Leukemic transformation by the v-ErbA oncoprotein entails constitutive binding to and repression of an erythroid enhancer in vivo

Paolo Ciana, Georgia G. Braliou, Florence G. Demay, Marieke Von Lindern, Domingo Barettino, Hartmut Beug, Hendrik G. Stunnenberg

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

32 Citaten (Scopus)

Samenvatting

v-ErbA, a mutated thyroid hormone receptor alpha (TRα), is thought to contribute to avian erythroblastosis virus (AEV)-induced leukemic transformation by constitutively repressing transcription of target genes. However, the binding of v-ErbA or any unliganded nuclear receptor to a chromatin-embedded response element as well as the role of the N-CoR-SMRT-HDAC co-repressor complex in mediating repression remain hypothetical. Here we identify a v-ErbA-response element, VRE, in an intronic DNase I hypersensitive site (HS2) of the chicken erythroid carbonic anhydrase II (CAII) gene. In vivo footprinting shows that v-ErbA is constitutively bound to this HS2-VRE in transformed, undifferentiated erythroblasts along with other transcription factors like GATA-1. Transfection assays show that the repressed HS2 region can be turned into a potent enhancer in v-ErbA-expressing cells by mutation of the VRE. Differentiation of transformed cells alleviates v-ErbA binding concomitant with activation of CAII transcription. Co-expression of a gag-TRα fusion protein in AEV-transformed cells and addition of ligand derepresses CAII transcription. Treatment of transformed cells with the histone deacetylase inhibitor, trichostatin A, derepresses the endogenous, chromatin-embedded CAII gene, while a transfected HS2-enhancer construct remains repressed. Taken together, our data suggest that v-ErbA prevents CAII activation by 'neutralizing' in cis the activity of erythroid transcription factors.

Originele taal-2Engels
Pagina's (van-tot)7382-7394
Aantal pagina's13
TijdschriftEMBO Journal
Volume17
Nummer van het tijdschrift24
DOI's
StatusGepubliceerd - 15 dec. 1998
Extern gepubliceerdJa

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