Pathway Map Details

Transcription_Ligand-dependent activation of the ESR1/SP pathway



view in full size
| open in MetaCore

Object list (links open in MetaCore):

Cyclin D1, CDC25A, NFYA, Cyclin E, Cyclin E2, Estradiol cytoplasm, PCAF, DNA polymerase alpha/primase, SP1/SP3 (complex), SP1, CBP, E2F1, ADA, CARM1, NCOA3 (pCIP/SRC3), NCOA1 (SRC1), p300, BAF, C/EBPbeta, HIF-1, Prolactin receptor, TYSY, ESR1, CAD, RARalpha, LDLR, EGFR, c-Fos, VEGF-A, SP3

Description:

Ligand-dependent activation of the ESR1/SP 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 manner [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). Sp1 transcription factor ( SP1 ) is one of transcription factors participating in the latter pathway [3]. 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 [4], [5] to estrogen-responsive promoters. Chromatin remodeling allows recruiting co-activators such as Nuclear receptor co-activator 1 ( NCOA1 ) [6]. 17beta-estradiol/ ESR1/ co-activator complex recruits integrator proteins and histone modifying enzymes such as CREB binding protein ( CBP ), E1A binding protein p300 ( p300 ) and K(lysine) acetyltransferase 2B ( PCAF ) [7], [6].

ESR1 forms a complex with SP1 in a ligand-dependent-manner. In most cases, non-classical pathways that involve ligand activation of ESR1/ SP1 do not require interactions of ESR1 with promoter DNA but with DNA-bound transcription factor SP1 [3]. For example, v-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) [8], Epidermal growth factor receptor ( EGFR ) [9], DNA polymerase alpha/primase [10], Thymidylate synthetase ( TYSY ) [11], Adenosine deaminase ( ADA ) [12], Retinoic acid receptor, alpha ( RARalpha ) [13] and Low density lipoprotein receptor ( LDLR ) [14] are regulated via DNA-bound ESR1 -activated SP1.

Some additional transcription factors participate in activation some genes via non-classical ESR1/ SP1 pathway. Thus, ESR1/ SP1 complex interacts with Nuclear transcription factor Y, alpha ( NFYA ) for a hormone-induced E2F transcription factor 1 ( E2F1 ) transcription [15]. ESR1/ SP1 and SP1 -bound NFYA and E2F1 are involved in activation of Cell division cycle 25A ( CDC25A ) by 17beta-estradiol [16]. Ligand-induced ESR1 stimulates Prolactin receptor transcription via direct activation of SP1/ Sp3 transcription factor ( SP3 ) ( SP1/ SP3 complex ) and CCAAT/enhancer binding protein beta ( C/EBPbeta ) transcription factors [6]. Cooperative interactions of ESR1/ SP1, ESR1/ SP3 and Hypoxia-inducible factor 1 ( HIF-1 ) are required for a 17beta-estradiol -induced Vascular endothelial growth factor A ( VEGF-A ) transcription [17], [7].

In a number of cases, both ESR1- and SP1- DNA interactions are required for transcription activation. Both ESR1 and SP1 are bound to promoters of Carbamoyl-phosphate synthetase 2 aspartate transcarbamylase and dihydroorotase ( CAD ) [18] and Cyclin D1 [19].

The genes regulated by ESR1/ SP1 play a role in cell cycle regulation and proliferation (e.g., CDC25A, c-Fos, Cyclin D1, DNA polymerase alpha/primase, E2F1, EGFR, Prolactin receptor and VEGF-A), purine/pyrimidine biosynthesis and metabolism (e.g., ADA, CAD, DNA polymerase alpha/primase and TYSY), immune response (e.g., Prolactin receptor ), regulation of lipid metabolism (e.g., LDLR and RARalpha ) and others.

