scholarly journals Steroidal Androgens and Nonsteroidal, Tissue-Selective Androgen Receptor Modulator, S-22, Regulate Androgen Receptor Function through Distinct Genomic and Nongenomic Signaling Pathways

2008 ◽  
Vol 22 (11) ◽  
pp. 2448-2465 ◽  
Author(s):  
Ramesh Narayanan ◽  
Christopher C. Coss ◽  
Muralimohan Yepuru ◽  
Jeffrey D. Kearbey ◽  
Duane D. Miller ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Levator Ani ◽  
Reproductive Organs ◽  
Cross Reactivity ◽  
Levator Ani Muscle ◽  
Xenopus Laevis Oocyte ◽  
Muscle Weight

Abstract Androgen receptor (AR) ligands are important for the development and function of several tissues and organs. However, the poor oral bioavailability, pharmacokinetic properties, and receptor cross-reactivity of testosterone, coupled with side effects, place limits on its clinical use. Selective AR modulators (SARMs) elicit anabolic effects in muscle and bone, sparing reproductive organs like the prostate. However, molecular mechanisms underlying the tissue selectivity remain ambiguous. We performed a variety of in vitro studies to compare and define the molecular mechanisms of an aryl propionamide SARM, S-22, as compared with dihydrotestosterone (DHT). Studies indicated that S-22 increased levator ani muscle weight but decreased the size of prostate in rats. Analysis of the upstream intracellular signaling events indicated that S-22 and DHT mediated their actions through distinct pathways. Modulation of these pathways altered the recruitment of AR and its cofactors to the PSA enhancer in a ligand-dependent fashion. In addition, S-22 induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases, through pathways distinct from steroids. These studies reveal novel differences in the molecular mechanisms by which S-22, a nonsteroidal SARM, and DHT mediate their pharmacological effects.

Estrogen, Progesterone, and Androgen Receptor Expression in Levator Ani Muscle and Fascia

2001 ◽  
Vol 10 (8) ◽  
pp. 785-795 ◽  
Author(s):  
Pleas Copas ◽  
Antonin Bukovsky ◽  
Bridgett Asbury ◽  
Robert F. Elder ◽  
Michael R. Caudle
Keyword(s):  
Androgen Receptor ◽  
Levator Ani ◽  
Receptor Expression ◽  
Androgen Receptor Expression ◽  
Levator Ani Muscle

scholarly journals IQGAP1 binds AMPK and is required for maximum AMPK activation

2020 ◽  
pp. jbc.RA120.016193
Author(s):  
Andrew C. Hedman ◽  
Zhigang Li ◽  
Laëtitia Gorisse ◽  
Swetha Parvathaneni ◽  
Chase J. Morgan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Intracellular Signaling ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Direct Interaction ◽  
Mitogen Activated Protein Kinase ◽  
Null Cell ◽  
Ampk Signaling ◽  
In Cells

AMP-activated protein kinase (AMPK) is a fundamental component of a protein kinase cascade that is an energy sensor. AMPK maintains energy homeostasis in the cell by promoting catabolic and inhibiting anabolic pathways. Activation of AMPK requires phosphorylation by the liver kinase B1 or by the Ca2+ /calmodulin-dependent protein kinase kinase 2 (CaMKK2). The scaffold protein IQGAP1 regulates intracellular signaling pathways, such as the mitogen-activated protein kinase and AKT signaling cascades. Recent work implicates the participation of IQGAP1 in metabolic function, but the molecular mechanisms underlying these effects are poorly understood. Here, using several approaches including binding analysis with fusion proteins, siRNA-mediated gene silencing, RT-PCR, and knockout mice, we investigated whether IQGAP1 modulates AMPK signaling. In vitro analysis reveals that IQGAP1 binds directly to the α1 subunit of AMPK. In addition, we observed a direct interaction between IQGAP1 and CaMKK2, which is mediated by the IQ domain of IQGAP1. Both CaMKK2 and AMPK associate with IQGAP1 in cells. The ability of metformin and increased intracellular free Ca2+ concentrations to activate AMPK is reduced in cells lacking IQGAP1. Importantly, Ca2+-stimulated AMPK phosphorylation was rescued by re-expression of IQGAP1 in IQGAP1-null cell lines. Comparison of the fasting response in wild-type and IQGAP1-null mice revealed that transcriptional regulation of the gluconeogenesis genes PCK1 and G6PC and the fatty acid synthesis genes FASN and ACC1 is impaired in IQGAP1-null mice. Our data disclose a previously unidentified functional interaction between IQGAP1 and AMPK and suggest that IQGAP1 modulates AMPK signaling.

