Mol Cell Biol, July 1998, p. 4252-4261, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
(CBF
) Subunit by
the Leukemia-Related PEBP2/CBF
-SMMHC Fusion Protein
Inhibits PEBP2/CBF-Mediated Transactivation
Department of Viral Oncology, Institute for Virus Research, Kyoto University, Kyoto 606, Japan
Received 4 March 1998/Returned for modification 7 April 1998/Accepted 21 April 1998
The polyomavirus enhancer binding protein 2 (PEBP2)/core binding
factor (CBF) is a transcription factor composed of two subunits,
and
. The gene encoding the
subunit is disrupted by inv(16), resulting in the formation of a chimeric protein,
-SMMHC, which is
associated with acute myelogenous leukemia. To understand the effect of
-SMMHC on PEBP2-mediated transactivation, we used a luciferase assay system in which contribution of both the
and
subunits was absolutely required to activate transcription. Using this
system, we found that the minimal region of the
subunit required
for transactivation resides between amino acid 1 and 135, which is
known to dimerize with the
subunit. In contrast,
-SMMHC, despite
having this minimal region for dimerization and transactivation, failed
to support transcription with the
subunit. Furthermore
-SMMHC
blocked the synergistic transcription achieved by PEBP2 and
CCAAT/enhancer binding protein
. By using a construct in which the
PEBP2
subunit was fused to the glucocorticoid receptor ligand
binding domain, we demonstrated that coexpressed
-SMMHC tightly
sequestered the
subunit in the cytoplasm and blocked dexamethasone-dependent nuclear translocation of the
subunit. Thus,
the result suggess that
-SMMHC inhibits PEBP2-mediated transcription via cytoplasmic sequestration of the
subunit. Lastly proliferation of ME-1 cells that harbor inv(16) was blocked by an antisense oligonucleotide complementary to the junction of the
chimeric mRNA, suggesting that
-SMMHC contributes to leukemogenesis by blocking the differentiation of myeloid cells.
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