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Molecular and Cellular Biology, October 1999, p. 7050-7060, Vol. 19, No. 10
VA Puget Sound Health Care System, Seattle,
Washington 981081; Departments of
Pathology,4 Laboratory
Medicine,5 and
Medicine,3 University of Washington
School of Medicine, Seattle, Washington 98195; Department of
Cell Biology, Vanderbilt University Medical Center, Nashville,
Tennessee 372322; and Laboratory of
Molecular Pharmacology, Division of Basic Science, National Cancer
Institute, National Institutes of Health, Bethesda, Maryland
208926
Received 3 November 1998/Returned for modification 11 January
1999/Accepted 29 June 1999
One of the most common chromosomal abnormalities in acute leukemia
is a reciprocal translocation involving the HRX gene (also called MLL, ALL-1, or HTRX) at
chromosomal locus 11q23, resulting in the formation of HRX fusion
proteins. Using the yeast two-hybrid system and human cell culture
coimmunoprecipitation experiments, we show here that HRX proteins
interact directly with the GADD34 protein. We have found that
transfected cells overexpressing GADD34 display a significant increase
in apoptosis after treatment with ionizing radiation, indicating that
GADD34 expression not only correlates with apoptosis but also can
enhance apoptosis. The amino-terminal third of the GADD34 protein was
necessary for this observed increase in apoptosis. Furthermore,
coexpression of three different HRX fusion proteins (HRX-ENL, HRX-AF9,
and HRX-ELL) had an anti-apoptotic effect, abrogating GADD34-induced
apoptosis. In contrast, expression of wild-type HRX gave rise to an
increase in apoptosis. The difference observed here between wild-type
HRX and the leukemic HRX fusion proteins suggests that inhibition of
GADD34-mediated apoptosis may be important to leukemogenesis. We also
show here that GADD34 binds the human SNF5/INI1 protein, a member of
the SNF/SWI complex that can remodel chromatin and activate
transcription. These studies demonstrate, for the first time, a gain of
function for leukemic HRX fusion proteins compared to wild-type
protein. We propose that the role of HRX fusion proteins as negative
regulators of post-DNA-damage-induced apoptosis is important to
leukemia progression.
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Leukemic HRX Fusion Proteins Inhibit GADD34-Induced
Apoptosis and Associate with the GADD34 and hSNF5/INI1
Proteins
*
Corresponding author. Mailing address: VA Puget Sound
Health Care System, 1660 S. Columbian Way, Department of Pathology Mail Stop 113, Seattle, WA 98108. Phone: (206) 764-2264. Fax: (206) 764-2001. E-mail: tkachuk{at}u.washington.edu.
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