scholarly journals TRIM59 is Suppressed by Androgen Receptor and Acts to Promote Lineage Plasticity and Neuroendocrine Differentiation in Prostate Cancer

2021 ◽  
Author(s):  
Liancheng Fan ◽  
Yiming Gong ◽  
Yuman He ◽  
Wei-Qiang Gao ◽  
Baijun Dong ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Molecular Mechanisms ◽  
Neuroendocrine Differentiation ◽  
Tumor Model ◽  
Strongly Correlated ◽  
Neuroendocrine Prostate Cancer ◽  
In Vitro Effects

Abstract Background: The incidence of treatment-induced neuroendocrine prostate cancer (t-NEPC) has been greatly increasing after the usage of second-generation androgen receptor (AR) pathway inhibitors (ARPIs). Neuroendocrine differentiation (NED) is closely associated with ARPI treatment failure and poor prognosis in prostate cancer (PCa) patients. However, the molecular mechanisms of NED are not fully understood. Methods: TRIM59 expression was evaluated in PCa samples from patients at first diagnosis or at relapse stage post ARPI treatment by immunohistochemistry; in vitro effects of TRIM59 were determined by cell proliferation, sphere formation and cell migration assays; while in vivo analysis was performed using subcutaneous tumor model. Western blot, qPCR assay, dual luciferase assessment, chromatin immunoprecipitation and RNA sequencing were applied for mechanistic exploration.Results: Here we report that upregulation of TRIM59, a TRIM family protein, is strongly correlated with ARPI treatment mediated NED and shorter patient survival in PCas. AR binds to TRIM59 promoter and represses its transcription. ARPI treatment leads to a reversal of repressive epigenetic modifications on TRIM59 gene and the transcriptional restraint on TRIM59 by AR. Upregulated TRIM59 then drives the NED of PCa by enhancing the degradation of RB1 and P53 and upregulating downstream lineage plasticity-promoting transcription factor SOX2. Conclusion: Altogether, TRIM59 is negatively regulated by AR and acts as a key driver for NED in PCas. Our study provides a novel prognostic marker for PCas and shed new light on the molecular pathogenesis of t-NEPC, a deadly variant of PCa.

scholarly journals Cytosolic androgen receptor in regenerating rat levator ani muscle

1981 ◽  
Vol 200 (1) ◽  
pp. 77-82 ◽  
Author(s):  
S R Max ◽  
S Mufti ◽  
B M Carlson
Keyword(s):  
Androgen Receptor ◽  
Striated Muscle ◽  
Fold Increase ◽  
Levator Ani ◽  
Muscle Fibres ◽  
Morphological Development ◽  
Levator Ani Muscle ◽  
Binding Characteristics ◽  
Crush Lesion ◽  
Androgen Binding

The development of the cytosolic androgen receptor was studied after degeneration and regeneration of the rat levator ani muscle after a crush lesion. Muscle regeneration appears to recapitulate myogenesis in many respects. It therefore provides a model tissue in sufficiently in large quantity for investigating the ontogenesis of the androgen receptor. The receptor in the cytosol of the normal levator ani muscle has binding characteristics similar to those of the cytosolic receptor in other androgen-sensitive tissues. By day 3 after a crush lesion of the levator ani muscle, androgen binding decreased to 25% of control values. This decrease was followed by a 4-5 fold increase in hormone binding, which attained control values by day 7 after crush. Androgen binding remained stable at the control value up to day 60 after crushing. These results were correlated with the morphological development of the regenerating muscle after crushing. It is concluded that there is little, if any, androgen receptor present in the early myoblastic stages of regeneration; rather, synthesis of the receptor may occur after the fusion of myoblasts and during the differentiation of myotubes into cross-striated muscle fibres.

Actin and creatine kinase mRNAs in rat levator ani and vastus muscles as a function of androgen status

1990 ◽  
Vol 68 (4) ◽  
pp. 1548-1561 ◽  
Author(s):  
G. Boissonneault ◽  
P. Chapdelaine ◽  
R. R. Tremblay
Keyword(s):  
Creatine Kinase ◽  
Vastus Lateralis ◽  
Control Level ◽  
Levator Ani ◽  
In Vitro Translation ◽  
Levator Ani Muscle ◽  
Time Intervals ◽  
Actin Expression ◽  
Fast Twitch

