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J. Biol. Chem., Vol. 278, Issue 17, 15412-15420, April 25, 2003
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From the Laboratory of Molecular Aspects of Hematopoiesis, Sloan
Kettering Institute for Cancer Research, New York, New York
10021
H-L(3)MBT, the human homolog of the
Drosophila lethal(3)malignant brain tumor protein, is a
member of the polycomb group (PcG) of proteins, which function
as transcriptional regulators in large protein complexes. Homozygous
mutations in the l(3)mbt gene cause brain tumors in
Drosophila, identifying l(3)mbt as a tumor
suppressor gene. The h-l(3)mbt gene maps to
chromosome 20q12, within a common deleted region associated with
myeloid hematopoietic malignancies. H-L(3)MBT contains three repeats of
100 residues called MBT repeats, whose function is unknown, and a
C-terminal
The Human L(3)MBT Polycomb Group Protein Is a Transcriptional
Repressor and Interacts Physically and Functionally with TEL
(ETV6)*
, and
-helical structure, the SPM (SCM,
PH, MBT domain, which is structurally
similar to the SAM (sterile alpha
motif) protein-protein interaction domain, found in several
ETS transcription factors, including TEL (translocation Ets leukemia). We report that H-L(3)MBT is a
transcriptional repressor and that its activity is largely dependent on
the presence of a region containing the three MBT repeats. H-L(3)MBT
acts as a histone deacetylase-independent transcriptional repressor,
based on its lack of sensitivity to trichostatin A. We found that
H-L(3)MBT binds in vivo to TEL, and we have mapped the
region of interaction to their respective SPM/SAM domains. We show that
the ability of TEL to repress TEL-responsive promoters is enhanced by
the presence of H-L(3)MBT, an effect dependent on the H-L(3)MBT and the
TEL interacting domains. These experiments suggest that histone deacetylase-independent transcriptional repression by TEL depends on
the recruitment of PcG proteins. We speculate that the interaction of
TEL with H-L(3)MBT can direct a PcG complex to genes repressed by TEL,
stabilizing their repressed state.
*
This work was supported by National Institutes of Health RO1
grant DK52208, the Sunshine Lady Foundation & the Gabrielle Rich Leukemia Research Foundation.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Charles A. Dana fellow.
§
To whom correspondence should be addressed: Memorial Sloan
Kettering Cancer Center, 1275 York Ave., Box 575, New York, NY 10021. E-mail: nimers@mskcc.org.
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