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. Kim K, Thu N, Saville B, Safe S
    Domains of estrogen receptor alpha (ERalpha) required for ERalpha/Sp1-mediated activation of GC-rich promoters by estrogens and antiestrogens in breast cancer cells. Molecular endocrinology (Baltimore, Md.) 2003 May;17(5):804-17
  4. 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
  5. 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
  6. Dong J, Tsai-Morris CH, Dufau ML
    A novel estradiol-dependent non-ERE mediated transcriptional mechanism controlling expression of the human prolactin receptor. The Journal of biological chemistry 2006 May 1;
  7. Kazi AA, Jones JM, Koos RD
    Chromatin immunoprecipitation analysis of gene expression in the rat uterus in vivo: estrogen-induced recruitment of both estrogen receptor alpha and hypoxia-inducible factor 1 to the vascular endothelial growth factor promoter. Molecular endocrinology (Baltimore, Md.) 2005 Aug;19(8):2006-19
  8. Duan R, Porter W, Safe S
    Estrogen-induced c-fos protooncogene expression in MCF-7 human breast cancer cells: role of estrogen receptor Sp1 complex formation. Endocrinology 1998 Apr;139(4):1981-90
  9. Salvatori L, Ravenna L, Felli MP, Cardillo MR, Russo MA, Frati L, Gulino A, Petrangeli E
    Identification of an estrogen-mediated deoxyribonucleic acid-binding independent transactivation pathway on the epidermal growth factor receptor gene promoter. Endocrinology 2000 Jun;141(6):2266-74
  10. Samudio I, Vyhlidal C, Wang F, Stoner M, Chen I, Kladde M, Barhoumi R, Burghardt R, Safe S
    Transcriptional activation of deoxyribonucleic acid polymerase alpha gene expression in MCF-7 cells by 17 beta-estradiol. Endocrinology 2001 Mar;142(3):1000-8
  11. Xie W, Duan R, Chen I, Samudio I, Safe S
    Transcriptional activation of thymidylate synthase by 17beta-estradiol in MCF-7 human breast cancer cells. Endocrinology 2000 Jul;141(7):2439-49
  12. Xie W, Duan R, Safe S
    Estrogen induces adenosine deaminase gene expression in MCF-7 human breast cancer cells: role of estrogen receptor-Sp1 interactions. Endocrinology 1999 Jan;140(1):219-27
  13. Sun G, Porter W, Safe S
    Estrogen-induced retinoic acid receptor alpha 1 gene expression: role of estrogen receptor-Sp1 complex. Molecular endocrinology (Baltimore, Md.) 1998 Jun;12(6):882-90
  14. Li C, Briggs MR, Ahlborn TE, Kraemer FB, Liu J
    Requirement of Sp1 and estrogen receptor alpha interaction in 17beta-estradiol-mediated transcriptional activation of the low density lipoprotein receptor gene expression. Endocrinology 2001 Apr;142(4):1546-53
  15. Wang W, Dong L, Saville B, Safe S
    Transcriptional activation of E2F1 gene expression by 17beta-estradiol in MCF-7 cells is regulated by NF-Y-Sp1/estrogen receptor interactions. Molecular endocrinology (Baltimore, Md.) 1999 Aug;13(8):1373-87
  16. Ru Lee W, Chen CC, Liu S, Safe S
    17beta-estradiol (E2) induces cdc25A gene expression in breast cancer cells by genomic and non-genomic pathways. Journal of cellular biochemistry 2006 Apr 5;
  17. Stoner M, Wormke M, Saville B, Samudio I, Qin C, Abdelrahim M, Safe S
    Estrogen regulation of vascular endothelial growth factor gene expression in ZR-75 breast cancer cells through interaction of estrogen receptor alpha and SP proteins. Oncogene 2004 Feb 5;23(5):1052-63
  18. Khan S, Abdelrahim M, Samudio I, Safe S
    Estrogen receptor/Sp1 complexes are required for induction of cad gene expression by 17beta-estradiol in breast cancer cells. Endocrinology 2003 Jun;144(6):2325-35
  19. Castro-Rivera E, Samudio I, Safe S
    Estrogen regulation of cyclin D1 gene expression in ZR-75 breast cancer cells involves multiple enhancer elements. The Journal of biological chemistry 2001 Aug 17;276(33):30853-61