The transcriptional corepressor MTG16a contains a novel nucleolar targeting sequence deranged in t (16; 21)-positive myeloid malignancies.
The MTG (Myeloid Translocation Gene) proteins are a family of novel transcriptional corepressors. We report that MTG16a, a protein isoform encoded by the MTG16 gene deranged by the t (16; 21) in myeloid malignancies, is targeted to the nucleolus. The amino acid sequence necessary for nucleolar localization was mapped to the MTG16a N-terminal region. MTG16a, like MTG8, the nuclear corepressor deranged by the t (8; 21), is capable to interact with specific histone deacetylases (HDACs) suggesting that the protein may mediate silencing of nucleolar gene transcription. In addition, MTG16a is capable to form oligomers with other MTG proteins. As a consequence of the t (16; 21) the AML1 DNA-binding domain replaces the MTG16a N-terminal region. The AML1-MTG16 fusion protein is targeted to the nucleoplasm where it is capable to oligomerize with MTG16a and interact with HDAC1 and HDAC3. The deficiency of HDAC-containing complexes at nucleolar sites and the accumulation of HDAC-containing complexes at AML1-sites may be critical in the pathogenesis of t (16; 21) myeloid malignancies.
Hoogeveen
André T
AT
Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands. hoogeveen@ikg.fgg.eur.nl
Rossetti
Stefano
S
Stoyanova
Violeta
V
Schonkeren
Joris
J
Fenaroli
Angelia
A
Schiaffonati
Luisa
L
van Unen
Leontine
L
Sacchi
Nicoletta
N
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002466:Cell Nucleolus / Q000378:metabolism*; D002885:Chromosomes, Human, Pair 16; D002891:Chromosomes, Human, Pair 21; D050676:Core Binding Factor Alpha 2 Subunit; D003593:Cytoplasm / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000032:analysis / Q000737:chemistry; D019281:Dimerization; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D010750:Phosphoproteins / Q000032:analysis / Q000737:chemistry; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D014178:Translocation, Genetic / Q000235:genetics*
C107844:AML1-ETO fusion protein, human; C112643:AML1-MTG16 protein, human; C110408:CBFA2T2 myeloid-transforming gene-related protein; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C082222:RUNX1T1 protein, human; D012097:Repressor Proteins; D014157:Transcription Factors; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases