G protein β interacts with the glucocorticoid receptor and suppresses its transcriptional activity in the nucleus

Extracellular stimuli that activate cell surface receptors modulate glucocorticoid actions via as yet unclear mechanisms. Here, we report that the guanine nucleotide-binding protein (G protein)–coupled receptor-activated WD-repeat Gβ interacts with the glucocorticoid receptor (GR), comigrates with it into the nucleus and suppresses GR-induced transactivation of the glucocorticoid-responsive genes. Association of Gγ with Gβ is necessary for this action of Gβ. Both endogenous and enhanced green fluorescent protein (EGFP)–fused Gβ2 and Gγ2 proteins were detected in the nucleus at baseline, whereas a fraction of EGFP-Gβ2 and DsRed2-GR comigrated to the nucleus or the plasma membrane, depending on the exposure of cells to dexamethasone or somatostatin, respectively. Gβ2 was associated with GR/glucocorticoid response elements (GREs) in vivo and suppressed activation function-2–directed transcriptional activity of the GR. We conclude that the Gβγ complex interacts with the GR and suppresses its transcriptional activity by associating with the transcriptional complex formed on GR-responsive promoters

Diabetes mellitus itself increases cardio- cerebrovascular risk and renal complications in primary aldosteronism

This is a pre-copyedited, author-produced version of an article accepted for publication in The Journal of Clinical Endocrinology & Metabolism following peer review. The version of record Aya Saiki, Michio Otsuki, Daisuke Tamada, Tetsuhiro Kitamura, Iichiro Shimomura, Isao Kurihara, Takamasa Ichijo, Yoshiyu Takeda, Takuyuki Katabami, Mika Tsuiki, Norio Wada, Toshihiko Yanase, Yoshihiro Ogawa, Junji Kawashima, Masakatsu Sone, Nobuya Inagaki, Takanobu Yoshimoto, Ryuji Okamoto, Katsutoshi Takahashi, Hiroki Kobayashi, Kouichi Tamura, Kohei Kamemura, Koichi Yamamoto, Shoichiro Izawa, Miki Kakutani, Masanobu Yamada, Akiyo Tanabe, Mitsuhide Naruse, Diabetes Mellitus Itself Increases Cardio-Cerebrovascular Risk and Renal Complications in Primary Aldosteronism, The Journal of Clinical Endocrinology & Metabolism, Volume 105, Issue 7, July 2020, Pages e2531–e2537 is available online at: https://doi.org/10.1210/clinem/dgaa177

Prevalence of adrenal masses in Japanese patients with type 2 diabetes mellitus

<p>Abstract</p> <p>Introduction</p> <p>To date, there have been no reports on the prevalence of adrenal masses in type 2 diabetic patients. The present study aimed to evaluate the prevalence of adrenal incidentaloma in type 2 diabetic patients in Japan.</p> <p>Subjects</p> <p>We retrospectively evaluated the presence of adrenal masses using abdominal CT scans in 304 type 2 diabetic patients. In those with adrenal masses, we examined the hormone production capacity of the adrenal mass.</p> <p>Results</p> <p>Fourteen patients (4.6%) had an adrenal mass. Hormonal analysis identified one case as having subclinical Cushing's syndrome, two with primary aldosteronism. Eleven cases had non-functioning masses.</p> <p>Discussion</p> <p>The reported prevalence of adrenal incidentaloma in normal subjects is 0.6-4.0% in abdominal CT scan series. Our results show a relatively high prevalence of adrenal tumors in diabetic patients. On the other hand, the frequency of functional adenoma in diabetic patients is 21.4%, which is similar to that of normal subjects.</p> <p>Conclusion</p> <p>Although further studies are needed to evaluate the prevalence of adrenal tumors in diabetic patients, our data suggest that evaluation of the presence of adrenal masses may be needed in patients with type 2 diabetes mellitus.</p

Activated glucocorticoid receptor interacts with the INHAT component Set/TAF-I beta and releases it from a glucocorticoid-responsive gene promoter, relieving repression: Implications for the pathogenesis of glucocorticoid resistance in acute undifferentiated leukemia with Set-Can translocation

Set/template-activating factor (TAF)-I beta, part of the Set-Can oncogene product found in acute undifferentiated leukemia, is a component of the inhibitor of acetyltransferases (INHAT) complex. Set/TAF-I beta interacted with the DNA-binding domain of the glucocorticoid receptor (GR) in yeast two-hybrid screening, and repressed GR-induced transcriptional activity of a chromatin-integrated glucocorticoid-responsive and a natural promoter. Set/TAF-I beta was co-precipitated with glucocorticoid response elements (GREs) of these promoters in the absence of dexamethasone, while addition of the hormone caused dissociation of Set/TAF-I beta from and attraction of the p160-type coactivator GRIP1 to the promoter GREs. Set-Can fusion protein, on the other hand, did not interact with GR, was constitutively co-precipitated with GREs and suppressed GRIP1-induced enhancement of GR transcriptional activity and histone acetylation. Thus, Set/TAF-I beta acts as a ligand-activated GR-responsive transcriptional repressor, while Set-Can does not retain physiologic responsiveness to ligand-bound GR, possibly contributing to the poor responsiveness of Set-Can-harboring leukemic cells to glucocorticoids. Published by Elsevier Ireland Ltd

A novel point mutation in helix 11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance

