Characterization of Receptor Interaction and Transcriptional Repression by the Corepressor SMRT

The retinoid X receptor (RXR) is a key regulator in multiple signaling pathways because it can form either a homodimer with itself or a heterodimer with members of the class I nuclear receptors. The RXR-containing dimers regulate transcription by recruiting coactivators or corepressors to the target promoters. The binding of coactivators to RXR is mediated through a hydrophobic pocket formed in part by the C-terminal activation helix (AF-2). However, little is known about interactions of corepressors with RXR and its roles in transcriptional repression. Here we show that the repression activity of RXR correlates with its binding to the corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT). This intrinsic repression activity is masked by the AF-2 helix, which antagonizes SMRT binding. Inhibition of SMRT binding by the AF-2 helix requires specific amino acid sequences and the helical structure. Furthermore, the SMRT-binding site on RXR is independent of helix 11 but overlaps with the coactivator-binding pocket. On the basis of these results, we propose a structural model to help understand the molecular mechanism of corepressor recruitment by RXR.

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“…1 A). These results are consistent with previous studies (9,22,35), and further suggest that RXR has a strong preference for SMRT-ID2.…”

Section: Rxr Interacts With the Smrt-id2 Domainsupporting

confidence: 93%

“…The corepressor SMRT contains two separate NR-interacting domains, termed ID1 and ID2 (22). Within each ID, an LxxLLlike corepressor motif (also called CoRNR box or LxxxIxxxI͞L motif) is responsible for interactions with NRs (23)(24)(25).…”

mentioning

confidence: 99%

Interactions that determine the assembly of a retinoid X receptor/corepressor complex

Ghosh

Yang

Zhang

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…First, ETO may serve as a platform upon which distinct complexes assemble. For example, NCoR and SMRT are capable of interacting with Sin3, and this interaction could be facilitated by ETO (Li et al, 1997;Nagy et al, 1997;Soderstrom et al, 1997). Second, different complexes might associate with ETO in different cell types.…”

Section: Direct Interactions With Hdacsmentioning

confidence: 99%

ETO interacting proteins

Hug

Lazar

2004

Oncogene

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The 8;21 translocation produces a fusion between the ETO gene and that encoding the myeloid transcription factor AML1. The AML1-ETO fusion substitutes the majority of the ETO protein for the coregulator recruitment domains of AML1. Biochemical analyses of ETO have led to the identification of numerous interacting proteins including many corepressors. Importantly, the proteins interacting with ETO are different from those of wild-type AML1, suggesting that altered coregulator recruitment underlies the oncogenic properties of AML1-ETO. The list of corepressors capable of binding ETO includes histone deacetylases (HDACs) and components of distinct HDAC core complexes. These investigations have provided mechanistic insight into corepressor recruitment by ETO and clues to the leukemogenic activity of AML1-ETO.

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“…Co-repressors are proteins that bridge repressors and their ultimate target, thereby reinforcing speci®c binding. Receptors for thyroid hormone (TR) and retinoic acid (RARa) can repress gene-speci®c transcription by interacting with corepressors (SMRT and N-Cor) which bind liganded and/or unliganded receptors (Li et al, 1997). N-Cor also represses Gal4-VP16 mediated transactivation by interacting directly with GTFs (TFIIB, TAFII32 and TAFII70) (Muscat et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

A murine ATFa-associated factor with transcriptional repressing activity

et al. 2000

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The ATFa proteins, which are members of the CREB/ ATF family of transcription factors, have previously been shown to interact with the adenovirus E1a oncoprotein and to mediate its transcriptional activity; they heterodimerize with Jun, Fos or related transcription factors, possibly altering their DNA-binding speci®city; they also stably bind JNK2, a stress-induced protein kinase. Here we report the identi®cation and characterization of a novel protein isolated in a yeast two-hybrid screen using the N-terminal half of ATFa as a bait. This 1306-residue protein (mAM, for mouse ATFa-associated Modulator) is rather acidic (pHi 4.5) and contains high proportions of Ser/Thr (21%) and Pro (11%) residues. It colocalizes and interacts with ATFa in mammalian cells, contains a bipartite nuclear localization signal and possesses an ATPase activity. Transfection experiments show that mAM is able to downregulate transcriptional activity, in an ATPase-independent manner. Our results indicate that mAM interacts with several components of the basal transcription machinery (TFIIE and TFIIH), including RNAPII itself. Together, these ®ndings suggest that mAM may be involved in the ®ne-tuning of ATFaregulated gene expression, by interfering with the assembly or stability of speci®c preinitiation transcription complexes.

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Characterization of Receptor Interaction and Transcriptional Repression by the Corepressor SMRT

Cited by 93 publications

References 54 publications

Interactions that determine the assembly of a retinoid X receptor/corepressor complex

Interactions that determine the assembly of a retinoid X receptor/corepressor complex

ETO interacting proteins

A murine ATFa-associated factor with transcriptional repressing activity

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