TRRAP as a hepatic coactivator of LXR and FXR function

Unno, Atsushi; Takada, Ichiro; Takezawa, Shinichiro; Oishi, Hajime; Baba, Atsushi; Shimizu, Takafumi; Tokita, Akifumi; Yanagisawa, Junn; Kato, Shigeaki

doi:10.1016/j.bbrc.2004.12.095

Cited by 31 publications

(22 citation statements)

References 28 publications

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“…In LXR␣ null mice, the LXR␣ function was completely lost (32). In DN2 transgenic mice, the overexpressed DN2 fragment might interfere with the interaction of LXR␣ with NCoA6 and other coactivators, since other coactivators, including TRRAP, PGC-1␣, SRC-1, and SRC-3, have been shown to interact with LXR␣ in the presence of T0901317 (1,30,39). In NCoA6…”

Section: Discussionmentioning

confidence: 99%

Tissue- and Nuclear Receptor-Specific Function of the C-Terminal LXXLL Motif of Coactivator NCoA6/AIB3 in Mice

Chu

2007

Molecular and Cellular Biology

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Although the LXXLL motif of nuclear receptor (NR) coactivators is essential for interaction with NRs, its role has not been assessed in unbiased animal models. The nuclear receptor coactivator 6 (NCoA6; also AIB3, PRIP, ASC-2, TRBP, RAP250, or NRC) is a coactivator containing an N-terminal LXXLL-1 (L1) and a C-terminal L2. L1 interacts with many NRs, while L2 interacts with the liver X receptor ␣ (LXR␣) and the estrogen receptor ␣ (ER␣). We generated mice in which L2 was mutated into AXXAL (L2m) to disrupt its interaction with LXR␣ and ER␣. NCoA6L2m/L2m mice exhibited normal reproduction, mammary gland morphogenesis, and ER␣ target gene expression. In contrast, when treated with an LXR␣ agonist, lipogenesis and the LXR␣ target gene expression were significantly reduced in NCoA6L2m/L2m mice. The induction of Cyp7A1 expression by a high-cholesterol diet was impaired in NCoA6 L2m/L2m mice, which reduced bile acid synthesis in the liver and excretion in the feces and resulted in cholesterol accumulation in the liver and blood. These results demonstrate that L2 plays a tissue-and NR-specific role: it is required for NCoA6 to mediate LXR␣-regulated lipogenesis and cholesterol/bile acid homeostasis in the liver but not required for ER␣ function in the mammary gland.The nuclear receptor (NR) superfamily consists of hormoneinducible transcription factors. Through regulation of gene expression, NRs control numerous biological events in development, growth, sexual maturation, reproduction, and metabolic homeostasis. Recent studies have identified a number of transcriptional coactivators and corepressors that modulate NR transcriptional activities and determine the expression levels of their target genes (28,36,41). Multiple coactivators usually form functional protein complexes which facilitate chromatin remodeling, general transcription factor assembly, RNA polymerase II recruitment, and transcriptional initiation. Mechanistically, most coactivators do not bind to DNA, and their recruitment to a gene promoter/enhancer is dependent on their interaction with specific agonist-bound NRs. Most coactivators contain one or more LXXLL (L, leucine; X, any amino acid) ␣-helix motifs required for interaction with the ligand-binding domain of NRs (10,26,27,37). Although the molecular basis and requirement of the LXXLL motif for NR coactivator function have been investigated using biochemical and cell culture experiments (10,26,27,37), the physiological function and the tissue and NR specificities of the LXXLL motif of coactivators have not been carefully assessed in an animal model using an unbiased molecular genetic approach.The nuclear receptor coactivator 6 (NCoA-6; also AIB3, PRIP, ASC-2, TRBP, RAP250, or NRC) is an NR coactivator amplified and overexpressed in some breast, colon, and lung cancers (4,9,16,20,24,25,50). Biochemical and cell culturebased experiments have demonstrated that NCoA6 interacts with and coactivates many NRs, including estrogen receptor ␣ (ER␣) and liver X receptor ␣ (LXR␣) (15,24,25). NCoA6 may enhance NR...

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Section: Discussionmentioning

confidence: 99%

Tissue- and Nuclear Receptor-Specific Function of the C-Terminal LXXLL Motif of Coactivator NCoA6/AIB3 in Mice

Chu

2007

Molecular and Cellular Biology

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“…These include c-Myc, p53, E2F1, E2F4, E1A, ERa, ERb, VDR, PPARg, LXR, FXR, b-catenin, Skp1 and BRCA1 Lang et al, 2001;Park et al, 2001;Ard et al, 2002;Yanagisawa et al, 2002;Lang and Hearing, 2003;Unno et al, 2005;Cheng et al, 2006;Oishi et al, 2006;Sierra et al, 2006;Finkbeiner and Herceg, unpublished results). Interestingly, the TRRAP domains that interact with diverse partners are not overlapping and it can be speculated that TRRAP may serve not only as a scaffold for HAT complexes but also as a platform for recruitment of different regulatory factors and complexes to chromatin.…”

Section: Cellular Pools Of Trrapmentioning

confidence: 91%

Orchestration of chromatin-based processes: mind the TRRAP

et al. 2007

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Chromatin modifications at core histones including acetylation, methylation, phosphorylation and ubiquitination play an important role in diverse biological processes. Acetylation of specific lysine residues within the N terminus tails of core histones is arguably the most studied histone modification; however, its precise roles in different cellular processes and how it is disrupted in human diseases remain poorly understood. In the last decade, a number of histone acetyltransferases (HATs) enzymes responsible for histone acetylation, has been identified and functional studies have begun to unravel their biological functions. The activity of many HATs is dependent on HAT complexes, the multiprotein assemblies that contain one HAT catalytic subunit, adapter proteins, several other molecules of unknown function and a large protein called TRansformation/tRanscription domain-Associated Protein (TRRAP). As a common component of many HAT complexes, TRRAP appears to be responsible for the recruitment of these complexes to chromatin during transcription, replication and DNA repair. Recent studies have shed new light on the role of TRRAP in HAT complexes as well as mechanisms by which it mediates diverse cellular processes. Thus, TRRAP appears to be responsible for a concerted and context-dependent recruitment of HATs and coordination of distinct chromatin-based processes, suggesting that its deregulation may contribute to diseases. In this review, we summarize recent developments in our understanding of the function of TRRAP and TRRAP-containing HAT complexes in normal cellular processes and speculate on the mechanism underlying abnormal events that may lead to human diseases such as cancer.

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“…The function of TOR as well as ATM has further been related to redox signaling (4,7). Transformation/transcription domain-associated protein (TRRAP) scaffolds several histone acetyltransferase complexes, thereby regulating gene transcription of target genes such as, for example, mitotic checkpoint genes or liver receptors that play a role in lipid metabolism (2,19,20). In addition, TRRAP is also suggested to be involved in double strand break repair processes (21).…”

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confidence: 99%