Differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways.
E2A is a member of the E-protein family of transcription factors. Previous studies have reported context-dependent regulation of E2A-dependent transcription. For example, whereas the E2A portion of the E2A-Pbx1 leukemia fusion protein mediates robust transcriptional activation in t(1;19) acute lymphoblastic leukemia, the transcriptional activity of wild-type E2A is silenced by high levels of corepressors, such as the AML1-ETO fusion protein in t(8;21) acute myeloid leukemia and ETO-2 in hematopoietic cells. Here, we show that, unlike the HEB E-protein, the activation domain 1 (AD1) of E2A has specifically reduced corepressor interaction due to E2A-specific amino acid changes in the p300/CBP and ETO target motif. Replacing E2A-AD1 with HEB-AD1 abolished the ability of E2A-Pbx1 to activate target genes and to induce cell transformation. On the other hand, the weak E2A-AD1-corepressor interaction imposes a critical importance on another ETO-interacting domain, downstream ETO-interacting sequence (DES), for corepressor-mediated repression. Deletion of DES abrogates silencing of E2A activity by AML1-ETO in t(8;21) leukemia cells or by ETO-2 in normal hematopoietic cells. Our results reveal an E2A-specific mechanism important for its context-dependent activation and repression function, and provide the first evidence for the differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways.
Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
Chien-Hung
CH
Gow
Chun
C
Guo
David
D
Wang
Qiande
Q
Hu
Jinsong
J
Zhang
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry* / Q000378:metabolism*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins / Q000378:metabolism*; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D051379:Mice; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D000075142:RUNX1 Translocation Partner 1 Protein; D015533:Transcriptional Activation
D000596:Amino Acids; D051792:Basic Helix-Loop-Helix Proteins; D056970:Co-Repressor Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C107844:AML1-ETO fusion protein, human; C407909:TCF3 protein, human; C089847:E2A-Pbx1 fusion protein