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Transcription Androgen Receptor nuclear signaling

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Transcription Androgen Receptor nuclear signaling

Androgen Receptor nuclear signaling

Androgen is the active metabolic product, 5alpha-Dihydrotestosterone, which isproduced from the transformation of Testosterone catalyzed by theSteroid-5-alpha-reductase, alpha polypeptides 1 and 2 ( S5AR1 and S5AR2 )[1], [2]. Biological activity of androgens is mediated bybinding to the Androgen receptor, a member of the nuclear receptorsuperfamily that functions as a ligand-activated transcription factor [3],[4].

Binding of Testosterone or 5alpha-Dihydrotestosterone to Androgenreceptor induces its dimerization, which is needed for binding to Androgenreceptor 's cognate response element and recruitment of co-regulators, such astranscriptional co-activator protein E1A binding protein p300 ( p300 ), Nuclearreceptor co-activators 1 and 2 ( NCOA1 (SRC1), NCOA2 (GRIP1/TIF2) ) [5]. Androgen receptor with co-regulators induces expression oftarget genes, such as Prostate specific antigen Kallikrein-related peptidase 3 (Kallikrein 3 (PSA) ) in prostate [6], cyclin-dependent kinaseinhibitor Cyclin-dependent kinase inhibitor 1A ( p21 ) [7], Ezrin (VIL2(ezrin) ) [8], Matrix metalloproteinase 2 ( MMP-2 ) [9] and SREBF chaperone ( SCAP ) [10]. Besides co-activators,Androgen receptor can also recruit co-repressors such as Cyclin D1 [11], RAD9 homologs ( RAD9 ) [12], Nuclear receptor co-repressor1 ( N-CoR ) [13] and others.

Androgen receptor activity is tightly regulated by distinct growthfactor cascades, which can induce Androgen receptor modifications,including phosphorylation and acetylation or changes in interactions of Androgenreceptor with other cofactors. Epidermal growth factor ( EGF), Insulin-likegrowth factor 1 ( IGF-1 ), Interleukin-6 ( IL-6 ) and ligands stimulatingthe Protein kinase A, cAMP-dependent ( PKA-cat (cAMP-dependent) ) pathwaysactivate Androgen receptor by phosphorylation in the absence of androgenseither directly or indirectly via mitogen-activated protein kinase (MAPK) cascade andother signaling pathways in certain prostate cancer cells and, thereby, contribute toAndrogen receptor -induced gene expression [14].

Binding of IGF-1 ligands to Insulin-like growth factor 1 receptor ( IGF-1receptor ) leads to activation of MAPK cascade. Phosphorylated IGF-1 receptorcan directly interact with and phosphorylate adaptor protein SHC (Src homology 2 domaincontaining) transforming protein 1 ( Shc ), resulting in the recruitment of thecomplex containing Growth factor receptor-bound protein 2 ( GRB2 ) and Son ofsevenless homolog ( SOS ) and activation of small GTPase v-Ha-ras Harvey ratsarcoma viral oncogene homolog ( H-Ras ), v-raf-1 murine leukemia viral oncogenehomolog 1 ( c-Raf-1 ), and the MAPK cascade Mitogen-activated protein kinasekinase 1 ( MEK1(MAP2K1) )/ Mitogen-activated protein kinase 1 ( ERK2(MAPK1)) [14].

ERK2(MAPK1) kinase, in turn, phosphorylates and activates Androgenreceptor itself and Androgen receptor co-activators such as NCOA1(SRC1) and NCOA2 (GRIP1/TIF2) [15].

EGF enhances activity of Androgen receptor through activation ofMAPK cascade [16], [17].

IL-6 enhances Androgen receptor transactivation mainly via Signaltransducer and activator of transcription 3 ( STAT3 ), which associates withAndrogen receptor and is also able to induce Androgen receptor-mediated gene activation [18].

There is a cross talk between members of wingless-type MMTV integration site family (WNT ) and androgen signaling pathways. Catenin (cadherin-associated protein), beta1 (Beta-catenin) protein, is a critical molecular component of canonicalWNT signaling, flowing through Galpha(q)-specific frizzled GPCRs andDishevelled ( Dsh ). Beta-catenin promotes androgen signaling throughbinding to Androgen receptor in a ligand-dependent fashion and thefollow-up transcription activation of androgen-regulated genes [19], [20], [21]. Glycogen synthase kinase 3 beta ( GSK3 beta )involved in WNT signaling pathway, also functions as a repressor ofAndrogen receptor -mediated transactivation and cell growth via directphosphorylation of Androgen receptor [22].

Transforming growth factor, beta 1 ( TGF-beta 1 ) - mediated action follows acomplex signaling pathway from its binding to Transforming growth factor, beta receptors1 and II ( TGF-beta receptor type I, TGF-beta receptor type II ) and theirphosphorylation to activation of transcription factor SMAD family member 3 ( SMAD3). SMAD3 interacts with Androgen receptor and activateAndrogen receptor transcriptional activity in context-dependent manner[23].

p21 protein (Cdc42/Rac)-activated kinase 6 ( PAK6 ) is a serine/threoninekinase from the p21-activated kinase family. Active PAK6 phosphorylatesAndrogen receptor and inhibits its nuclear translocation [24].

Activation of the Phosphoinositide-3-kinase/ v-akt murine thymoma viral oncogenehomolog 1 ( AKT1 ) pathway results in AKT1- dependent phosphorylation ofAndrogen Receptor, suppression of Androgen receptor target genes,such as p21, and the decrease of androgen/ Androgen receptor-mediated apoptosis [25].

Proline-rich tyrosine kinase 2 ( Pyk2(FAK2) ) can repress Androgenreceptor transactivation via inactivation of Androgen receptorco-activator Transforming growth factor beta 1 induced transcript 1 ( Hic-5/ARA55). This inactivation may result from the direct phosphorylation of Hic-5/ARA55 byPyk2(FAK2) at tyrosine 43, impairing the co-activator activity ofHic-5/ARA55 and/or its sequestering to reduce the interaction with Androgenreceptor [26].