Alien, a Highly Conserved Protein with Characteristics of a Corepressor for Members of the Nuclear Hormone Receptor Superfamily

Abstract

Corepressors are involved in gene silencing by various transcriptional repressor proteins such as MAD/MAX and MxiI (2), YY1 (74), KRAB domain proteins (27), NGF1-A, KROX 20 (59, 63) and some members of the nuclear hormone receptor (NHR) superfamily, such as thyroid hormone receptor (TR) and retinoic acid receptor (RAR) (8,19,38,50). Both TR and RAR repress gene activity in the absence of hormone in vivo (3, 4, 21, 73) and in vitro (28, 67, 68). This repression is mediated by a silencing domain in the carboxy terminus, encompassing about 250 amino acids (aa) (3,33,46,58). In addition to the silencing function, TR and RAR harbor several other functions C-terminal to their DNA binding domain (DBD) including dimerization, hormone binding and hormone-dependent transactivation. These activities can be transferred to heterologous proteins and therefore represent functional domains (for reviews, see references 6, 50, and 65).Gene silencing by NHRs is relieved by addition of the cognate ligand, which induces a conformational change and transforms the receptor into a transcriptional activator. In this way, both hormone binding and the small conserved receptor activation domain, AF2/AF2-AD/4/c (8, 11, 12, 22, 49, 50), representing helix 12 (14, 38, 55, 57, 71), are required to dissociate corepressors from the receptors (8,9,19,38). It is yet unknown why so many different coactivators are involved in transcriptional activation by NHRs. Gene silencing by TR, RAR, Rev-erbA␣, and COUP-TF is mediated, at least in part, by corepressors in vivo (8, 10, 19, 25, 38, 61) and in vitro (68), which bind to the unliganded (apo) receptors. Only one class of nuclear receptor corepressors has been identified, which exhibit hormone-sensitive interaction. This class contains two related members, 38). These corepressors were isolated by the yeast twohybrid system and bind to the silencing domains of TR and RAR only in the absence of ligand. Hormone binding by the receptor leads to dissociation of these corepressors. Furthermore, SMRT and N-CoR are localized in the cell nucleus and harbor an autonomous silencing function when bound to DNA (19,38). The mechanism of repression by the SMRT/N-CoR class involves interaction with SIN3 and a histone deacetylase function (1,35,52).Here, we describe a novel corepressor, Alien, which is unrelated to SMRT and N-CoR and is highly conserved from humans to Drosophila. Conserved sequences are even found in Ricinus communis and Caenorhabditis elegans. Alien interacts with TR only in the absence of hormone and does not interact with RAR, retinoid X receptor (RXR), or glucocorticoid

Ligand-independent requirements of steroid receptors EcR and USP for cell survival

“…The Drosophila homolog of Alien, COUP-TF1, is a corepressor reported to bind EcR but not USP. 47,48 Out of the current transcriptional cofactors known to bind EcR and USP, histone methyltransferases TRR, 49 dSet2, 50 dG9a, 51 nucleosome remodeling factor NURF 52 and Taiman, 53 all of them act as co-activators, rather than co-repressors. In any event, assuming co-repressors, in the light of the current data, the search for them should be conducted in the PG.…”

Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism

“…It has been shown that eIF3/INT-6 interacts strongly with CSN6 and that A. thaliana deficient in CSN6 exhibit diverse developmental defects, including homeotic organ transformation, symmetric body organization, and organ boundary definition, and have a high level of ubiquinated proteins. 32,33 In addition, VIP-1 has been shown to be embryonically lethal in mice shortly after transplantation into the blastocyst, and antisense-mediated inhibition leads to cell cycle arrest. However, any conclusions drawn from Vpr-VIP-1 interaction as a causation of apoptosis or cell cycle arrest remains premature because loss of function experiments with antisense VIP-1 could be a result of various bystander effects including alterations in proteolysis, ubiquitination, translation, etc.…”

Linking the ubiquitin–proteasome pathway to chromatin remodeling/modification by nuclear receptors

“…The most conserved of the CSN subunits are CNS2/Alien and CSN5/Jab1. CSN2/ Alien, also known as thyroid hormone receptor (TR) interacting protein (Trip15) is a co-repressor of NR, TR and vitamin D receptor (VDR) (Lee et al 1995, Dressel et al 1999, Altincicek et al 2000. CSN5/Jab1 is a c-Jun activating binding protein that specifically stabilizes c-Jun DNA complexes to activate c-Jun-mediated transcription (Chamovitz & Segal 2001).…”