• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of embojLink to Publisher's site
EMBO J. Jan 2, 1998; 17(1): 232–243.
PMCID: PMC1170374

Isoforms of steroid receptor co-activator 1 differ in their ability to potentiate transcription by the oestrogen receptor.

Abstract

Steroid receptor co-activator (SRC1) is one of a number of transcriptional co-activators that are capable of potentiating the activity of nuclear receptors including the oestrogen receptor (ER). Here we report that two isoforms, SRC1a and SRC1e, which diverge at their C-termini, are functionally distinct as they differ in their abilities to enhance the activity of the ER in intact cells. SRC1e enhanced the ability of the ER to stimulate transcription to a greater extent than SRC1a, which had negligible effects on certain promoters. To elucidate the basis of this functional difference, we compared the nuclear receptor-binding properties and mapped the transcriptional activation domains in the two SRC1 isoforms. Both isoforms share a triplet of nuclear receptor-binding motifs (LXXLL motifs) for binding to functional ER dimers, and an activation domain which co-localizes with the CBP-binding domain, while SRC1a contains a unique LXXLL motif in its C-terminus. Although this LXXLL motif increases the affinity for the ER in vitro, it does not appear to be responsible for the functional difference between the two isoforms. This difference is due to a second activation domain that is CBP independent and is suppressed in the SRC1a isoform. Thus, SRC1 exists as functionally distinct isoforms which are likely to play different roles in ER-mediated transcription.

Full Text

The Full Text of this article is available as a PDF (516K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Adan RA, Cox JJ, van Kats JP, Burbach JP. Thyroid hormone regulates the oxytocin gene. J Biol Chem. 1992 Feb 25;267(6):3771–3777. [PubMed]
  • Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science. 1997 Aug 15;277(5328):965–968. [PubMed]
  • Bannister AJ, Kouzarides T. The CBP co-activator is a histone acetyltransferase. Nature. 1996 Dec 19;384(6610):641–643. [PubMed]
  • Barettino D, Vivanco Ruiz MM, Stunnenberg HG. Characterization of the ligand-dependent transactivation domain of thyroid hormone receptor. EMBO J. 1994 Jul 1;13(13):3039–3049. [PMC free article] [PubMed]
  • Beato M, Herrlich P, Schütz G. Steroid hormone receptors: many actors in search of a plot. Cell. 1995 Dec 15;83(6):851–857. [PubMed]
  • Bourguet W, Ruff M, Chambon P, Gronemeyer H, Moras D. Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-alpha. Nature. 1995 Jun 1;375(6530):377–382. [PubMed]
  • Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engström O, Ohman L, Greene GL, Gustafsson JA, Carlquist M. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature. 1997 Oct 16;389(6652):753–758. [PubMed]
  • Bunone G, Briand PA, Miksicek RJ, Picard D. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J. 1996 May 1;15(9):2174–2183. [PMC free article] [PubMed]
  • Cavaillès V, Dauvois S, Danielian PS, Parker MG. Interaction of proteins with transcriptionally active estrogen receptors. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10009–10013. [PMC free article] [PubMed]
  • Cavaillès V, Dauvois S, L'Horset F, Lopez G, Hoare S, Kushner PJ, Parker MG. Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J. 1995 Aug 1;14(15):3741–3751. [PMC free article] [PubMed]
  • Chakravarti D, LaMorte VJ, Nelson MC, Nakajima T, Schulman IG, Juguilon H, Montminy M, Evans RM. Role of CBP/P300 in nuclear receptor signalling. Nature. 1996 Sep 5;383(6595):99–103. [PubMed]
  • Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J. 1996 Jul;10(9):940–954. [PubMed]
  • Chang KH, Chen Y, Chen TT, Chou WH, Chen PL, Ma YY, Yang-Feng TL, Leng X, Tsai MJ, O'Malley BW, et al. A thyroid hormone receptor coactivator negatively regulated by the retinoblastoma protein. Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9040–9045. [PMC free article] [PubMed]
  • Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell. 1997 Aug 8;90(3):569–580. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Danielian PS, White R, Lees JA, Parker MG. Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. EMBO J. 1992 Mar;11(3):1025–1033. [PMC free article] [PubMed]
  • Danielian PS, White R, Hoare SA, Fawell SE, Parker MG. Identification of residues in the estrogen receptor that confer differential sensitivity to estrogen and hydroxytamoxifen. Mol Endocrinol. 1993 Feb;7(2):232–240. [PubMed]
  • DiRenzo J, Söderstrom M, Kurokawa R, Ogliastro MH, Ricote M, Ingrey S, Hörlein A, Rosenfeld MG, Glass CK. Peroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressors. Mol Cell Biol. 1997 Apr;17(4):2166–2176. [PMC free article] [PubMed]
  • Durand B, Saunders M, Gaudon C, Roy B, Losson R, Chambon P. Activation function 2 (AF-2) of retinoic acid receptor and 9-cis retinoic acid receptor: presence of a conserved autonomous constitutive activating domain and influence of the nature of the response element on AF-2 activity. EMBO J. 1994 Nov 15;13(22):5370–5382. [PMC free article] [PubMed]
  • Fawell SE, Lees JA, White R, Parker MG. Characterization and colocalization of steroid binding and dimerization activities in the mouse estrogen receptor. Cell. 1990 Mar 23;60(6):953–962. [PubMed]
  • Folkers GE, van der Saag PT. Adenovirus E1A functions as a cofactor for retinoic acid receptor beta (RAR beta) through direct interaction with RAR beta. Mol Cell Biol. 1995 Nov;15(11):5868–5878. [PMC free article] [PubMed]
  • Glynne R, Kerr LA, Mockridge I, Beck S, Kelly A, Trowsdale J. The major histocompatibility complex-encoded proteasome component LMP7: alternative first exons and post-translational processing. Eur J Immunol. 1993 Apr;23(4):860–866. [PubMed]
  • Green S, Issemann I, Sheer E. A versatile in vivo and in vitro eukaryotic expression vector for protein engineering. Nucleic Acids Res. 1988 Jan 11;16(1):369–369. [PMC free article] [PubMed]