Background: Generalized glucocorticoid resistance is a rare condition characterized by partial, end- organ insensitivity to glucocorticoids, compensatory elevations in adrenocorticotropic hormone and cortisol secretion, and increased production of adrenal steroids with androgenic and/ or mineralocorticoid activity. We have identified a new case of glucocorticoid resistance caused by a novel mutation of the human glucocorticoid receptor ( hGR) gene and studied the molecular mechanisms through which the mutant receptor impairs glucocorticoid signal transduction. Methods and Results: We identified a novel, single, heterozygous nucleotide (T -&gt; C) substitution at position 2209 (exon 9 alpha) of the hGR gene, which resulted in phenylalanine ( F) to leucine ( L) substitution at amino acid position 737 within helix 11 of the ligand- binding domain of the protein. Compared with the wild- type receptor, the mutant receptor hGR alpha F737L demonstrated a significant ligand-exposure time-dependent decrease in its ability to transactivate the glucocorticoid- inducible mouse mammary tumor virus promoter in response to dexamethasone and displayed a 2- fold reduction in the affinity for ligand, a 12- fold delay in nuclear translocation, and an abnormal interaction with the glucocorticoid receptor- interacting protein 1 coactivator. The mutant receptor preserved its ability to bind to DNA and exerted a dominant- negative effect on the wild- type hGR alpha only after a short duration of exposure to the ligand. Conclusions: The mutant receptor hGR alpha F737L causes generalized glucocorticoid resistance because of decreased affinity for the ligand, marked delay in nuclear translocation, and/ or abnormal interaction with the glucocorticoid receptor- interacting protein 1 coactivator. These findings confirm the importance of the C terminus of the ligand-binding domain of the receptor in conferring transactivational activity

G protein beta interacts with the glucocorticoid receptor and suppresses its transcriptional activity in the nucleus

Extracellular stimuli that activate cell surface receptors modulate glucocorticoid actions via as yet unclear mechanisms. Here, we report that the guanine nucleotide-binding protein (G protein)-coupled receptor-activated WD-repeat G beta interacts with the glucocorticoid receptor (GR), comigrates with it into the nucleus and suppresses GR-induced transactivation of the glucocorticoid-responsive genes. Association of G gamma with G beta is necessary for this action of G beta. Both endogenous and enhanced green fluorescent protein (EGFP)-fused G beta 2 and G gamma 2 proteins were detected in the nucleus at baseline, whereas E a fraction of EGFP-G beta 2 and DsRed2-GR comigrated to the nucleus or the plasma membrane, depending on the exposure of cells to dexamethasone or somatostatin, respectively. G beta 2 was associated with GR/glucocorticoid response elements (GREs) in vivo and suppressed activation function-2-directed transcriptional activity of the GR. We conclude that the G beta gamma complex interacts with the GR and suppresses its transcriptional activity by associating with the transcriptional complex formed on GR-responsive promoters

Hepatic Venous Stasis Index Reflects Hepatic Congestion and Predicts Adverse Outcomes in Patients With Heart Failure

Background It has been reported that the hepatic vein waveforms determined by abdominal ultrasonography can assess hepatic congestion in patients with heart failure (HF). However, the parameter that quantifies hepatic vein waveforms has not been established. We suggest the hepatic venous stasis index (HVSI) as the novel indicator to evaluate hepatic congestion quantitatively. To examine the clinical significance of HVSI in patients with HF, we aimed to clarify the associations of HVSI with the parameters of cardiac function and right heart catheterization, as well as that with prognosis, in patients with HF. Methods and Results We performed abdominal ultrasonography, echocardiography, and right heart catheterization in patients with HF (n=513). The patients were divided into 3 groups based on HVSI as follows: HVSI 0 (HVSI=0, n=253), low HVSI (HVSI 0.01–0.20, n=132), and high HVSI (HVSI>0.20, n=128). We examined the associations of HVSI with parameters of cardiac function and right heart catheterization and followed up for cardiac events defined as cardiac death or worsening HF. There was a significant increase in level of B‐type natriuretic peptide, inferior vena cava diameter, and mean right atrial pressure with increasing HVSI. During the follow‐up period, cardiac events occurred in 87 patients. In the Kaplan–Meier analysis, cardiac event rate increased across increasing HVSI (log‐rank, P=0.002). Conclusions HVSI assessed by abdominal ultrasonography reflects hepatic congestion and right‐sided HF and is associated with adverse prognosis in patients with HF

Cyclin-dependent kinase 5 differentially regulates the transcriptional activity of the glucocorticoid receptor through phosphorylation: Clinical implications for the nervous system response to glucocorticoids and stress

Glucocorticoids, major end effectors of the stress response, play an essential role in the homeostasis of the central nervous system and influence diverse functions of neuronal cells. We found that cyclin-dependent kinase 5 (CDK5), which plays important roles in the morphogenesis and functions of the nervous system and whose aberrant activation is associated with development of neurodegenerative disorders, interacted with the ligand-binding domain of the glucocorticoid receptor (GR) through its activator p35 or its active proteolytic fragment p25. CDK5 phosphorylated GR at multiple serines, including Ser203 and Ser211 of its N-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to DNA. In microarray analyses using rat cortical neuronal cells, the CDK5 inhibitor roscovitine differentially regulated the transcriptional activity of the GR on more than 90% of the endogenous glucocorticoid-responsive genes tested. Thus, CDK5 exerts some of its biological activities in neuronal cells through the GR, dynamically modulating GR transcriptional activity in a target promoter-dependent fashion