A Chicken Ovalbumin Upstream Promoter Transcription Factor I (COUP-TFI) Complex Represses Expression of the Gene Encoding Tumor Necrosis Factor α-induced Protein 8 (TNFAIP8)

Ling-Juan Zhang,Xiao Liu,Philip R Gafken,Chrissa Kioussi,Mark Leid

doi:10.1074/jbc.m807713200

Abstract

The orphan nuclear receptor chicken ovalbumin upstream promoter transcription factor I (COUP-TFI) plays key roles in development and homeostasis. A tandem affinity purification procedure revealed that COUP-TFI associated with a number of transcriptional regulatory proteins in HeLa S3 cells, including the nuclear receptor corepressor (NCoR), TIF1beta/KAP-1, HDAC1, and the SWI/SNF family member Brahma. The proapoptotic protein DBC1 was also identified in COUP-TFI complexes. In vitro experiments revealed that COUP-TFI interacted directly with NCoR but in a manner different from that of other nuclear receptors. DBC1 stabilized the interaction between COUP-TFI and NCoR by interacting directly with both proteins. The gene encoding the anti-apoptotic protein TNFAIP8 (tumor necrosis factor alpha (TNFalpha)-induced protein 8) was identified as being repressed by COUP-TFI in a manner that required several of the component proteins of the COUP-TFI complex. Finally, our studies highlight a central role for COUP-TFI in the induction of the TNFAIP8 promoter by TNFalpha. Together, these studies identify a novel COUP-TFI complex that functions as a repressor of transcription and may play a role in the TNFalpha signaling pathways.

Highlights

Tors that regulate critical processes in growth, development, and homeostasis [4, 5]
We identified a number of COUP-TFI-interacting proteins using a tandem affinity purification strategy, and we found that the orphan receptor and several of these proteins co-occupied the promoter of a COUP-TFI target gene that was first identified TNFAIP8
As with many other nuclear receptor complexes, nuclear receptor corepressor (NCoR) appears to serve as a scaffold protein that couples COUP-TFI to histone deacetylases, which may underlie the mechanistic basis for COUP-TFI-mediated transcriptional repression

Summary

Introduction

Tors that regulate critical processes in growth, development, and homeostasis [4, 5] Some nuclear receptors, such as thyroid hormone receptors and retinoic acid receptors, bind to regulatory elements in the target gene promoters in the absence of their cognate ligands. These aporeceptors function as repressors of transcription by interactively recruiting nuclear receptor corepressor (NCoR)2- or SMRT-containing corepressor complexes, which harbor multiple histone deacetylases, to the promoter template [6, 7]. COUP-TFIIIϪ/Ϫ mice exhibit disruption of noradrenergic homeostasis in the locus coeruleus and rostral cerebral cortex, along with enhanced nociception and dysregulation of period and period, clock genes that are important for proper circadian timing [17] These findings highlight the absolute essentiality of the COUP-TF family of orphan nuclear. Our findings implicate COUP-TFI in the TNF␣ signaling pathways in mammalian cells

Methods

Results

Conclusion