The plasticity of two selected mRNAs was studied in two typical fast-twitch muscles at different time intervals after orchiectomy (GDX). The levator ani muscle of the rat (LA) is exquisitely sensitive to androgens, whereas the superficial vastus lateralis (SVL) lacks such sensitivity. In vitro translation of RNA isolated from both tissues indicated that actin was among the most repressed proteins of the LA at day 10 postsurgery (GDX-10 days), whereas the template activity of the SVL mRNAs remains virtually unmodified. We used an available actin cDNA and demonstrated that the expression of the LA actin message is reduced by 85% in GDX-10 days and can be recovered after testosterone propionate (TP) injections (GDX + TP). In contrast, the actin expression in SVL remains constant up to day 20 postsurgery. In the LA, the expression of creatine kinase (CK) mRNA was increased 140% in GDX-5 days and decreased 34 and 17% in GDX-10 days and GDX-20 days, respectively, although the measured CK activity, as well as the in vitro translation of the message, remained elevated in those two latter groups. Control level of the CK mRNA expression was recovered in the GDX + TP group. Again, the expression of the message was unchanged in SVL, suggesting that the protein synthesis of this skeletal muscle is far less sensitive to androgen deprivation than that of the LA muscle.

THE GROWTH OF THE VENTRAL PROSTATE THE DORSOLATERAL PROSTATE, THE COAGULATING GLANDS AND THE SEMINAL VESICLES IN CASTRATED MALE RATS INJECTED WITH ACTH AND/OR INSULIN

1969 ◽  
Vol 62 (4) ◽  
pp. 694-710 ◽  
Author(s):  
Lars-Eric Tisell ◽  
Lennart Angervall
Keyword(s):  
Morphological Changes ◽  
Levator Ani ◽  
Regular Insulin ◽  
Reproductive Organs ◽  
Seminal Vesicles ◽  
Male Rats ◽  
Ventral Prostate ◽  
Levator Ani Muscle ◽  
Adrenal Steroids ◽  
Protamine Zinc Insulin

ABSTRACT The growth of the ventral and the dorsolateral prostate, the coagulating glands, seminal vesicles and levator ani muscle was studied in castrated male rats after fifteen days of daily injections with ACTH or insulin alone, or in combination. ACTH was given in a dose of 8 IU daily. Insulin was administered in increasing daily doses, i. e. regular insulin up to 8 IU and protamine zinc insulin up to 10 IU. After ACTH treatment there were variable histological signs of stimulation of the dorsolateral prostate, while the other accessory reproductive organs showed no response. Regular insulin produced no quantitative or morphological changes in the accessory reproductive organs, and no morphological signs of increased secretion of the adrenal steroids. Administration of ACTH and regular insulin in combination stimulated the growth of all the accessory reproductive organs. Protamine zinc insulin produced prolonged hypoglycaemia and morphological signs of increase secretion of adrenal steroids, thus the adrenals became enlarged and the thymus atrophic. Protamine zinc insulin stimulated growth of all the accessory reproductive organs, a stimulation which was further accentuated after combination with ACTH. Possible mechanisms for the action of insulin on the male accessory reproductive organs are discussed. The varying response of the different parts of the prostate and the seminal vesicles emphasizes the importance of the simultaneous examination of these organs.

scholarly journals Tetrahydrogestrinone induces a genomic signature typical of a potent anabolic steroid

2005 ◽  
Vol 184 (2) ◽  
pp. 427-433 ◽  
Author(s):  
Fernand Labrie ◽  
Van Luu-The ◽  
Ezequiel Calvo ◽  
Céline Martel ◽  
Julie Cloutier ◽  
...  
Keyword(s):  
Anabolic Steroid ◽  
Gastrocnemius Muscle ◽  
Mouse Genome ◽  
Levator Ani ◽  
Levator Ani Muscle ◽  
Muscle Weight ◽  
Mouse Muscle ◽  
Anabolic Activity ◽  
Androgenic Activity

Tetrahydrogestrinone (THG) is a recently identified compound having the greatest impact in the world of sports. In order to obtain a highly accurate and sensitive assessment of the potential anabolic/androgenic activity of THG, we have used microarrays to identify its effect on the expression of practically all the 30 000 genes in the mouse genome and compared it with the effect of dihydrotestosterone (DHT), the most potent natural androgen. Quite remarkably, we found that 671 of the genes modulated by THG in the mouse muscle levator ani are modulated in a similar fashion by DHT, while in the gastrocnemius muscle and prostate, 95 and 939 genes respectively, are modulated in common by the two steroids. On the other hand, THG is more potent than DHT in binding to the androgen receptor, while, under in vivo conditions, THG possesses 20% of the potency of DHT in stimulating prostate, seminal vesicle and levator ani muscle weight in the mouse. The present microarray data provide an extremely precise and unquestionable signature of the androgenic/anabolic activity of THG, an approach which should apply to the analysis of the activity of any anabolic steroid.

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