Two silencing sub-domains of v-erbA synergize with each other, but not with RXR

Martin, Bernd; Renkawitz, Rainer; Müller, Marc

doi:10.1093/nar/22.23.4898

Cited by 14 publications

(14 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5B) and in this assay did not interact at all with N-CoR or SMRT (Fig. 5A), which is consistent with the results of others (17,20,26,34,37). However, coexpression of Gal4-TR␣1(L374R) with Gal4-RXR resulted in potent transcriptional repression (Fig.…”

Section: Ninth-heptad Mutations That Eliminate Rxr Interaction Also Asupporting

confidence: 91%

Differential Recognition of Liganded and Unliganded Thyroid Hormone Receptor by Retinoid X Receptor Regulates Transcriptional Repression

Zhang

Zamir

Lazar

1997

Molecular and Cellular Biology

View full text Add to dashboard Cite

Thyroid hormone receptor (TR) functions as part of multiprotein complexes that also include retinoid X receptor (RXR) and transcriptional coregulators. We have found that both the TR CoR box and ninth heptad are required for RXR interaction and in turn for interaction with corepressor proteins N-CoR and SMRT. Remarkably, the recruitment of RXR to repression-defective CoR box and ninth-heptad mutants via a heterologous dimerization interface restores both corepressor interaction and repression. The addition of thyroid hormone obviates the CoR box requirement for RXR interaction, provided that the AF2 activation helix at the C terminus of TR is intact. These results indicate that RXR differentially recognizes the unliganded and liganded conformations of TR and that these differences appear to play a major role in the recruitment of corepressors to TR-RXR heterodimers.Thyroid hormone receptor (TR) is a multifunctional protein. It is a transcriptional repressor in the absence of ligand and a transcriptional activator in the presence of thyroid hormone (T3). Repression is mediated by interaction with a family of corepressor proteins, including N-CoR and SMRT (10,17,34,45). A ligand-induced conformational change causes dissociation of the corepressor and recruitment of a transcriptional coactivator to the DNA-bound TR. TR binds DNA most effectively as a heterodimer with retinoid X receptor (RXR) (6,19,22,23,25,44,47). Although RXR itself is a retinoid receptor (24), its main function in TR action does not appear to require retinoid binding (14). The TR-RXR interaction is stable in solution in both the presence and absence of ligand, and it has previously been suggested that the primary role of RXR is to increase the affinity and specificity of TR for T3 response elements, which often consist of two TR half-sites separated by 4 bp (39).The primary region of importance for the TR-RXR interaction in solution is the region which is generally known as the ninth heptad, corresponding to helices 10 and 11 of the crystal structure of the TR ligand binding domain (LBD) (40). The importance of this domain explains why C-terminal deletions of TR and the C-terminal variant TR␣2 do not interact with RXR in solution (31, 42). Interestingly, although the interaction between TR and RXR is ligand independent, two groups have previously described TR ninth-heptad point mutants which interact with RXR only in the presence of T3 (1, 28). Although the TR LBD structure has been solved only in the presence of ligand, a comparison with the unliganded RXR suggests that one of the effects of ligand binding is conformational change in the region between helices 10 and 11 in addition to the turning back of the amphipathic AF2 helix (helix 12) towards the core of the TR (5, 40).In contrast to the importance of C-terminal domains for RXR interaction, previous studies of TR interaction with NCoR and SMRT have focused on the CoR box within the hinge region of TR (10, 17). Like the ninth heptad, the CoR box is highly conserved among receptors that int...

show abstract

Section: Ninth-heptad Mutations That Eliminate Rxr Interaction Also Asupporting

confidence: 91%

Differential Recognition of Liganded and Unliganded Thyroid Hormone Receptor by Retinoid X Receptor Regulates Transcriptional Repression

Zhang

Zamir

Lazar

1997

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…2). In addition, we indicated the amino acid borders of the TR/v-ErbA silencing domain and deletion end points that have lost silencing function (5,14,29).…”

Section: Downloaded Frommentioning

confidence: 99%

“…Thus, the corepressor Alien interacts with the transcriptional silencer DAX-1. Family-The silencing domain of TR and that of the closely related v-ErbA oncogene product are localized in the receptor C terminus and have been well characterized (5,14,29,33). This domain encompasses 230 amino acids that include helices 1-11 of the receptor C terminus.…”

Section: Dax-1 Interacts With the Corepressor Alien-mentioning

confidence: 99%

“…The silencing domain of NHRs is localized in the C terminus and overlaps with the hormone-binding domain to a great extent. In the case of TR and RAR, the silencing domain encompasses 230 amino acids (5,14). Hormone binding by NHRs leads to a conformational change, dissociation of corepressors, subsequent binding of coactivators, and gene activation (for review, see Ref.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Interaction of the Corepressor Alien with DAX-1 Is Abrogated by Mutations of DAX-1 Involved in Adrenal Hypoplasia Congenita

