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Blood, Vol. 93 No. 10 (May 15), 1999:
pp. 3216-3224
RAPID COMMUNICATION
Transcriptional Inhibition of p53 by the MLL/MEN Chimeric Protein
Found in Myeloid Leukemia
Kazuhiro Maki,
Kinuko Mitani,
Tetsuya Yamagata,
Mineo Kurokawa,
Yoshinobu Kanda,
Yoshio Yazaki, and
Hisamaru Hirai
From the Department of Hematology and Oncology, Faculty of Medicine,
University of Tokyo, Tokyo, Japan.
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.
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