SMRTe, a silencing mediator for retinoid and thyroid hormone receptors-extended isoform that is more related to the nuclear receptor corepressor

Abstract

SMRT (silencing mediator for retinoid and thyroid hormone receptors) and N-CoR (nuclear receptor copressor) mediate transcriptional repression of important regulators that are involved in many signaling pathways. SMRT and N-CoR are related proteins that form complexes with mSin3A͞B and histone deacetylases to induce local chromatin condensation and transcriptional repression. However, SMRT is substantially smaller than N-CoR, lacking an N-terminal domain of approximately 1,000 aa that are present in N-CoR. Here, we report the identification of SMRTextended (SMRTe), which contains an N-terminal sequence that shows striking similarity with N-CoR. As in N-CoR, this SMRTe-N-terminal domain also represses basal transcription. We find that SMRTe expression is regulated during cell cycle progression and SMRTe transcripts are present in many embryonic tissues. These data redefine a structurally and functionally more related nuclear receptor corepressor family and suggest an additional role for SMRTe in the regulation of cycle-specific gene expression in diverse signaling pathways.Transcriptional repression plays an important role in the proper regulation of cell growth, differentiation, and development (1-3). In one mechanism of transcriptional inhibition, a repressor competes with an activator for DNA binding. Alternatively, transcriptional repressors also can inhibit basal transcription through direct interaction with general transcription factors, or indirectly by promoting chromatin condensation, thereby preventing the loading of general transcription factors to the promoter (1-3).Transcriptional repression by unliganded nuclear receptors such as TR (thyroid hormone receptor) and RAR (retinoic acid receptor) provide an excellent system for dissecting the pathways that lead to gene repression. TR and RAR play important roles in the regulation of cell growth, differentiation, and homeostasis. In the absence of hormone, TR and RAR actively repress target gene expression (4). Unliganded TR and RAR interact with the corepressors SMRT (silencing mediator for retinoid and thyroid hormone receptors) and N-CoR (nuclear receptor corepressor) (5, 6), which are components of corepressor complexes that also contain mSin3A͞B and histone deacetylases (7-9). The binding of hormone to these receptors induces active conformations (10-12), causing dissociation of the corepressor complex. A coactivator complex then is recruited, leading to transcriptional activation (13).In addition to TR and RAR, SMRT and N-CoR interact with other transcriptional regulators involved in various signaling pathways. These regulators include the orphan nuclear receptors COUP-TF1 (14), Rev-Erb, RVR (15), and DAX-1 (16), the latter of which is involved in congenital X-linked adrenal hypoplasia (17). SMRT and N-CoR also interact with antagonist-bound progesterone and estrogen receptors (18,19), suggesting that the corepressors may play a role in determining the antagonistic activities of antihormones. Functional complexes containing SMRT and N-CoR al...

The adenovirus E1A binding protein BS69 is a corepressor of transcription through recruitment of N-CoR

“…U2OS cells were transiently transfected with 5 mg of each construct and lysed 36 h post transfection. Lysates were separated on 10% SDS ± PAGE and Western blotted on immobilon-P membrane, detection using the 5C1 monoclonal antibody directed against the GAL4 DNA binding domain larger SMRT cDNA that is highly homologous to NCoR, has only recently been isolated (Ordentlich et al, 1999;Park et al, 1999). N-CoR and SMRT have been shown to be a component of large protein complexes that include histone deacetylase 1 and 2 Nagy et al, 1997) and Sin3A/B (Alland et al, 1997;Hassig et al, 1997;Soderstrom et al, 1997).…”

A critical role for the co-repressor N-CoR in erythroid differentiation and heme synthesis

“…Future work is needed to determine whether Ara-C increases the level of N-CoR by enhancing the translation of N-CoR mRNA and/or protein stability. and its related protein SMRT [36,37] form stable protein complexes with HDAC3 and other proteins and function as co-repressors for many transcriptional factors [1,[38][39][40][41]. In rare cases, N-CoR and HDAC3 have also been implicated in the transcriptional activation process [5], although the underlying mechanism is unknown.…”

HDAC3: taking the SMRT-N-CoRrect road to repression

“…Both N-CoR and SMRT had been discovered as interacting partners of unliganded TR and RAR and mediators of their repressive functions (Chen and Evans, 1995;Horlein et al, 1995). The two corepressors are high-molecular-weight proteins (B270 kDa), very similar at the amino acid level, containing nuclear receptor-interacting domains as well as multiple repressor domains (Chen and Evans, 1995;Horlein et al, 1995;Ordentlich et al, 1999;Park et al, 1999).…”