Transcription - Androgen Receptor nuclear signaling

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Androgen Receptor nuclear signaling

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

Binding of Testosterone or 5alpha-Dihydrotestosterone to Androgen receptor induces its dimerization, which is needed for binding to Androgen receptor's cognate response element and recruitment of co-regulators, such as transcriptional co-activator protein E1A binding protein p300 (p300), Nuclear receptor co-activators 1 and 2 (NCOA1 (SRC1), NCOA2 (GRIP1/TIF2)) [5]. Androgen receptor with co-regulators induces expression of target genes, such as Prostate specific antigen Kallikrein-related peptidase 3 (Kallikrein 3 (PSA)) in prostate [6], cyclin-dependent kinase inhibitor 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-repressor 1 (N-CoR) [13] and others.

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

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

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

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

IL-6 enhances Androgen receptor transactivation mainly via Signal transducer and activator of transcription 3 (STAT3), which associates with Androgen 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), beta 1 (Beta-catenin) protein, is a critical molecular component of canonical WNT signaling, flowing through Frizzled and Dishevelled (Dsh). Beta-catenin promotes androgen signaling through binding to Androgen receptor in a ligand-dependent fashion and the follow-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 of Androgen receptor -mediated transactivation and cell growth via direct phosphorylation of Androgen receptor [22].

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

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

Activation of the Phosphoinositide-3-kinase/ v-akt murine thymoma viral oncogene homolog 1 (AKT1) pathway results in AKT1- dependent phosphorylation of Androgen 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 Androgen receptor transactivation via inactivation of Androgen receptor co-activator Transforming growth factor beta 1 induced transcript 1 (Hic-5/ARA55). This inactivation may result from the direct phosphorylation of Hic-5/ARA55 by Pyk2(FAK2)at tyrosine 43, impairing the co-activator activity of Hic-5/ARA55 and/or its sequestering to reduce the interaction with Androgen receptor [26].

References:

