Interaction and functional cooperation of the leukemia-associated factors AML1 and p300 in myeloid cell differentiation.
The AML1 transcription factor and the transcriptional coactivators p300 and CBP are the targets of chromosome translocations associated with acute myeloid leukemia and myelodysplastic syndrome. In the t(8;21) translocation, the AML1 (CBFA2/PEBP2alphaB) gene becomes fused to the MTG8 (ETO) gene. We previously found that the terminal differentiation step leading to mature neutrophils in response to granulocyte colony-stimulating factor (G-CSF) was inhibited by the ectopic expression of the AML1-MTG8 fusion protein in L-G murine myeloid progenitor cells. We show here that overexpression of normal AML1 proteins reverses this inhibition and restores the competence to differentiate. Immunoprecipitation analysis shows that p300 and CREB-binding protein (CBP) interact with AML1. The C-terminal region of AML1 is responsible for the induction of cell differentiation and for the interaction with p300. Overexpression of p300 stimulates AML1-dependent transcription and the induction of cell differentiation. These results suggest that p300 plays critical roles in AML1-dependent transcription during the differentiation of myeloid cells. Thus, AML1 and its associated factors p300 and CBFbeta, all of which are targets of chromosomal rearrangements in human leukemia, function cooperatively in the differentiation of myeloid cells.
Kitabayashi
I
I
Radiobiology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104, Japan. ikitabay@ncc.go.jp
Yokoyama
A
A
Shimizu
K
K
Ohki
M
M
D000123:Acetyltransferases / Q000378:metabolism* / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism* / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004357:Drug Synergism; D005786:Gene Expression Regulation; D006131:Growth Inhibitors / Q000502:physiology; D006412:Hematopoietic Stem Cells; D051548:Histone Acetyltransferases; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014407:Tumor Cells, Cultured; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D051548:Histone Acetyltransferases; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C082222:RUNX1T1 protein, human; C493726:Runx1 protein, mouse