  • Halachmi S, Marden E, Martin G, MacKay H, Abbondanza C, Brown M. Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription. Science. 1994 Jun 3;264(5164):1455–1458. [PubMed]
  • Hanstein B, Eckner R, DiRenzo J, Halachmi S, Liu H, Searcy B, Kurokawa R, Brown M. p300 is a component of an estrogen receptor coactivator complex. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11540–11545. [PMC free article] [PubMed]
  • Heery DM, Kalkhoven E, Hoare S, Parker MG. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature. 1997 Jun 12;387(6634):733–736. [PubMed]
  • Henttu PM, Kalkhoven E, Parker MG. AF-2 activity and recruitment of steroid receptor coactivator 1 to the estrogen receptor depend on a lysine residue conserved in nuclear receptors. Mol Cell Biol. 1997 Apr;17(4):1832–1839. [PMC free article] [PubMed]
  • Hong H, Kohli K, Garabedian MJ, Stallcup MR. GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors. Mol Cell Biol. 1997 May;17(5):2735–2744. [PMC free article] [PubMed]
  • Ing NH, Beekman JM, Tsai SY, Tsai MJ, O'Malley BW. Members of the steroid hormone receptor superfamily interact with TFIIB (S300-II). J Biol Chem. 1992 Sep 5;267(25):17617–17623. [PubMed]
  • Jacq X, Brou C, Lutz Y, Davidson I, Chambon P, Tora L. Human TAFII30 is present in a distinct TFIID complex and is required for transcriptional activation by the estrogen receptor. Cell. 1994 Oct 7;79(1):107–117. [PubMed]
  • Jones T, Sheer D, Bevec D, Kappel B, Hauber J, Steinkasserer A. The human HIV-1 Rev binding-protein hRIP/Rab (HRB) maps to chromosome 2q36. Genomics. 1997 Feb 15;40(1):198–199. [PubMed]
  • Kalkhoven E, Roelen BA, de Winter JP, Mummery CL, van den Eijnden-van Raaij AJ, van der Saag PT, van der Burg B. Resistance to transforming growth factor beta and activin due to reduced receptor expression in human breast tumor cell lines. Cell Growth Differ. 1995 Sep;6(9):1151–1161. [PubMed]
  • Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA, Rose DW, Glass CK, et al. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell. 1996 May 3;85(3):403–414. [PubMed]
  • Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science. 1995 Dec 1;270(5241):1491–1494. [PubMed]
  • Kurokawa R, Söderström M, Hörlein A, Halachmi S, Brown M, Rosenfeld MG, Glass CK. Polarity-specific activities of retinoic acid receptors determined by a co-repressor. Nature. 1995 Oct 5;377(6548):451–454. [PubMed]
  • Lahooti H, White R, Danielian PS, Parker MG. Characterization of ligand-dependent phosphorylation of the estrogen receptor. Mol Endocrinol. 1994 Feb;8(2):182–188. [PubMed]
  • Le Douarin B, Zechel C, Garnier JM, Lutz Y, Tora L, Pierrat P, Heery D, Gronemeyer H, Chambon P, Losson R. The N-terminal part of TIF1, a putative mediator of the ligand-dependent activation function (AF-2) of nuclear receptors, is fused to B-raf in the oncogenic protein T18. EMBO J. 1995 May 1;14(9):2020–2033. [PMC free article] [PubMed]
  • Lee JW, Ryan F, Swaffield JC, Johnston SA, Moore DD. Interaction of thyroid-hormone receptor with a conserved transcriptional mediator. Nature. 1995 Mar 2;374(6517):91–94. [PubMed]
  • Lees JA, Fawell SE, Parker MG. Identification of two transactivation domains in the mouse oestrogen receptor. Nucleic Acids Res. 1989 Jul 25;17(14):5477–5488. [PMC free article] [PubMed]
  • L'Horset F, Dauvois S, Heery DM, Cavaillès V, Parker MG. RIP-140 interacts with multiple nuclear receptors by means of two distinct sites. Mol Cell Biol. 1996 Nov;16(11):6029–6036. [PMC free article] [PubMed]
  • Li H, Gomes PJ, Chen JD. RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8479–8484. [PMC free article] [PubMed]
  • Lillie JW, Green MR. Transcription activation by the adenovirus E1a protein. Nature. 1989 Mar 2;338(6210):39–44. [PubMed]
  • Mangelsdorf DJ, Umesono K, Kliewer SA, Borgmeyer U, Ong ES, Evans RM. A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR. Cell. 1991 Aug 9;66(3):555–561. [PubMed]
  • Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schütz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, et al. The nuclear receptor superfamily: the second decade. Cell. 1995 Dec 15;83(6):835–839. [PubMed]