  1. Wilson JD
    The role of 5alpha-reduction in steroid hormone physiology. Reproduction, fertility, and development 2001;13(7-8):673-8
  2. Heinlein CA, Chang C
    Androgen receptor in prostate cancer. Endocrine reviews 2004 Apr;25(2):276-308
  3. Gelmann EP
    Molecular biology of the androgen receptor. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2002 Jul 1;20(13):3001-15
  4. McEwan IJ
    Molecular mechanisms of androgen receptor-mediated gene regulation: structure-function analysis of the AF-1 domain. Endocrine-related cancer 2004 Jun;11(2):281-93
  5. Roy AK, Tyagi RK, Song CS, Lavrovsky Y, Ahn SC, Oh TS, Chatterjee B
    Androgen receptor: structural domains and functional dynamics after ligand-receptor interaction. Annals of the New York Academy of Sciences 2001 Dec;949:44-57
  6. Kim J, Coetzee GA
    Prostate specific antigen gene regulation by androgen receptor. Journal of cellular biochemistry 2004 Oct 1;93(2):233-41
  7. Lu S, Liu M, Epner DE, Tsai SY, Tsai MJ
    Androgen regulation of the cyclin-dependent kinase inhibitor p21 gene through an androgen response element in the proximal promoter. Molecular endocrinology (Baltimore, Md.) 1999 Mar;13(3):376-84
  8. Chuan YC, Pang ST, Cedazo-Minguez A, Norstedt G, Pousette A, Flores-Morales A
    Androgen induction of prostate cancer cell invasion is mediated by ezrin. The Journal of biological chemistry 2006 Oct 6;281(40):29938-48
  9. Li BY, Liao XB, Fujito A, Thrasher JB, Shen FY, Xu PY
    Dual androgen-response elements mediate androgen regulation of MMP-2 expression in prostate cancer cells. Asian journal of andrology 2007 Jan;9(1):41-50
  10. Heemers H, Verrijdt G, Organe S, Claessens F, Heyns W, Verhoeven G, Swinnen JV
    Identification of an androgen response element in intron 8 of the sterol regulatory element-binding protein cleavage-activating protein gene allowing direct regulation by the androgen receptor. The Journal of biological chemistry 2004 Jul 16;279(29):30880-7
  11. Petre CE, Wetherill YB, Danielsen M, Knudsen KE
    Cyclin D1: mechanism and consequence of androgen receptor co-repressor activity. The Journal of biological chemistry 2002 Jan 18;277(3):2207-15
  12. Wang L, Hsu CL, Ni J, Wang PH, Yeh S, Keng P, Chang C
    Human checkpoint protein hRad9 functions as a negative coregulator to repress androgen receptor transactivation in prostate cancer cells. Molecular and cellular biology 2004 Mar;24(5):2202-13
  13. Wu Y, Kawate H, Ohnaka K, Nawata H, Takayanagi R
    Nuclear compartmentalization of N-CoR and its interactions with steroid receptors. Molecular and cellular biology 2006 Sep;26(17):6633-55
  14. Culig Z
    Androgen receptor cross-talk with cell signalling pathways. Growth factors (Chur, Switzerland) 2004 Sep;22(3):179-84
  15. Rowan BG, Weigel NL, O'Malley BW
    Phosphorylation of steroid receptor coactivator-1. Identification of the phosphorylation sites and phosphorylation through the mitogen-activated protein kinase pathway. The Journal of biological chemistry 2000 Feb 11;275(6):4475-83
  16. Reinikainen P, Palvimo JJ, Janne OA
    Effects of mitogens on androgen receptor-mediated transactivation. Endocrinology 1996 Oct;137(10):4351-7
  17. Gupta C
    Modulation of androgen receptor (AR)-mediated transcriptional activity by EGF in the developing mouse reproductive tract primary cells. Molecular and cellular endocrinology 1999 Jun 25;152(1-2):169-78
  18. De Miguel F, Lee SO, Onate SA, Gao AC
    Stat3 enhances transactivation of steroid hormone receptors. Nuclear receptor 2003 Jun 13;1(1):3
  19. Song LN, Herrell R, Byers S, Shah S, Wilson EM, Gelmann EP
    Beta-catenin binds to the activation function 2 region of the androgen receptor and modulates the effects of the N-terminal domain and TIF2 on ligand-dependent transcription. Molecular and cellular biology 2003 Mar;23(5):1674-87
  20. Chesire DR, Isaacs WB
    Beta-catenin signaling in prostate cancer: an early perspective. Endocrine-related cancer 2003 Dec;10(4):537-60
  21. Mulholland DJ, Dedhar S, Coetzee GA, Nelson CC
    Interaction of nuclear receptors with the Wnt/beta-catenin/Tcf signaling axis: Wnt you like to know? Endocrine reviews 2005 Dec;26(7):898-915
  22. Wang L, Lin HK, Hu YC, Xie S, Yang L, Chang C
    Suppression of androgen receptor-mediated transactivation and cell growth by the glycogen synthase kinase 3 beta in prostate cells. The Journal of biological chemistry 2004 Jul 30;279(31):32444-52
  23. Kang HY, Huang KE, Chang SY, Ma WL, Lin WJ, Chang C
    Differential modulation of androgen receptor-mediated transactivation by Smad3 and tumor suppressor Smad4. The Journal of biological chemistry 2002 Nov 15;277(46):43749-56
  24. Schrantz N, da Silva Correia J, Fowler B, Ge Q, Sun Z, Bokoch GM
    Mechanism of p21-activated kinase 6-mediated inhibition of androgen receptor signaling. The Journal of biological chemistry 2004 Jan 16;279(3):1922-31
  25. Lin HK, Yeh S, Kang HY, Chang C
    Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proceedings of the National Academy of Sciences of the United States of America 2001 Jun 19;98(13):7200-5
  26. Wang X, Yang Y, Guo X, Sampson ER, Hsu CL, Tsai MY, Yeh S, Wu G, Guo Y, Chang C
    Suppression of androgen receptor transactivation by Pyk2 via interaction and phosphorylation of the ARA55 coregulator. The Journal of biological chemistry 2002 May 3;277(18):15426-31

