The MYND motif is required for repression of basal transcription from the multidrug resistance 1 promoter by the t(8;21) fusion protein.

Lutterbach B, Sun D, Schuetz J, Hiebert SW
Mol Cell Biol. 1998 18 (6): 3604-11

PMID: 9584201 · PMCID: PMC108942 · DOI:10.1128/mcb.18.6.3604

Chromosomal translocations in acute leukemia that affect the AML-1/CBFbeta transcription factor complex create dominant inhibitory proteins. However, the mechanisms by which these proteins act remain obscure. Here we demonstrate that the multidrug resistance 1 (MDR-1) promoter is a target for AML/ETO transcriptional repression. This repression is of basal, not activated, expression from the MDR-1 promoter and thus represents a new mechanism for AML/ETO function. We have defined two domains in AML/ETO that are required for repression of basal transcription from the MDR-1 promoter: a hydrophobic heptad repeat (HHR) motif and a conserved zinc finger (ZnF) domain termed the MYND domain. The HHR mediates formation of AML/ETO homodimers and AML/ETO-ETO heterodimers. Single serine substitutions at conserved cysteine residues within the predicted ZnFs also abrogate transcriptional repression. Finally, we observe that AML/ETO can also inhibit Ets-1 activation of the MDR-1 promoter, indicating that AML/ETO can disrupt both basal and Ets-1-dependent transcription. The fortuitous inhibition of MDR-1 expression in t(8;21)-containing leukemias may contribute to the favorable response of these patients to chemotherapeutic drugs.

MeSH Terms (24)

ATP Binding Cassette Transporter, Subfamily B, Member 1 Chromosomes, Human, Pair 8 Chromosomes, Human, Pair 21 Core Binding Factor Alpha 2 Subunit Dimerization DNA-Binding Proteins Gene Expression Regulation, Neoplastic Humans Leukemia, Myeloid Neoplasm Proteins Oncogene Proteins, Fusion Point Mutation Promoter Regions, Genetic Proto-Oncogene Protein c-ets-1 Proto-Oncogene Proteins Proto-Oncogene Proteins c-ets Recombinant Fusion Proteins Repressor Proteins RUNX1 Translocation Partner 1 Protein Structure-Activity Relationship Transcription Factors Translocation, Genetic Tumor Cells, Cultured Zinc Fingers

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