v-ErbA, a mutated thyroid hormone receptor alpha (TR alpha), 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-TR alpha 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.
Leukemic transformation by the v-ErbA oncoprotein entails constitutive binding to and repression of an erythroid enhancer in vivo / P. Ciana, G.G. Braliou, F.G. Demay, M. von Lindern, D. Barettino, H. Beug, H.G. Stunnenberg. - In: EMBO JOURNAL. - ISSN 0261-4189. - 17:24(1998), pp. 7382-7394.
|Titolo:||Leukemic transformation by the v-ErbA oncoprotein entails constitutive binding to and repression of an erythroid enhancer in vivo|
CIANA, PAOLO (Primo)
|Parole Chiave:||Carbonic anhydrase II; Repression; Thyroid hormone; Trichostatin A; v-ErbA|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
Settore BIO/18 - Genetica
|Data di pubblicazione:||1998|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1093/emboj/17.24.7382|
|Appare nelle tipologie:||01 - Articolo su periodico|