CCAR1, a Key Regulator of Mediator Complex Recruitment to Nuclear Receptor Transcription Complexes

Abstract

Summary DNA-bound transcription factors recruit many coactivator proteins to remodel chromatin and activate transcription. The Mediator complex is believed to recruit RNA polymerase II to most protein-encoding genes. It is generally assumed that interaction of Mediator subunits with DNA-binding transcription factors is responsible for Mediator recruitment to promoters. However, we report here that Mediator recruitment by nuclear receptors (NR) requires a new coactivator protein, CCAR1 (cell cycle and apoptosis regulator 1). CCAR1 associates with components of the Mediator and p160 coactivator complexes and is recruited to endogenous NR target genes in response to the appropriate hormone. Reduction of endogenous CCAR1 levels inhibited hormone-induced expression of endogenous NR target genes, hormone-induced recruitment of Mediator components and RNA polymerase II to target gene promoters, and estrogen-dependent growth of breast cancer cells. Thus, CCAR1 regulates expression of key proliferation inducing genes. CCAR1 also functions as a p53 coactivator, suggesting a broader role in transcriptional regulation.

Microarray analysis of cytoplasmic versus whole cell RNA reveals a considerable number of missed and false positive mRNAs

“…Redundant perturbations within specific signaling cascades and the capacity of pancreatic cancer cells to exhibit perturbations in a dozen key pathways (Jones et al 2008) serve to underscore the difficulties in designing effective therapies for this deadly cancer. In the case of TCDD exposure to mouse Hepa1c1c7 cells, two missed genes include Sltm and Ccar1 (Table 1; Supplemental Tables S3, S4), which play recently discovered critical roles in transcriptional regulation (Chan et al 2007;Kim et al 2008). Our findings support the hypothesis that whole cell preparation of RNA does not accurately represent steady-state mRNA levels because of the nuclear RNA contribution and that the cytoplasmic RNA fraction produces a more precise determination of the mRNA steadystate profile and impact on possible cellular processes.…”

Recruitment of the SWI/SNF Chromatin Remodeling Complex to Steroid Hormone-regulated Promoters by Nuclear Receptor Coactivator Flightless-I

“…6A), suggesting that both Fli-I and Mediator contribute to recruitment of RNA polymerase II to the pS2 promoter after hormone treatment. We also recently showed that another coactivator, CCAR1, is required for recruiting the Mediator complex to the pS2 promoter (50). Because both Fli-I (this study) and CCAR1 (50) can interact with ER and with components of the p160 complex, Fli-I and CCAR1 would appear to provide a possible mechanism for coordination of the complementary functions of three important coactivator complexes, i.e.…”

The Transcriptional Mediator Subunit MED1/TRAP220 in Stromal Cells Is Involved in Hematopoietic Stem/Progenitor Cell Support through Osteopontin Expression

“…In terms of the mechanism, our data clearly show that (i) MED1 is a bona fide important ligand-dependent coactivator for VDR, (ii) Runx2 acts synergistically as an activator with VDR in a MED1-dependent manner, and (iii) MED1(1-602), missing the VDR interaction site, is a coactivator for a putative activator(s) that maintains basal ligand-independent transcription. A candidate molecule(s) for the putative activator(s) might be CCAR1, which was recently reported to bypass nuclear receptor signaling (17), and/or an unknown activator(s); the presence of such an activator might explain the role of MED1(1-602) in MEFs in growth stress on BM cells (this study). Further molecular and functional dissection may resolve this issue in the future.…”