Transcriptional inhibition of p53 by the MLL/MEN chimeric protein found in myeloid leukemia.
The t(11;19)(q23;p13.1) translocation is frequently found in adult myeloid leukemia. In the MLL/MEN fusion protein generated by this translocation, most of the coding region of the MEN protein, an RNA polymerase II elongation factor, is fused to the N-terminal third of the MLL protein, a possible transcriptional regulator. However, the molecular mechanism of leukemogenesis by the fusion protein remains unclear. We investigated the effects of the fusion protein on p53 function using luciferase assays. Overexpression of the fusion protein suppressed the transactivation ability of p53. This negative effect of the fusion protein on p53 function was dependent on the region derived from MEN. Moreover, p53 coimmunoprecipitated with MLL/MEN as well as MEN, suggesting that the fusion protein binds to p53 through the MEN region. We found that MEN binding to p53 was mediated by its N-terminal region and repression of p53 transcriptional activity was mediated by its C-terminal region. We also found that these two functional regions were essential for the transformation of Rat1 cells mediated by MEN. Although we could not demonstrate a functional difference between MLL/MEN and MEN in this study, these data suggest that the MLL/MEN chimeric transcriptional regulator may exert its oncogenic activity by inhibiting the function of the p53 tumor-suppressor protein by binding to it. Our findings provide a novel insight into the leukemogenic mechanism exerted by the t(11;19)(q23;p13.1) translocation.
Maki
K
K
Department of Hematology and Oncology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Mitani
K
K
Yamagata
T
T
Kurokawa
M
M
Kanda
Y
Y
Yazaki
Y
Y
Hirai
H
H
D000328:Adult; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D002888:Chromosomes, Human, Pair 19; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D051788:Myeloid-Lymphoid Leukemia Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010445:Peptide Elongation Factors; D011519:Proto-Oncogenes; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D035602:Transcriptional Elongation Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C090862:ELL protein, human; C497422:KMT2A protein, human; C497424:Mllt1 protein, rat; D009363:Neoplasm Proteins; D010445:Peptide Elongation Factors; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; D016159:Tumor Suppressor Protein p53; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase