The receptor-associated coactivator 3 activates transcription through CREB-binding protein recruitment and autoregulation
UMass Chan Affiliations
Department of Pharmacology and Molecular ToxicologyDocument Type
Journal ArticlePublication Date
1998-03-06Keywords
AnimalsCREB-Binding Protein
Cell Line
Cercopithecus aethiops
Histone Acetyltransferases
Nuclear Proteins
Peptide Fragments
RNA, Messenger
Receptors, Steroid
Retinoids
Trans-Activation (Genetics)
Trans-Activators
Transcription Factors
Transfection
transcriptional coactivators
nuclear hormone receptors
receptor-associated coactivator 3
RAC3
nuclear receptor coactivators
Biochemistry
Cell Biology
Cellular and Molecular Physiology
Molecular Biology
Metadata
Show full item recordAbstract
Transcriptional coactivators are involved in gene activation by nuclear hormone receptors. The receptor-associated coactivator 3 (RAC3) was recently identified to be highly related to the steroid receptor coactivator-1 and transcriptional intermediate factor 2, thereby establishing a novel family of nuclear receptor coactivators. In this study, we identified a RAC3 fragment containing three LXXLL motifs conserved among this family, which is sufficient to mediate nuclear receptor interaction in vivo and in vitro. Point mutations that disrupt ligand-dependent activation function of the receptor inhibited the interaction. We found that a 162-amino acid fragment of RAC3 conferred transcriptional activation and recruited the CREB-binding protein and that three distinct LXXLL motifs mediated the transcriptional activation. A trimeric far Western analysis demonstrated the formation of a ternary complex containing CREB-binding protein, RAC3, and the receptor. In addition, we showed that RAC3, transcriptional intermediate factor 2, and steroid receptor coactivator-1 are expressed in specific tissues and cancer cells and that RAC3 transcript is directly up-regulated by retinoid treatment. These results suggest that RAC3 may contribute to amplified transcriptional responses through both recruitment of additional coactivators and autoregulation by the receptor-coactivator complex.Source
This research was originally published in: J Biol Chem. 1998 Mar 6;273(10):5948-54. Link to article on publisher's site
DOI
10.1074/jbc.273.10.5948Permanent Link to this Item
http://hdl.handle.net/20.500.14038/42431PubMed ID
9488734Related Resources
Rights
© 1998 by The American Society for Biochemistry and Molecular Biology, Inc. Publisher PDF posted after 12 months as allowed by the publisher's author rights policy at https://www.asbmb.org/journals-news/editorial-policies.ae974a485f413a2113503eed53cd6c53
10.1074/jbc.273.10.5948
Scopus Count
Collections
Related items
Showing items related by title, author, creator and subject.
-
The role of TNF-receptor family members and other TRAF-dependent receptors in bone resorptionGravallese, Ellen M.; Galson, Deborah L.; Goldring, Steven R.; Auron, Philip E. (2001-02-15)The contribution of osteoclasts to the process of bone loss in inflammatory arthritis has recently been demonstrated. Studies in osteoclast biology have led to the identification of factors responsible for the differentiation and activation of osteoclasts, the most important of which is the receptor activator of NF-kappa B ligand/osteoclast differentiation factor (RANKL/ODF), a tumor necrosis factor (TNF)-like protein. The RANKL/ODF receptor, receptor activator of NF-kappa B (RANK), is a TNF-receptor family member present on both osteoclast precursors and mature osteoclasts. Like other TNF-family receptors and the IL-1 receptor, RANK mediates its signal transduction via TNF receptor-associated factor (TRAF) proteins, suggesting that the signaling pathways activated by RANK and other inflammatory cytokines involved in osteoclast differentiation and activation are interconnected.
-
Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transductionFitzgerald, Katherine A.; Palsson-McDermott, Eva M.; Bowie, Andrew G.; Jefferies, Caroline A.; Mansell, Ashley S.; Brady, Gerard; Brint, Elizabeth K.; Dunne, Aisling; Gray, Pearl; Harte, Mary T.; et al. (2001-09-07)The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria. All TLRs have a Toll/IL-1 receptor (TIR) domain, which is responsible for signal transduction. MyD88 is one such protein that contains a TIR domain. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling; however, our understanding of how TLR-4 signals is incomplete. Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome. Mal activates NF-kappaB, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. Mal can form homodimers and can also form heterodimers with MyD88. Activation of NF-kappaB by Mal requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TIR domain. A dominant negative form of Mal inhibits NF-kappaB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-kappaB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.
-
The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signalingSchoenemeyer, Annett; Barnes, Betsy J.; Mancl, Margo E.; Latz, Eicke; Goutagny, Nadege; Pitha, Paula M.; Fitzgerald, Katherine A.; Golenbock, Douglas T. (2005-02-08)Interferon regulatory factors (IRFs) are critical components of virus-induced immune activation and type I interferon regulation. IRF3 and IRF7 are activated in response to a variety of viruses or after engagement of Toll-like receptor (TLR) 3 and TLR4 by double-stranded RNA and lipopolysaccharide, respectively. The activation of IRF5, is much more restricted. Here we show that in contrast to IRF3 and IRF7, IRF5 is not a target of the TLR3 signaling pathway but is activated by TLR7 or TLR8 signaling. We also demonstrate that MyD88, interleukin 1 receptor-associated kinase 1, and tumor necrosis factor receptor-associated factor 6 are required for the activation of IRF5 and IRF7 in the TLR7 signaling pathway. Moreover, ectopic expression of IRF5 enabled type I interferon production in response to TLR7 signaling, whereas knockdown of IRF5 by small interfering RNA reduced type I interferon induction in response to the TLR7 ligand, R-848. IRF5 and IRF7, therefore, emerge from these studies as critical mediators of TLR7 signaling.