Androgen_Signaling
发布时间：2019-12-09 18:19 来源：SABiosciences
- 通路
- 概述
Review
Androgens mediate a wide range of developmental and physiological responses and are especially important in male sexual differentiation and pubertal sexual maturation, the maintenance of spermatogenesis, and male gonadotropin regulation (Ref.1). The principle steroidal androgens, testosterone and its metabolite DHT (5-Alpha-Dihydrotestosterone), mediate their biological effects predominantly through binding to the AR (Androgen Receptor), an androgen-inducible member of the nuclear receptor superfamily of transcription factors (Ref.2).
Structurally, AR can be subdivided into four functional domains: the NH2-terminal transactivation domain (or A/B domain), the DBD (DNA-Binding Domain), hinge region, and the LBD (Ligand-Binding Domain). An NH2-terminal AF1 (Activation Function-1), functions in a ligand-independent manner when artificially separated from the LBD, creating a constitutively active receptor. A ligand-dependent AF2 function is located in the LBD, which is responsible for an optimum transcriptional activation in response to the ligand (Ref.3). The unbound AR forms a complex with HSPs (Heat-Shock Proteins). The binding of androgens to AR induces dissociation of the AR from the HSPs and subsequent receptor dimerization and translocation into the nucleus, facilitating the ability of AR to bind to its cognate response element, and recruit coregulators to promote the expression of target genes. The transcriptional activity of AR is greatly modulated by coregulatory proteins. Coactivators such as ARA70 (Androgen Receptor Coactivator, 70-Kd) and ARA55 stabilize the process of ligand binding to AR. The ability of AR to be translocated to the nucleus is regulated by several coregulators, for example, the F-Actin binding protein: Filamin. Inside the nucleus, AR interacts with DNA by targeting specific nucleotide palindromic sequences termed ARE (Androgen Response Element) (Ref.2).
A number of coregulators themselves perform enzymatic activities such as phosphorylation or acetylation, modifying either the chromatin surrounding the promoter of the target gene or other coregulators. The prototypic coactivators of this type that possess acetyltransferase activity include, CBP (CREB Binding Protein), the closely related p300 and other nuclear receptor coactivators: p/CAF (p300/CBP Associated Factor), SRC1 (Steroid Receptor Coactivator-1), and SRC3 (Ref.3). PIAS [Protein Inhibitor of Activated Signal Transducer and Activator of Transcription (STAT)] family of proteins and ANPK (Androgen Receptor-Interacting Nuclear Kinase) also interact with and coactivate AR. Transcriptional activation by AR ultimately requires the recruitment of RNA Pol II (RNA polymerase-II) to the promoter of target genes. RNA Pol II recruitment is mediated through the assembly of GTFs (General Transcription Factors) to form the preinitiation complex, the first step of which is the binding of TBP (TATA box-Binding Protein) near the transcriptional start site. TBP is part of a multiprotein complex, TFIID (Transcription Factor-IID), which also contains general and promoter-specific TAFII (TBP-Associated Factors) proteins. TBP binding induces DNA bending, bringing sequences upstream of the TATA element in closer proximity, presumably enabling interaction between GTFs and steroid receptor-coregulator complexes. TFIIB binds directly to TBP and functions to recruit the TFIIF-RNA Pol II complex. TFIIF domains, in addition to interacting with TFIIB and RNA Pol II, apparently also serve in transcription initiation and elongation. The ATPase and kinase TFIIE and the helicase TFIIH are then recruited to RNA Pol II to facilitate DNA strand separation before transcription initiation. TFIIE and TFIIF recruitment to RNA pol II are acetylated by p300 and p/CAF (Ref.2). Ubiquitin ligase activity has been identified for two AR coactivators, ARA54 and E6-AP. The coactivators with ubiquitin ligase activity contribute to nuclear receptor transcription through targeting the degradation of corepressors. AR can also interact with a number of transcription factors including Activator Protein-1, SMAD3 (Sma and Mad Related Family), NF-KappaB (Nuclear Factor-KappaB), SRY (Sex-determining Region-Y), and the Ets family of transcription factors.
