The E2A and tal-1 helix-loop-helix proteins associate in vivo and are modulated by Id proteins during interleukin 6-induced myeloid differentiation.
The immunoglobulin enhancer-binding proteins, E12 and E47, encoded by the E2A gene belong to the basic helix-loop-helix (bHLH) family of regulatory proteins and act as transcriptional activators. In addition to their critical role in B-lymphocyte development, the E12 and E47 proteins have been implicated in the induction of myogenesis as heterodimeric partners of myogenic bHLH proteins, MyoD and myogenin. Here we demonstrate that the E2A proteins form heterodimers with the bHLH oncoprotein tal-1 in myeloid and erythroid cells and that these heterodimers specifically bind to the CANNTG DNA motif. Heterodimerization with tal-1 represses transactivation by E47 and could function to prevent the expression of immunoglobulin genes in cells other than B lymphocytes. DNA binding by E2A-tal-1 heterodimers in the M1 mouse myeloid cell line is abrogated upon terminal macrophage differentiation induced by the cytokine interleukin 6. The loss of E2A-tal-1 DNA binding is correlated with elevated expression of mRNA encoding the dominant negative HLH proteins, Id1 and particularly Id2. Moreover, recombinant Id proteins inhibit the E2A-tal-1-specific DNA binding activity from undifferentiated M1 cells. These results suggest that E2A-tal-1 heterodimers may play a role in preventing terminal differentiation in the myeloid lineage and provide a possible explanation for oncogenic transformation induced by ectopic tal-1 expression in acute T-cell lymphoblastic leukemias.
Voronova
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AF
DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA 94304-1104.
Lee
F
F
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D002999:Clone Cells; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D015870:Gene Expression; D018257:Helix-Loop-Helix Motifs; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1; D015850:Interleukin-6 / Q000494:pharmacology*; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D010954:Plasmacytoma; D014176:Protein Biosynthesis; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012097:Repressor Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D004268:DNA-Binding Proteins; D051798:Inhibitor of Differentiation Protein 1; D015850:Interleukin-6; D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012097:Repressor Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; C497453:ID1 protein, human; C497455:Idb1 protein, mouse; C544912:TCF7L1 protein, human; C489366:Tal1 protein, mouse; C544913:Tcf7l1 protein, mouse; C067143:TAL1 protein, human