  • McInerney EM, Tsai MJ, O'Malley BW, Katzenellenbogen BS. Analysis of estrogen receptor transcriptional enhancement by a nuclear hormone receptor coactivator. Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10069–10073. [PMC free article] [PubMed]
  • Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell. 1996 Nov 29;87(5):953–959. [PubMed]
  • Oñate SA, Tsai SY, Tsai MJ, O'Malley BW. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science. 1995 Nov 24;270(5240):1354–1357. [PubMed]
  • Parker MG. Steroid and related receptors. Curr Opin Cell Biol. 1993 Jun;5(3):499–504. [PubMed]
  • Renaud JP, Rochel N, Ruff M, Vivat V, Chambon P, Gronemeyer H, Moras D. Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid. Nature. 1995 Dec 14;378(6558):681–689. [PubMed]
  • Saatcioglu F, Bartunek P, Deng T, Zenke M, Karin M. A conserved C-terminal sequence that is deleted in v-ErbA is essential for the biological activities of c-ErbA (the thyroid hormone receptor). Mol Cell Biol. 1993 Jun;13(6):3675–3685. [PMC free article] [PubMed]
  • Sadovsky Y, Webb P, Lopez G, Baxter JD, Fitzpatrick PM, Gizang-Ginsberg E, Cavailles V, Parker MG, Kushner PJ. Transcriptional activators differ in their responses to overexpression of TATA-box-binding protein. Mol Cell Biol. 1995 Mar;15(3):1554–1563. [PMC free article] [PubMed]
  • Sadowski I, Ptashne M. A vector for expressing GAL4(1-147) fusions in mammalian cells. Nucleic Acids Res. 1989 Sep 25;17(18):7539–7539. [PMC free article] [PubMed]
  • Sleigh MJ. A nonchromatographic assay for expression of the chloramphenicol acetyltransferase gene in eucaryotic cells. Anal Biochem. 1986 Jul;156(1):251–256. [PubMed]
  • Smith CL, Oñate SA, Tsai MJ, O'Malley BW. CREB binding protein acts synergistically with steroid receptor coactivator-1 to enhance steroid receptor-dependent transcription. Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):8884–8888. [PMC free article] [PubMed]
  • Spencer TE, Jenster G, Burcin MM, Allis CD, Zhou J, Mizzen CA, McKenna NJ, Onate SA, Tsai SY, Tsai MJ, et al. Steroid receptor coactivator-1 is a histone acetyltransferase. Nature. 1997 Sep 11;389(6647):194–198. [PubMed]
  • Tasset D, Tora L, Fromental C, Scheer E, Chambon P. Distinct classes of transcriptional activating domains function by different mechanisms. Cell. 1990 Sep 21;62(6):1177–1187. [PubMed]
  • Tone Y, Collingwood TN, Adams M, Chatterjee VK. Functional analysis of a transactivation domain in the thyroid hormone beta receptor. J Biol Chem. 1994 Dec 9;269(49):31157–31161. [PubMed]
  • Tora L, White J, Brou C, Tasset D, Webster N, Scheer E, Chambon P. The human estrogen receptor has two independent nonacidic transcriptional activation functions. Cell. 1989 Nov 3;59(3):477–487. [PubMed]
  • Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK, Rosenfeld MG. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature. 1997 Jun 12;387(6634):677–684. [PubMed]
  • vom Baur E, Zechel C, Heery D, Heine MJ, Garnier JM, Vivat V, Le Douarin B, Gronemeyer H, Chambon P, Losson R. Differential ligand-dependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1. EMBO J. 1996 Jan 2;15(1):110–124. [PMC free article] [PubMed]
  • Wagner RL, Apriletti JW, McGrath ME, West BL, Baxter JD, Fletterick RJ. A structural role for hormone in the thyroid hormone receptor. Nature. 1995 Dec 14;378(6558):690–697. [PubMed]
  • White R, Jobling S, Hoare SA, Sumpter JP, Parker MG. Environmentally persistent alkylphenolic compounds are estrogenic. Endocrinology. 1994 Jul;135(1):175–182. [PubMed]
  • Wurtz JM, Bourguet W, Renaud JP, Vivat V, Chambon P, Moras D, Gronemeyer H. A canonical structure for the ligand-binding domain of nuclear receptors. Nat Struct Biol. 1996 Jan;3(1):87–94. [PubMed]
  • Yang XJ, Ogryzko VV, Nishikawa J, Howard BH, Nakatani Y. A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature. 1996 Jul 25;382(6589):319–324. [PubMed]
  • Yao TP, Ku G, Zhou N, Scully R, Livingston DM. The nuclear hormone receptor coactivator SRC-1 is a specific target of p300. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10626–10631. [PMC free article] [PubMed]
  • Yeh S, Chang C. Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5517–5521. [PMC free article] [PubMed]

Articles from The EMBO Journal are provided here courtesy of The European Molecular Biology Organization

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...