  1. Wilson JD
    The role of 5alpha-reduction in steroid hormone physiology. Reproduction, fertility, and development 2001;13(7-8):673-8
  2. Heinlein CA, Chang C
    Androgen receptor in prostate cancer. Endocrine reviews 2004 Apr;25(2):276-308
  3. Gelmann EP
    Molecular biology of the androgen receptor. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2002 Jul 1;20(13):3001-15
  4. McEwan IJ
    Molecular mechanisms of androgen receptor-mediated gene regulation: structure-function analysis of the AF-1 domain. Endocrine-related cancer 2004 Jun;11(2):281-93
  5. Roy AK, Tyagi RK, Song CS, Lavrovsky Y, Ahn SC, Oh TS, Chatterjee B
    Androgen receptor: structural domains and functional dynamics after ligand-receptor interaction. Annals of the New York Academy of Sciences 2001 Dec;949:44-57
  6. Kim J, Coetzee GA
    Prostate specific antigen gene regulation by androgen receptor. Journal of cellular biochemistry 2004 Oct 1;93(2):233-41
  7. Lu S, Liu M, Epner DE, Tsai SY, Tsai MJ
    Androgen regulation of the cyclin-dependent kinase inhibitor p21 gene through an androgen response element in the proximal promoter. Molecular endocrinology (Baltimore, Md.) 1999 Mar;13(3):376-84
  8. Chuan YC, Pang ST, Cedazo-Minguez A, Norstedt G, Pousette A, Flores-Morales A
    Androgen induction of prostate cancer cell invasion is mediated by ezrin. The Journal of biological chemistry 2006 Oct 6;281(40):29938-48
  9. Li BY, Liao XB, Fujito A, Thrasher JB, Shen FY, Xu PY
    Dual androgen-response elements mediate androgen regulation of MMP-2 expression in prostate cancer cells. Asian journal of andrology 2007 Jan;9(1):41-50
  10. Heemers H, Verrijdt G, Organe S, Claessens F, Heyns W, Verhoeven G, Swinnen JV
    Identification of an androgen response element in intron 8 of the sterol regulatory element-binding protein cleavage-activating protein gene allowing direct regulation by the androgen receptor. The Journal of biological chemistry 2004 Jul 16;279(29):30880-7
  11. Petre CE, Wetherill YB, Danielsen M, Knudsen KE
    Cyclin D1: mechanism and consequence of androgen receptor co-repressor activity. The Journal of biological chemistry 2002 Jan 18;277(3):2207-15
  12. Wang L, Hsu CL, Ni J, Wang PH, Yeh S, Keng P, Chang C
    Human checkpoint protein hRad9 functions as a negative coregulator to repress androgen receptor transactivation in prostate cancer cells. Molecular and cellular biology 2004 Mar;24(5):2202-13
  13. Wu Y, Kawate H, Ohnaka K, Nawata H, Takayanagi R
    Nuclear compartmentalization of N-CoR and its interactions with steroid receptors. Molecular and cellular biology 2006 Sep;26(17):6633-55
  14. Culig Z
    Androgen receptor cross-talk with cell signalling pathways. Growth factors (Chur, Switzerland) 2004 Sep;22(3):179-84
  15. Rowan BG, Weigel NL, O'Malley BW
    Phosphorylation of steroid receptor coactivator-1. Identification of the phosphorylation sites and phosphorylation through the mitogen-activated protein kinase pathway. The Journal of biological chemistry 2000 Feb 11;275(6):4475-83
  16. Reinikainen P, Palvimo JJ, Janne OA
    Effects of mitogens on androgen receptor-mediated transactivation. Endocrinology 1996 Oct;137(10):4351-7
  17. Gupta C
    Modulation of androgen receptor (AR)-mediated transcriptional activity by EGF in the developing mouse reproductive tract primary cells. Molecular and cellular endocrinology 1999 Jun 25;152(1-2):169-78
  18. De Miguel F, Lee SO, Onate SA, Gao AC
    Stat3 enhances transactivation of steroid hormone receptors. Nuclear receptor 2003 Jun 13;1(1):3
  19. Song LN, Herrell R, Byers S, Shah S, Wilson EM, Gelmann EP
    Beta-catenin binds to the activation function 2 region of the androgen receptor and modulates the effects of the N-terminal domain and TIF2 on ligand-dependent transcription. Molecular and cellular biology 2003 Mar;23(5):1674-87
  20. Chesire DR, Isaacs WB
    Beta-catenin signaling in prostate cancer: an early perspective. Endocrine-related cancer 2003 Dec;10(4):537-60
  21. Mulholland DJ, Dedhar S, Coetzee GA, Nelson CC
    Interaction of nuclear receptors with the Wnt/beta-catenin/Tcf signaling axis: Wnt you like to know? Endocrine reviews 2005 Dec;26(7):898-915
  22. Wang L, Lin HK, Hu YC, Xie S, Yang L, Chang C
    Suppression of androgen receptor-mediated transactivation and cell growth by the glycogen synthase kinase 3 beta in prostate cells. The Journal of biological chemistry 2004 Jul 30;279(31):32444-52
  23. Kang HY, Huang KE, Chang SY, Ma WL, Lin WJ, Chang C
    Differential modulation of androgen receptor-mediated transactivation by Smad3 and tumor suppressor Smad4. The Journal of biological chemistry 2002 Nov 15;277(46):43749-56
  24. Schrantz N, da Silva Correia J, Fowler B, Ge Q, Sun Z, Bokoch GM
    Mechanism of p21-activated kinase 6-mediated inhibition of androgen receptor signaling. The Journal of biological chemistry 2004 Jan 16;279(3):1922-31
  25. Lin HK, Yeh S, Kang HY, Chang C
    Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proceedings of the National Academy of Sciences of the United States of America 2001 Jun 19;98(13):7200-5
  26. Wang X, Yang Y, Guo X, Sampson ER, Hsu CL, Tsai MY, Yeh S, Wu G, Guo Y, Chang C
    Suppression of androgen receptor transactivation by Pyk2 via interaction and phosphorylation of the ARA55 coregulator. The Journal of biological chemistry 2002 May 3;277(18):15426-31

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