Interaction of the corepressor Alien with DAX-1 is abrogated by mutations of DAX-1 involved in adrenal hypoplasia congenita.
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.
Altincicek
B
B
Genetisches Institut, Justus-Liebig-Universität, Heinrich-Buff-Ring 58-62, Giessen D-35392, Germany.
Tenbaum
S P
SP
Dressel
U
U
Thormeyer
D
D
Renkawitz
R
R
Baniahmad
A
A
D000309:Adrenal Insufficiency / Q000151:congenital* / Q000209:etiology / Q000235:genetics; D000595:Amino Acid Sequence; D000075686:COP9 Signalosome Complex; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D019476:Insect Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D056985:Nuclear Receptor Co-Repressor 2; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
C402762:COPS2 protein, human; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D019476:Insect Proteins; C539130:NCOR2 protein, human; C539965:NR0B1 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D014157:Transcription Factors; D000075686:COP9 Signalosome Complex