Silencing subdomains of v-ErbA interact cooperatively with corepressors: involvement of helices 5/6

Animals; Binding Sites; Cell Line; DNA-Binding Proteins/genetics/metabolism; Gene Silencing; Genetic Complementation Test; Mutation; Nuclear Proteins/genetics/metabolism; Oncogene Proteins v-erbA/chemistry/*genetics/*metabolism; Point Mutation; Recombinant Proteins/chemistry/genetics/metabolism; Repressor Proteins/genetics/*metabolism

Abstract :

[en] Members of the thyroid hormone receptor (TR) family act on vertebrate development and homeostasis by activating or repressing transcription of specific target genes in a ligand-dependent way. Repression by TR in the absence of ligand is mediated by an active silencing mechanism. The oncogene v-ErbA is a variant form of TR unable to bind hormone and thus acts as a constitutive repressor. Functional studies and mutation analysis revealed that the TR/v-ErbA silencing domain is composed of three silencing subdomains (SSD1-3) which, although nonfunctional individually, synergize such that silencing activity is restored when they are combined in a heteromeric complex. Here we demonstrate, using protein interaction assays in vitro and in vivo, that the inactive v-ErbA point mutant L489R within helix 5/6 in SSD2 fails to interact with the two corepressors N-CoR (nuclear receptor corepressor) or SMRT (silencing mediator of retinoic acid and thyroid hormone receptor). Furthermore, mutants in SSD1 and SSD3 exhibit a reduced corepressor recruitment corresponding to their weak residual silencing activity. In mammalian two-hybrid assays, only the combination of all three silencing subdomains, SSD1-3, leads to a cooperative binding to the corepressors N-CoR or SMRT comparable to that of the full-length v-ErbA repression domain. In conclusion, full silencing activity requires corepressor interaction with all three silencing subdomains, SSD1-3. Among these, SSD2 is a new target for N-CoR and SMRT and is essential for corepressor binding and function.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Busch, Kerstin

Martin, Bernd

Baniahmad, Aria

Martial, Joseph ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire

Renkawitz, Rainer

Muller, Marc ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire

Language :

English

Title :

Silencing subdomains of v-ErbA interact cooperatively with corepressors: involvement of helices 5/6

Publication date :

2000

Journal title :

Molecular Endocrinology

ISSN :

0888-8809

eISSN :

1944-9917

Publisher :

Endocrine Society, Chevy Chase, United States - Maryland

Volume :

Issue :

Pages :

201-11

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

http://mend.endojournals.org/cgi/content/full/14/2/201

Available on ORBi :

since 04 December 2009

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