title: Regulation of androgen receptor-dependent transcription by coactivator MED1 is mediated through a newly discovered noncanonical binding motif.
abstract: Nuclear receptor (NR) activation by cognate ligand generally involves allosteric realignment of C-terminal α-helices thus generating a binding surface for coactivators containing canonical LXXLL α-helical motifs. The androgen receptor (AR) is uncommon among NRs in that ligand triggers an intramolecular interaction between its N- and C-terminal domains (termed the N/C interaction) and that coactivators can alternatively bind to surfaces in the AR N-terminal or hinge regions. The evolutionary conserved Mediator complex plays a key coregulatory role in steroid hormone-dependent transcription and is chiefly targeted to NRs via the LXXLL-containing MED1 subunit. Whereas MED1 has been demonstrated to serve as a key transcriptional coactivator for AR, the mechanisms by which AR recruits MED1 have remained unclear. Here we show that MED1 binds to a distinct AR N-terminal region termed transactivation unit-1 (Tau-1) via two newly discovered noncanonical α-helical motifs located between MED1 residues 505 and 537. Neither of the two MED1 LXXLL motifs is required for AR binding, whereas loss of the intramolecular AR N/C interaction decreases MED1 binding. We further demonstrate that mitogen-activated protein kinase phosphorylation of MED1 enhances the AR-MED1 interaction in prostate cancer cells. In sum, our findings reveal a novel AR-coactivator binding mechanism that may have clinical implications for AR activity in prostate cancer.
authors.affiliation: Department of Physiology and Biophysics, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Jin
authors.forename: Frank
authors.initials: F
authors.lastname: Claessens
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Fondell
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D056913:Mediator Complex Subunit 1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; D011944:Receptors, Androgen; D048049:Extracellular Signal-Regulated MAP Kinases
references.citation: PLoS Biol. 2004 Sep;2(9):E274
references.pmid: 15328534
references.citation: J Biol Chem. 2000 Jul 28;275(30):22986-94
references.pmid: 10816582
references.citation: J Cell Biochem. 2004 Jan 1;91(1):13-25
references.pmid: 14689577
references.citation: Rev Physiol Biochem Pharmacol. 2006;156:23-43
references.pmid: 16634145
references.citation: Nat Rev Genet. 2010 Nov;11(11):761-72
references.pmid: 20940737
references.citation: J Biol Chem. 2004 Feb 20;279(8):7119-30
references.pmid: 14662770
references.citation: Cancer Res. 1999 Jan 15;59(2):279-84
references.pmid: 9927031
references.citation: J Biol Chem. 2001 Dec 7;276(49):46469-79
references.pmid: 11591711
references.citation: Curr Opin Cell Biol. 1998 Jun;10(3):384-91
references.pmid: 9640540
references.citation: Mol Endocrinol. 1997 Feb;11(2):148-61
references.pmid: 9013762
references.citation: Mol Cell. 2004 Jun 4;14(5):675-83
references.pmid: 15175162
references.citation: Cell. 2006 Feb 10;124(3):615-29
references.pmid: 16469706
references.citation: Mol Cell. 2005 Jul 1;19(1):89-100
references.pmid: 15989967
references.citation: Genes Dev. 2000 Jan 15;14(2):121-41
references.pmid: 10652267
references.citation: Cell. 2009 Jul 23;138(2):245-56
references.pmid: 19632176
references.citation: J Biol Chem. 2005 Mar 11;280(10):8819-30
references.pmid: 15625066
references.citation: Mol Endocrinol. 2007 Dec;21(12):2855-63
references.pmid: 17636035
references.citation: J Biol Chem. 2006 Aug 11;281(32):22656-64
references.pmid: 16769725
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14477-82
references.pmid: 16973750
references.citation: Cancer Res. 2003 Apr 15;63(8):1981-9
references.pmid: 12702592
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3100-5
references.pmid: 16492776
references.citation: Cancer Res. 2004 Oct 1;64(19):7156-68
references.pmid: 15466214
references.citation: J Biol Chem. 2003 Mar 7;278(10):8212-8
references.pmid: 12509416
references.citation: Endocr Rev. 2001 Apr;22(2):153-83
references.pmid: 11294822
references.citation: Mol Cell. 2005 Sep 2;19(5):631-42
references.pmid: 16137620
references.citation: Nature. 1997 Jun 12;387(6634):733-6
references.pmid: 9192902
references.citation: J Biol Chem. 2002 Nov 8;277(45):42852-8
references.pmid: 12218053
references.citation: EMBO J. 2000 Oct 16;19(20):5406-17
references.pmid: 11032808
references.citation: Nature. 1998 Sep 10;395(6698):137-43
references.pmid: 9744270
references.citation: Mol Cell Biol. 1999 Dec;19(12):8383-92
references.pmid: 10567563
references.citation: Cancer Res. 2006 Jan 1;66(1):543-53
references.pmid: 16397271
references.citation: Mol Endocrinol. 2006 Apr;20(4):776-85
references.pmid: 16373397
references.citation: Genes Dev. 1998 Nov 1;12(21):3343-56
references.pmid: 9808622
references.citation: EMBO J. 1999 Oct 1;18(19):5380-8
references.pmid: 10508170
references.citation: Nucleic Acids Res. 2009 Aug;37(14):4826-38
references.pmid: 19520769
references.citation: EMBO J. 2003 May 1;22(9):2146-55
references.pmid: 12727881
references.citation: J Biol Chem. 2002 Dec 20;277(51):49230-7
references.pmid: 12370175
references.citation: Cancer Res. 2008 Jun 15;68(12):4551-8
references.pmid: 18559499
references.citation: Mol Cell Biol. 2008 Jun;28(12):3932-42
references.pmid: 18391015
references.citation: Transcription. 2011 Jan-Feb;2(1):28-31
references.pmid: 21326907
references.citation: J Biol Chem. 1995 Mar 31;270(13):7341-6
references.pmid: 7706276
references.citation: EMBO J. 1992 Mar;11(3):1025-33
references.pmid: 1372244
references.citation: Science. 1994 Aug 12;265(5174):966-70
references.pmid: 8052857
references.citation: Nucl Recept Signal. 2008 Jun 27;6:e008
references.pmid: 18612376
references.citation: J Biol Chem. 2010 Mar 19;285(12):9161-71
references.pmid: 20086010
references.citation: EMBO J. 2011 May 10;30(12):2405-19
references.pmid: 21556051
references.citation: Mol Cell Endocrinol. 1993 Aug;94(2):165-72
references.pmid: 8224520
references.citation: Mol Endocrinol. 2004 Sep;18(9):2132-50
references.pmid: 15178743
references.citation: Trends Biochem Sci. 2005 May;30(5):235-9
references.pmid: 15896740
references.citation: Mol Cell Biol. 1999 Sep;19(9):6085-97
references.pmid: 10454556
references.citation: Cancer Res. 1997 Mar 1;57(5):995-1002
references.pmid: 9041206
references.citation: Cancer Res. 2007 May 1;67(9):4034-41
references.pmid: 17483314
references.citation: Mol Cell Biol. 2005 Dec;25(24):10695-710
references.pmid: 16314496
references.citation: Mol Cell Biol. 2000 Aug;20(15):5433-46
references.pmid: 10891484
references.citation: Mol Cell. 2004 Nov 5;16(3):425-38
references.pmid: 15525515
references.citation: Mol Cell Endocrinol. 1999 Jun 25;152(1-2):199-206
references.pmid: 10432237