A mechanism of repression by acute myeloid leukemia-1, the target of multiple chromosomal translocations in acute leukemia.
AML1 is one of the most frequently translocated genes in human leukemia. Here we demonstrate that acute myeloid leukemia-1 (AML-1) (Runx-1) represses transcription from a native promoter, p21(Waf1/Cip1). Unexpectedly, this repression did not require interactions with the Groucho co-repressor. To define the mechanism of repression, we asked whether other co-repressors could interact with AML-1. We demonstrate that AML-1 interacts with the mSin3 co-repressors. Moreover, endogenous AML-1 associated with endogenous mSin3A in mammalian cells. A deletion mutant of AML-1 that did not interact with mSin3A failed to repress transcription. The AML-1/mSin3 association suggests a mechanism of repression for the chromosomal translocation fusion proteins that disrupt AML-1.
Lutterbach
B
B
Departments of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Westendorf
J J
JJ
Linggi
B
B
Isaac
S
S
Seto
E
E
Hiebert
S W
SW
D000208:Acute Disease; D001665:Binding Sites; D050676:Core Binding Factor Alpha 2 Subunit; D050657:Core Binding Factor alpha Subunits; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006655:Histone Deacetylases; D007951:Leukemia, Myeloid / Q000235:genetics*; D009363:Neoplasm Proteins; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000378:metabolism*; D014178:Translocation, Genetic
D050676:Core Binding Factor Alpha 2 Subunit; D050657:Core Binding Factor alpha Subunits; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C071731:SIN3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D006655:Histone Deacetylases