Molecular and cellular endocrinology
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Mol. Cell. Endocrinol. · Mar 1999
The glucocorticoid properties of the synthetic steroid pregna-1,4-diene-11beta-ol-3,20-dione (deltaHOP) are not entirely correlated with the steroid binding to the glucocorticoid receptor.
The natural steroid 11beta-hydroxyprogesterone is not only a modulator of 11beta-hydroxy-steroid dehydrogenase activity, but also an efficient inducer of tyrosine aminotransferase activity in hepatocytes. In contrast with the low affinity for the mineralocorticoid receptor. 11beta-hydroxyprogesterone binds well to both the glucocorticoid receptor and the carrier protein transcortin. It is accepted that the introduction of a 1:ene double bond into 3-keto 4:ene steroids increases the glucocorticoid potency, so that 3-keto-1,4:diene steroids show improved chemical stability and are more potent glucocorticoids than their respective 4:ene analogs. ⋯ However, the inhibition of the uptake of amino acids and nucleotides observed in the presence of deltaHOP is not efficiently blocked when thymocytes are coincubated in the presence of steroids with known antiglucocorticoid activity. deltaHOP is similarly inefficient in inducing chloramphenicol-acetyl transferase activity in cells transfected with a plasmid that possesses two canonical glucocorticoid-responsive elements. Unlike most glucocorticoids, deltaHOP does not induce the fragmentation of DNA in a regular pattern characteristic of apoptosis and it does not reduce thymus weight. This unusual dissociation of glucocorticoid parameters makes deltaHOP a useful tool to discriminate between mechanisms of action by which steroids can exert their biological effects.
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Mol. Cell. Endocrinol. · Oct 1998
ReviewInsulin resistance in polycystic ovary syndrome: treating a phenotype without a genotype.
PCOS women are uniquely insulin resistant. The underlying genetic defect in insulin action is unknown. Obesity aggravates the underlying predisposition to insulin resistance. ⋯ The lack of a clear etiologic mechanism to the syndrome has led to a multitude of symptom-oriented treatments with few therapies improving all aspects of the endocrine syndrome of PCOS. Empirical studies of interventions improving insulin sensitivity in PCOS, either weight loss/diet programs or pharmaceutical agents, have been shown to improve the endocrine abnormalities in the syndrome. These initial results with anti-diabetic agents, though promising, need to be confirmed in larger, randomized studies.
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Mol. Cell. Endocrinol. · Dec 1997
Regulation of the human interleukin-2 gene by the alpha and beta isoforms of the glucocorticoid receptor.
The immunosuppressive effects of glucocorticoids are largely due to transcriptional inhibition of immunologically relevant genes, such as the interleukin-2 (IL-2) gene. These effects are mediated by the intracellular glucocorticoid receptor (GR). In humans, alternative splicing of the GR precursor mRNA gives rise to two receptor isoforms, termed GRalpha and GRbeta. ⋯ Surprisingly, overexpression of GRbeta in Jurkat cells did not cause significant inhibition of GRalpha-induced transactivation of a GRE-dependent luciferase reporter gene either. We conclude that the transrepressive effect of glucocorticoids on IL-2 gene transcription is exclusively mediated by GRalpha. GRbeta can neither antagonize GRalpha-mediated transactivation nor transrepression in Jurkat cells, indicating a cell type-specific pattern of GRbeta-mediated antiglucocorticoid activity.
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Mol. Cell. Endocrinol. · May 1997
The last proline of Box 1 is essential for association with JAK2 and functional activation of the prolactin receptor.
The interaction of prolactin (PRL) with its receptor leads to activation of the tyrosine kinase, Janus kinase 2 (JAK2). In the cytoplasmic juxtamembrane region, a short segment (Box 1) which is conserved in other receptors of the PRL/growth hormone (GH)/cytokine receptor family, is required for signal transduction. ⋯ Our data suggest that the Box 1 region of the PRL receptor and particularly the last proline is critical for JAK2 association and subsequent activation. These results support the notion that the tyrosine kinase JAK2 is implicated in activation of downstream protein effectors such as Stat5, which are involved in transcription of PRL-responsive genes.
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Mol. Cell. Endocrinol. · Mar 1997
Prolactin signal transduction to milk protein genes: carboxy-terminal part of the prolactin receptor and its tyrosine phosphorylation are not obligatory for JAK2 and STAT5 activation.
In this study, we have developed several Chinese Hamster ovary (CHO) cell clones stably expressing various deletion mutant forms of the rabbit prolactin receptor (rbPRL-R) to better define the domains of the receptor involved in JAK2 kinase interaction, STAT5 activation, and to assess the role of tyrosine phosphorylation of the PRL-R in signal transduction. We observed that the box 1 region of the receptor was critical for productive interaction with JAK2 and its tyrosine phosphorylation after PRL stimulation. However, this region appeared to require the presence of additional cytoplasmic domain region(s), such as box 2, to exert its complete effect. ⋯ The absence of tyrosine phosphorylation of this C-terminal rbPRL-R mutant upon PRL stimulation indicated that the phosphorylation of the PRL-R normally occured in the last 141 animo acids (aa) containing three tyrosines and was not absolutely necessary for induction of these early events in PRL signal transduction. Transfectant cell lines expressing wild type (WT) PRL-R and this C-terminal mutant form were able to induce CAT activity upon PRL stimulation when transiently transfected with the ovine-beta-lactoglobulin promoter, containing STAT5 recognition sites, fused to the CAT reporter gene. The comparison between transcriptional activity of these two receptor forms leads to the conclusion that the C-terminal region of the rbPRL-R, containing the physiological sites for tyrosine phosphorylation, is probably responsible for an amplification of the PRL signal to milk protein genes.