The v-ErbA oncoprotein quenches the activity of an erythroid-specific enhancer.
v-ErbA is a mutated variant of thyroid hormone receptor (TRalpha/NR1A1) borne by the Avian Erythroblastosis virus causing erythroleukemia. TRalpha is known to activate transcription of specific genes in the presence of its cognate ligand, T3 hormone, while in its absence it represses it. v-ErbA is unable to bind ligand, and hence is thought to contribute to leukemogenesis by actively repressing erythroid-specific genes such as the carbonic anhydrase II gene (CA II). In the prevailing model, v-ErbA occludes liganded TR from binding to its cognate elements and constitutively interacts with the corepressors NCoR/SMRT. We previously identified a v-ErbA responsive element (VRE) within a DNase I hypersensitive region (HS2) located in the second intron of the CA II gene. We now show that HS2 fulfils all the requirements for a genuine enhancer that functions independent of its orientation and position with a profound erythroid-specific activity in normal erythroid progenitors (T2ECs) and in leukemic erythroid cell lines. We find that the HS2 enhancer activity is governed by two adjacent GATA-factor binding sites. v-ErbA as well as unliganded TR prevent HS2 activity by nullifying the positive function of factors bound to GATA-sites. However, v-ErbA, in contrast to TR, does not convey active repression to silence the transcriptional activity intrinsic to a heterologous tk promoter. We propose that depending on the sequence and context of the binding site, v-ErbA contributes to leukemogenesis by occluding liganded TR as well as unliganded TR thereby preventing activation or repression, respectively.
Braliou
G G
GG
Department of Molecular Biology, NCMLS University of Nijmegen, Geert Groote plein 26 PO Box 9101, 6500 HB Nijmegen, The Netherlands.
Ciana
P
P
Klaassen
W
W
Gandrillon
O
O
Stunnenberg
H G
HG
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002256:Carbonic Anhydrases / Q000235:genetics*; D002645:Chickens; D004742:Enhancer Elements, Genetic; D015672:Erythroid Precursor Cells; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics*; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D018774:Oncogene Proteins v-erbA / Q000235:genetics*; D011485:Protein Binding; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D014407:Tumor Cells, Cultured
D018774:Oncogene Proteins v-erbA; D011988:Receptors, Thyroid Hormone; D002256:Carbonic Anhydrases