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Molecular and Cellular Biology, October 1999, p. 7050-7060, Vol. 19, No. 10
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

Haskell T. Adler,1 Rebecca Chinery,2 Daniel Y. Wu,1,3 Steven J. Kussick,1,4,5 John M. Payne,1 Albert J. Fornace Jr.,6 and Douglas C. Tkachuk1,4,*

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.

* 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.

Molecular and Cellular Biology, October 1999, p. 7050-7060, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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