E protein silencing by the leukemogenic AML1-ETO fusion protein.
The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 15% of acute myeloid leukemia (AML) cases. This study shows that AML1-ETO, as well as ETO, inhibits transcriptional activation by E proteins through stable interactions that preclude recruitment of p300/CREB-binding protein (CBP) coactivators. These interactions are mediated by a conserved ETO TAF4 homology domain and a 17-amino acid p300/CBP and ETO target motif within AD1 activation domains of E proteins. In t(8;21) leukemic cells, very stable interactions between AML1-ETO and E proteins underlie a t(8;21) translocation-specific silencing of E protein function through an aberrant cofactor exchange mechanism. These studies identify E proteins as AML1-ETO targets whose dysregulation may be important for t(8;21) leukemogenesis, as well as an E protein silencing mechanism that is distinct from that associated with differentiation-inhibitory proteins.
Zhang
Jinsong
J
Laboratory of Biochemistry and Molecular Biology, Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Kalkum
Markus
M
Yamamura
Soichiro
S
Chait
Brian T
BT
Roeder
Robert G
RG
D000208:Acute Disease; D000595:Amino Acid Sequence; D051792:Basic Helix-Loop-Helix Proteins; D050882:CREB-Binding Protein; D002460:Cell Line; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006367:HeLa Cells; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000075142:RUNX1 Translocation Partner 1 Protein; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014178:Translocation, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D050882:CREB-Binding Protein; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; C107844:AML1-ETO fusion protein, human; C407909:TCF3 protein, human; C544894:TCF7L2 protein, human; C073366:TCF12 protein, human; C494363:CREBBP protein, human