidence: 99%

Decreased ligand affinity rather than glucocorticoid receptor down-regulation in patients with endogenous Cushing's syndrome

Huizenga¹,

Herder²,

Koper³

et al. 2000

European Journal of Endocrinology

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“…These effects are mediated by the translocation ofthe GR-ligand complex to the cell nucleus (30), and there is a direct correlation between GR concentration and glucocorticoid responsiveness (31). More recent studies utilizing cotransfection of the GR gene and reporter genes into GR negative cells have shown that the magnitude of the transcriptional response of the reporter gene was proportional to the number of GR gene copies (32).…”

Section: Discussionmentioning

confidence: 99%

Developmental and hormonal regulation of glucocorticoid receptor messenger RNA in the rat.

Kalinyak¹,

Griffin²,

Hamilton³

et al. 1989

J. Clin. Invest.

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The biological action of glucocorticoids is dependent upon tissue-specific levels of the glucocorticoid receptor (GR). During stress, the hypothalamic-pituitary-adrenal axis is stimulated, and high levels of glucocorticoids circulate. This axis is modulated by negative feedback by glucocorticoids, which inhibit hypothalamic and pituitary hormone secretion and downregulate GR gene expression. To study the developmental tissuespecific regulation of the GR, we measured the relative concentration of GR mRNA in fetal, neonatal, adult, and aged rats and examined the effects of dexamethasone on GR gene expression. Three different tissue-specific developmental patterns of GR mRNA accumulation were found. In addition, there was an age-dependent tissue-specific pattern in the feedback regulation of GR mRNA by glucocorticoids. In the fetus and neonate, GR mRNA abundance was not regulated by circulating glucocorticoids. The adult pattern of glucocorticoid feedback inhibition of GR mRNA expression appeared between 2 and 7 d of life in liver, and after 7 but before 14 d of age in brain. The GR was biologically active in the 2-d-old neonate, however, since dexamethasone enhanced gene expression of angiotensinogen, which is another glucocorticoid responsive gene. These data demonstrate that the GR gene is regulated by both developmental and tissue-specific factors, and provide another molecular basis for ontogenic variations in the hypothalamic-pituitary-adrenal response to stress.

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“…The inactive, cytoplasmic GR binds the GC hormone to form an activated GR-ligand complex, which then translocates to the nucleus, recognizes and binds to specific DNA sequences in the gene promoter called glucocorticoid response elements (GREs), and affects the expression of these genes (7,8,11,12). It is not yet clear how GCs cause apoptosis in certain lymphoblasts, but this fact is effectively used in chemotherapy regimens for certain types of leukemias and lymphomas (13)(14)(15)(16)(17)(18)(19).…”

Section: Glucocorticoids (Gcs)mentioning

confidence: 99%

c-Myb and Members of the c-Ets Family of Transcription Factors Act as Molecular Switches to Mediate Opposite Steroid Regulation of the Human Glucocorticoid Receptor 1A Promoter

Geng

Vedeckis

2005

Journal of Biological Chemistry

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Cellular receptor levels and glucocorticoid responsiveness of lymphoma cells

Cited by 68 publications

References 28 publications

Decreased ligand affinity rather than glucocorticoid receptor down-regulation in patients with endogenous Cushing's syndrome

Decreased ligand affinity rather than glucocorticoid receptor down-regulation in patients with endogenous Cushing's syndrome

Developmental and hormonal regulation of glucocorticoid receptor messenger RNA in the rat.

c-Myb and Members of the c-Ets Family of Transcription Factors Act as Molecular Switches to Mediate Opposite Steroid Regulation of the Human Glucocorticoid Receptor 1A Promoter

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