Identification of a transcriptionally active peroxisome proliferator-activated receptor α-interacting cofactor complex in rat liver and characterization of PRIC285 as a coactivator

Abstract

Peroxisome proliferator-activated receptor ␣ (PPAR␣) plays a central role in the cell-specific pleiotropic responses induced by structurally diverse synthetic chemicals designated as peroxisome proliferators. Transcriptional regulation by liganded nuclear receptors involves the participation of cofactors that form multiprotein complexes to achieve cell-and gene-specific transcription. Here we report the identification of such a transcriptionally active PPAR␣-interacting cofactor (PRIC) complex from rat liver nuclear extracts that interacts with full-length PPAR␣ in the presence of ciprofibrate, a synthetic ligand, and leukotriene B 4, a natural ligand. The liganded PPAR␣-PRIC complex enhanced transcription from a peroxisomal enoyl-CoA hydratase͞L-3-hydroxyacyl-CoA dehydrogenase bifunctional enzyme gene promoter template that contains peroxisome proliferator response elements. Rat liver PRIC complex comprises some 25 polypeptides, and their identities were established by mass spectrometry and limited sequence analysis. Eighteen of these peptides contain one or more LXXLL motifs necessary for interacting with nuclear receptors. PRIC complex includes known coactivators or coactivator-binding proteins (CBP, SRC-1, PBP, PRIP, PIMT, TRAP100, SUR-2, and PGC-1), other proteins that have not previously been described in association with transcription complexes (CHD5, TOG, and MORF), and a few novel polypeptides designated PRIC300, -285, -215, -177, and -145. We describe the cDNA for PRIC285, which contains five LXXLL motifs. It interacts with PPAR␣ and acts as a coactivator by moderately stimulating PPAR␣-mediated transcription in transfected cells. We conclude that liganded PPAR␣ recruits a distinctive multiprotein complex from rat liver nuclear extracts. The composition of this complex may provide insight into the basis of tissue and species sensitivity to peroxisome proliferators.

The MYST family of histone acetyltransferases and their intimate links to cancer

“…Both proteins possess transcriptional activation ability that appears to be separable from their HAT activity, and function as co-activators for two Runt-domain transcription factors -Runx1 and -2 (sometimes referred to as AML1 and -3) (Kitabayashi et al, 2001a;Pelletier et al, 2002;Collins et al, 2006). Additionally, MORF has been discovered in an unrelated co-activator complex in rat liver (Surapureddi et al, 2002), whereas transcriptional co-activation by MOZ has been recently linked to expression of a tumour marker gene in liver carcinogenesis (Ohta et al, 2006). In line with the evidence linking MOZ to leukaemia, two recent studies highlighted its essential role in development and maintenance of hematopoietic stem cells -a function that is apparently also linked to its transcription activation ability (Katsumoto et al, 2006;Thomas et al, 2006).…”

Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk

“…Tryptic peptides were identified by mass spectrometry ( Figure 1A). Mapped peptides corresponded to Mediator complex components (Med1/DRIP205, Med13, Med14, Med24, and Med17) and PRIC complex subunits (17), such as the known coactivators or coactivator-binding proteins (PRIC285, CBP, SRC-3, PGC-1α). Other coregulators such as p300, SWI/SNF complex subunits (BAF250 and BAF60), MTA-1, and RIP140 were also identified.…”

MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells

“…MOZ has been shown to physically and functionally interact with PU.1, an ETS transcription factor that is essential for the development of myeloid and lymphoid lineages (Katsumoto et al, 2006), whereas MORF is present in the transcriptional co-activator complex associated with the nuclear receptor peroxisome proliferator-activated receptor-a (PPARa) (Surapureddi et al, 2002). Studies in mouse and zebrafish indicate MOZ plays a key role in controlling Hox gene expression (Miller et al, 2004;Camos et al, 2006;Crump et al, 2006;Katsumoto et al, 2006), so unknown DNA-binding transcription factors may recruit MOZ to achieve this goal.…”