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In this paper, the authors report the structure of the TBLR1 gene …

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- TBLR1 regulates the expression of nuclear hormone receptor co-repressors

TBLR1 is a transcriptional regulator interacting with the co-repressors of nuclear hormone receptor activity. We cloned the gene encoding this protein and identified it as a member of a small family of proteins that include at least two isoforms encoded by the same gene and closely related, X- and Y linked proteins, called TBL1X and TBL1Y. The TBLR1 protein interacts with NHR (nuclear hormone receptors), a class of molecules that plays a critical role in transcription [1]. These co-repressors mediate the down-regulation of gene expression and play important roles in the life and death choices that regulate normal development.

The nuclear hormone receptor (NHR) superfamily is a large family of mainly ligand-dependent transcription factors that play a role in the regulation of reproduction, growth, differentiation, and homeostasis. Members of the family share several structural features including a conserved DNA binding domain (DBD) that targets the receptor to hormone response element (HRE) sequences. The carboxyl-end of the receptors contains a ligand-binding domain (LBD) in which is embedded a hormone-dependent transcriptional activation domain. The LBD serves as a molecular switch that recruits co-activator or co-repressor proteins that regulate transcription of the target genes. Ligand-dependent receptors like the thyroid hormone receptor (T3R) and retinoic acid receptor (RAR) stimulate transcription when ligand is bound and repress it when the ligand is absent [2].

N-CoR (nuclear receptor co-repressor)[3] and SMRT (silencing mediator of retinoid and thyroid hormone receptors [4] were the first identified co-repressors. They fill overlapping but non-redundant roles in regulating transcription. Both SMRT and N-CoR exist in multi- protein complexes that have an estimated size of 1.5–2 mDa. A SMRT complex, isolated by a combination of conventional and immunoaffinity chromatography has been shown to contain histone deacetylase 3 (HDAC3) and transducin (beta)-like I (TBL1). The HDAC3-containing, SMRT and N-CoR complexes can bind to unliganded thyroid hormone receptors (T3Rs) in vitro[5]. Although both co-repressors are expressed widely, extensive hematological abnormalities, including blocks in erythrocyte and T-cell development [6], follow targeted deletion of N-CoR.

Co-repressors mediate transcriptional silencing by inhibiting the basal transcription machinery and by recruiting chromatin-modifying enzymes [2,5,7-11] Histone deacetylation, which produces a more compact chromatin structure that is inaccessible to transcriptional activators [8], appears to be the predominant means of chromatin modification. Studies of RAR and T3R show that ligand binding leads to the displacement of an HDAC-containing complex from the nuclear receptor in exchange for a histone acetyltransferase (HAT)-containing complex and this may serve as a general mechanism for switching nuclear receptors from a transcriptionally repressive to a transcriptionally active state [12]. Changes in repression correlate with alterations in the level of N-CoR and/or SMRT. These levels are regulated by both the rate of synthesis of the co-repressors and, more dramatically, by their rate of degradation. Targeted proteolysis of transcriptional co-regulators has been established as a mechanism for cell-specific regulation of gene transcription [13]. Although the composition of the repressor complex is not fully understood, both TBLR1 and a protein called TBL1 that is highly homologous to TBLR1, are present and in some cells, the extent of transcriptional repression correlates with the amount of TBL1 present [9,14,15].

We originally isolated TBLR1 as a 201 bp fragment in a cDNA library prepared from a bone marrow preparation highly enriched for human hematopoietic stem cells [16]. This fragment, which had no homology with any sequence in the GenBank, hybridized with RNA from K562 (a human erythroleukemia cell line) and a placental library and cDNAs prepared from these tissues were used as a source of mRNAs for subsequent analysis. 5' RACE identified an open reading frame (ORF) encoding a putative 514 a.a. protein. In this paper, we report the structure of the TBLR1 gene and analyze its pattern of expression. These results indicate that alternative splicing of the mRNA results in the formation of at least two protein isoforms (termed α and β). Over expression of TBLR1 interferes with cell replication. Like TBL1, TBLR1 forms a complex with nuclear co-repressors and appears to play a role in stabilizing the active co-repressor complex.

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