Transcriptional corepression of androgen-bound AR can be attributed to three corepressors: cyclin-D1, calreticulin and HBO1. Cyclin-D1 inhibits AR transactivation through a mechanism independent of its function in cell cycle regulation (Ref.4). The calcium-binding protein calreticulin is localized to the endoplasmic reticulum and nucleus and has also been characterized as a corepressor of AR. The AR corepressor HBO1 is a member of the MYST protein family that is characterized by a homologous zinc finger and carries an acetyltransferase domain. Although AR is normally thought to function as a homodimer, it has been found to heterodimerize with other nuclear receptors including the ER (Estrogen Receptor), GR (Glucocorticoid Receptor) and TR4 (Testicular Orphan Receptor-4) and in each case result in a decrease in AR transcriptional activity.
In addition to the transcriptional or genomic mode of action by steroids, androgens, can also exert rapid, nongenomic effects. Nongenomic steroid activity typically involves the rapid induction of conventional second messenger signal transduction cascades. Nongenomic action of androgens can occur through multiple receptors. Androgens can activate cAMP and PKA through the SHBG (Sex Hormone Binding Globulin)/SHBGR complex (Ref.1). Androgens also stimulate an elevation in intracellular Ca2+ through a GPCR (G-Protein Coupled Receptor) by activating an influx through nonvoltage-gated Ca2+ channels. The elevation of intracellular calcium activates signal transduction cascades, including PKA (Protein Kinase-A), PKC (Protein Kinase-C), and MAPKs (Mitogen-Activated Protein Kinase), that can modulate the activity of the ARs and other transcription factors. AR also interacts with the intracellular tyrosine kinase c-Src, triggering c-Src activation. One of the targets of c-Src is the adapter protein SHC (SH2 Containing Protein), an upstream regulator of the MAPK pathway. The activity of AR and AR coactivators are influenced by direct phosphorylation by MAPK (Ref.3). AR phosphorylation by ERK2 is associated with enhanced AR transcriptional activity and an increased ability to recruit the coactivator ARA70. The SRC family of transcriptional coactivators: SRC1, SRC3, and TIF2 (Transcription Intermediary Factor-2) are targets of MAPK phosphorylation that results in an increased ability of these coactivators to recruit additional coactivator complexes to the DNA-bound receptor. The nongenomic, rapid stimulation of second messenger cascades by androgens may ultimately exert biological effects through modulation of the transcriptional activity of AR or other transcription factors. Such modulation may occur through direct phosphorylation of transcriptional activators or their coregulators (Ref.1). The AR can also be activated in the absence of its cognate ligand, androgen by signaling pathways initiated by various growth factors.
The appropriate regulation of androgen activity is necessary for a range of developmental and physiological processes, particularly male sexual development and maturation. However, excessive production of adrenal androgens can cause premature puberty in young boys and their hypersecretion in females, may produce a masculine pattern of body hair and cessation of menstruation (Ref.4). Their mis-regulation is also implicated in the formation and progression of prostatic adenocarcinoma (Ref.3). Therefore, the removal of testicular androgens by castration has long been recognized to result in tumor regression, and surgical or pharmacological androgen ablation remain the predominant form of treatment for advanced prostate cancer. Androgen ablation therapy is often combined with treatment with nonsteroidal antiandrogens, such as hydroxyflutamide, to block residual adrenal androgen action. Androgen Replacement Therapy has been in use for over 60 years to treat, with proven efficacy and safety, on patients with male hypogonadal disorders and/or failure of sexual development. Apart from that, the last decade has witnessed a wider therapeutic role of androgens for nonclassical indications. These include male contraception; aplastic anemia; and sarcopenic, osteopenic, and depressive states frequently associated with an expanding variety of chronic systemic conditions (characterized by reduced circulating testosterone) such as AIDS, rheumatoid arthritis, chronic renal failure, chronic obstructive airways disease, and physiological aging (Ref.5).
References
- 1
- Heinlein CA, Chang C. The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions.
- 2
- Lee DK, Chang C. Molecular communication between androgen receptor and general transcription machinery.
- 3
- Culig Z, Klocker H, Bartsch G, Steiner H, Hobisch A. Androgen Receptors in Prostate Cancer.
- 4
- Petre CE, Wetherill YB, Danielsen M, Knudsen KE. Cyclin D1: mechanism and consequence of androgen receptor co-repressor activity.
- 5
- Wu FC, Von Eckardstein A. Androgens and coronary artery disease.
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