Development - Ligand-dependent activation of the ESR1/AP-1 pathway

Ligand-dependent activation of the ESR1/AP-1 pathway

Estrogen receptor 1 (ESR1) is a major ligand-activated transcription factor, member of the family nuclear receptors [1]. ESR1 acts via two main pathways: a ligand-dependent and ligand-independent [2]. Activated by a ligand, ESR1 stimulates transcription directly (classical pathway), or by activation of other transcription factors in ligand-dependent manner (non-classical pathway). Members of AP-1 family Jun oncogene (c-Jun) and v-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos) are a one of these transfactors [3], [4], [5].

Active ESR1 is a dimer bound to DNA at specific target sequences called estrogen response elements [2].

17beta-estradiol is a physiological ligand of the ESR1. In the absence of the 17beta-estradiol, ESR1 resides primarily in the nucleus, with some presence in cytoplasm. Ligand-bound ESR1 moves to the nucleus.

In the present of 17beta-estradiol, ESR1 recruits ATP-dependent chromatin remodeling complex BAF [6], [7] to estrogen-responsive promoters. Chromatin remodeling allows recruiting co-activators such as Nuclear receptor co-activator 1 (NCOA1 (SRC1)) [8] and Nuclear receptor co-activator 2 (NCOA2 (GRIP1/TIF2)) [4], [5].

17beta-estradiol/ ESR1/ co-activator complex then recruits integrator proteins and histone modifying enzymes such as CREB binding protein (CBP) and E1A binding protein p300 (p300) [3], [5], [9].

Then, ESR1 directly binds to c-Jun protein. This interaction is stabilized by the coactivator NCOA2 (GRIP1/TIF2), which interacts with both c-Jun and ESR1 [4], [5]. In addition, NCOA1 (SRC1) may participate in this process interacting with c-Jun, c-Fos and ESR1 [3].

Nuclear receptor interacting protein 1 (RIP140) is a regulator in ESR1/ AP-1 pathway. RIP140 physically interacts with c-Jun and ESR1 and inhibits estradiol-induced AP-1-mediated transcription. In addition, RIP140 directly binds to histone deacetylases (e.g, Histone deacetylase 4, HDAC4) and to co-repressor C-terminal binding protein 1 (CtBP1) which itself interacts with histone deacetylases (e.g, Histone deacetylase 1, HDAC1). Deacetylation of chromatin proteins by histone deacetylases leads to inhibition of ESR1/ AP-1-induced transcription [5]. In addition, CtBP1 represses p300-mediated transcriptional activation by direct association with its bromodomain [10].

ESR1 may activate transcription of RIP140, thus establishing a regulatory feedback loop [11].

References:

1. Glass CK, Rosenfeld MG
   The coregulator exchange in transcriptional functions of nuclear receptors. Genes & development 2000 Jan 15;14(2):121-41
2. Shupnik MA
   Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation. Oncogene 2004 Oct 18;23(48):7979-89
3. Lee SK, Kim HJ, Na SY, Kim TS, Choi HS, Im SY, Lee JW
   Steroid receptor coactivator-1 coactivates activating protein-1-mediated transactivations through interaction with the c-Jun and c-Fos subunits. The Journal of biological chemistry 1998 Jul 3;273(27):16651-4
4. Teyssier C, Belguise K, Galtier F, Chalbos D
   Characterization of the physical interaction between estrogen receptor alpha and JUN proteins. The Journal of biological chemistry 2001 Sep 28;276(39):36361-9
5. Teyssier C, Belguise K, Galtier F, Cavailles V, Chalbos D
   Receptor-interacting protein 140 binds c-Jun and inhibits estradiol-induced activator protein-1 activity by reversing glucocorticoid receptor-interacting protein 1 effect. Molecular endocrinology (Baltimore, Md.) 2003 Feb;17(2):287-99
6. Belandia B, Orford RL, Hurst HC, Parker MG
   Targeting of SWI/SNF chromatin remodelling complexes to estrogen-responsive genes. The EMBO journal 2002 Aug 1;21(15):4094-103
7. Nie Z, Yan Z, Chen EH, Sechi S, Ling C, Zhou S, Xue Y, Yang D, Murray D, Kanakubo E, Cleary ML, Wang W
   Novel SWI/SNF chromatin-remodeling complexes contain a mixed-lineage leukemia chromosomal translocation partner. Molecular and cellular biology 2003 Apr;23(8):2942-52
8. Dong J, Tsai-Morris CH, Dufau ML
   A novel estradiol/estrogen receptor alpha-dependent transcriptional mechanism controls expression of the human prolactin receptor. The Journal of biological chemistry 2006 Jul 7;281(27):18825-36
9. Moggs JG, Orphanides G
   Estrogen receptors: orchestrators of pleiotropic cellular responses. EMBO reports 2001 Sep;2(9):775-81
10. Kim JH, Cho EJ, Kim ST, Youn HD
    CtBP represses p300-mediated transcriptional activation by direct association with its bromodomain. Nature structural & molecular biology 2005 May;12(5):423-8
11. Augereau P, Badia E, Fuentes M, Rabenoelina F, Corniou M, Derocq D, Balaguer P, Cavailles V
    Transcriptional regulation of the human NRIP1/RIP140 gene by estrogen is modulated by dioxin signalling. Molecular pharmacology 2006 Apr;69(4):1338-46