Estrogen down-regulation of the corepressor N-CoR: Mechanism and implications for estrogen derepression of N-CoR-regulated genes

Abstract

C ellular activity is precisely regulated by a finely tuned balance between coactivator and corepressor proteins that control transcriptional networks during development and in normal and cancerous states (1). The corepressors N-CoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors) play crucial roles in transcriptional repression by multiple classes of transcription factors, including some nuclear hormone receptors. Repression by N-CoR and SMRT results from their association with large histone deacetylase complexes, which lead to histone deacetylation, altered chromatin structure, and decreased gene transcription (reviewed in ref. 2). Although few studies have demonstrated that N-CoR expression is regulated at the level of gene transcription, several examples of posttranslational regulation of N-CoR expression and activity have been described. Recent studies have shown that N-CoR interaction with transcription factors, such as NF-B and estrogen receptor (ER), can be reduced through translocation of N-CoR out of the nucleus and into the cytoplasm (3-5). N-CoR has also been shown to be regulated by ubiquitin-mediated protein degradation through an interaction with the E3 ubiquitin ligase Siah2, a mammalian homolog of Drosophila seven in absentia (Sina), which leads to the ubiquitination and degradation of N-CoR by the 26S proteasome (6).The majority of estrogen's effects on its numerous target tissues are mediated by its two receptors, ER␣ and ER␤, which act primarily as ligand-dependent transcription factors. Upon binding to its ligand, the ER associates with DNA either directly at estrogen response elements or through tethering to other transcription factors, leading to the recruitment of transcriptional coregulators and chromatin-modifying complexes and the regulation of gene expression (7). We and others (8-17) have used microarray gene expression profiling to identify estrogen target genes in breast cancer cells, where estrogen has been shown to stimulate proliferation and suppress apoptosis through the regulation of multiple genes. These studies have demonstrated that, as expected, estrogen up-regulates many cell-cycle regulators, growth factors, and antiapoptotic genes but also down-regulates a number of cell-cycle inhibitors and proapoptotic genes.Estrogen also regulates the mRNA expression of important transcriptional regulators, both transcription factors and transcriptional coactivators and corepressors (12). Evidence supporting the idea that 17␤-estradiol (E2) is capable of regulating the expression of coregulators has grown in the past few years. For example, this hormone has been shown to up-regulate mRNA levels for the corepressors RIP140 (12, 18), SHP (19), and SHARP (20) and also to down-regulate mRNA levels for the coactivators 21). In addition to the regulation of mRNA for some coregulators, the activity of these proteins can be modulated by hormone by changing the protein's state of phosphorylation, as observed for the coactivator SRC3͞AIB1...

A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells

“…Several previously known ERa-regulated genes were detected in this study, for example, TFF1/pS2 (FC 34.8), GREB1 (FC B8 for three transcript variants), SIAH 2 (FC 5.3), SDF1/CXCL12 (FC 5.6), IGFBP-4 (FC 5.5), CCNA2 (FC 4.2), STC2 (FC 2.3), PR (FC 1.9), RBBP-8 (FC 1.7), NRIP1/RIP140 (FC 1.7), CTSD (FC 1.6) and NR5A2/LRH1 (FC 1.7), all confirming the data previously published (Roberts et al, 1988;Inoue et al, 2002;Hall and Korach, 2003;Annicotte et al, 2005;Frasor et al, 2005). Also downregulated genes such as ERa itself (FC 0. by ERa and decrease of S100A6/calcyclin by ERb correlates to the earlier findings of in vivo gene expression in wt and ER knockout mouse bone tissue (Lindberg et al, 2003).…”

Transient over-expression of estrogen receptor-α in breast cancer cells promotes cell survival and estrogen-independent growth

“…However, the ubiquitin ligase mSiah2 has been implicated in regulating proteasomal degradation of NCoR [32]. Siah2 expression has been shown to be estrogen-regulated and to mediate the estrogen-stimulated down-regulation of NCoR, but not SMRT protein [33], although examination of the microarray data did not show a significant difference in Siah2 levels between MCF-7 and MLET5 cells, with 2.3 and 2.1 fold stimulation of Siah2 expression by estrogen, respectively.…”

Novel Function of E3 Ubiquitin Ligase Siah2 to Regulate ROS Metabolism

“…Siah contains functional binding sites that recognize a peptide motif within many substrates and adaptors [16] . Siah proteins bind to a highly conserved PxAxVxP motif in their substrates [17] , and interact with numerous cellular proteins such as a transcriptional repressor, Tramtrack; peptide inhibitor, PHYL; the oncogenic protein, b-catenin; a nuclear receptor co-repressor, N-Cor; a motor protein Kid; and the tumor suppressor TGF-b induced early gene (TIEG) [12,15,[18][19][20] . In some cases, such interaction requires an adaptor protein such as PHYL, and SIP to degrade Drosophila Tramtrack and mammalian b-catenin, respectively.…”

“…The phosphorylation of Siah2 by p38 MAPK results in stabilization and subsequent activation of the Siah2 protein in the cytoplasm [26] . In addition, the expression of Siah2 is up-regulated by estrogen in estrogen-receptor (ER)-positive breast cancer cells, in which Siah2 degrades the repressor of ER signaling, N-CoR, resulting in resistance to apoptosis induction and affecting mitochondrial function [18] . Furthermore, ubiquitin specific peptidase 13 (USP13) reduces the substrate degradation activity of Siah2 protein with a concomitant inhibitory effect on activity of Siah2 under normoxia [27] .…”