Altincicek¹,

Tenbaum²,

Dressel³

et al. 2000

Journal of Biological Chemistry

Self Cite

102

View full text Add to dashboard Cite

DAX-1 is an unusual member of the nuclear hormone receptor (NHR) superfamily. Lack of DAX-1-mediated silencing leads to adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Gene silencing through NHRs such as the thyroid hormone receptor (TR) is mediated by corepressors. We have previously characterized a novel corepressor, termed Alien, which interacts with TR and the ecdysone receptor but not with the retinoic acid receptors RAR or RXR. Here, we show that DAX-1 interacts with the corepressor Alien but not with the corepressor SMRT. This interaction is mediated by the DAX-1-silencing domain. Naturally occurring mutants of the DAX-1 gene fail to interact with Alien and have lost silencing function. Because the silencing domain of DAX-1 is unusual for NHRs, we mapped the interaction of Alien with DAX-1 and with TR. We show that Alien exhibits different binding characteristics to DAX-1 and TR. Furthermore, Northern experiments demonstrate that Alien is expressed in the adrenal gland and testis in tissues where DAX-1 is specifically expressed. Interestingly, a novel adrenal gland-specific mRNA of Alien was discovered. Thus, the impairment of Alien binding seems to play an important role in the pathogenesis mediated by DAX-1 mutants.The gene superfamily of nuclear hormone receptors (NHRs) 1 represents a large class of transcription factors including receptors for steroids, nonsteroids, and members for which no ligand has yet been identified, the so-called orphan receptors (for reviews, see Refs. 1 and 2). Gene silencing is mediated by a few members such as receptors for thyroid hormone (TR (NR1A)) (3) and retinoic acid (RAR (NR1B)) (4 -10). Thereby, the receptor is associated with corepressors, and the complex of receptor and corepressors mediates target gene repression (2, 9 -12). Among corepressors, N-CoR and SMRT represent one class, and Alien represents another class, which interacts in a hormone-sensitive manner with NHR (10 -13). The silencing domain of NHRs is localized in the C terminus and overlaps with the hormone-binding domain to a great extent. In the case of TR and RAR, the silencing domain encompasses 230 amino acids (5,14). Hormone binding by NHRs leads to a conformational change, dissociation of corepressors, subsequent binding of coactivators, and gene activation (for review, see Ref. 15). The transcriptional properties of nuclear receptors can be transferred to heterologous proteins and therefore represent functional domains (for review, see Refs. 2,16,and 17).DAX-1 (NR0B1) is an unusual member of the NHR superfamily (18,19). The DNA-binding domain is unrelated to other nuclear receptors and is composed of four repeat sequences, which are able to recognize and bind to hairpin structures (20). The C terminus, however, is homologous to members of the NHR superfamily (18). Mutations in the DAX-1 gene cause the X-linked disorder of adrenal hypoplasia congenita and the associated hypogonadotropic hypogonadism (18,19,21,22). DAX-1 is predominantly expressed in adrenal gland and testis (18), w...

show abstract

“…Leaky expression levels were found to be between 20-to 70-fold higher in NIH3T3, CHO-K1, HEK 293, and COS-1 cells compared to basal expression levels in HeLa cells (Freundlieb et al, 1999). Several TetR-KRAB-derived trans-silencers (TetR-NLS-KRAB; Deuschle et al, 1995; Figure 12) have been constructed that contain different silencing domains derived from ErbA (tTS erb ; Martin et al, 1994), EVE (tTS eve ; Han and Manley, 1993), and Kid-1 (tTS Kid ; Witzgall et al, 1994). In a direct comparison using a P hCMV*-1 promoter that was linked 5′ to a P hCMV -derived enhancer element (enh-P hCMV*-1 ), the Tc-dependent trans-silencing potential of tTS erb , tTS eve and tTS Kid was assessed in different cell lines (HeLa, C243; HEK293 and NIH3T3).…”

Section: Two-vector Vs One-vector Installation Of Tet-responsive Exprmentioning

confidence: 99%

The Impact of Mammalian Gene Regulation Concepts on Functional Genomic Research, Metabolic Engineering, and Advanced Gene Therapies

2001

View full text Add to dashboard Cite

Regulation of heterologous gene expression is of prime importance for a wide variety of basic and applied biological research areas including functional genomics, tissue engineering, gene therapy, and biopharmaceutical manufacturing. Initial gene regulation strategies employed endogenous responsive elements, which resulted in pleiotropic interference of transgene expression with host regulatory networks. Current regulation systems are binary and consist of chimeric transactivators and responsive target promoters of heterologous bacterial or insect origin, or they contain artificially designed components. Regulation of generic systems is based on binding of a transactivator to its cognate promoter, which is modulated by specific molecules such as antibiotics or hormones and brings the transactivation domain into contact with a minimal promoter, thereby inducing target gene expression. Binary gene regulation concepts have been significantly refined in recent years with a focus to improve their regulation performance and their compatibility with human-therapeutic use. In this review we present a detailed analysis of currently available mammalian gene regulation systems and document progress that has pioneered the use of such systems in various aspects of human therapy.

show abstract

Two silencing sub-domains of v-erbA synergize with each other, but not with RXR

Cited by 14 publications

References 57 publications

Differential Recognition of Liganded and Unliganded Thyroid Hormone Receptor by Retinoid X Receptor Regulates Transcriptional Repression

Differential Recognition of Liganded and Unliganded Thyroid Hormone Receptor by Retinoid X Receptor Regulates Transcriptional Repression

Interaction of the Corepressor Alien with DAX-1 Is Abrogated by Mutations of DAX-1 Involved in Adrenal Hypoplasia Congenita

The Impact of Mammalian Gene Regulation Concepts on Functional Genomic Research, Metabolic Engineering, and Advanced Gene Therapies

Contact Info

Product

Resources

About