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J. Biol. Chem., Vol. 276, Issue 15, 11465-11468, April 13, 2001
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Dana-Farber Cancer Institute, Harvard Medical School, Boston,
Massachusetts 02115 and The Abl family of mammalian nonreceptor tyrosine
kinases consists of c-Abl and ARG (Abl-related gene). Certain insights
are available regarding the involvement c-Abl in the response of cells to stress. ARG, however, has no known function in cell signaling. The
present studies demonstrate that ARG associates with the proapoptotic Siva-1 protein. The functional significance of the ARG-Siva-1 interaction is supported by the finding that ARG is activated by
oxidative stress and that this response involves ARG-mediated phosphorylation of Siva-1 on Tyr48. The proapoptotic
effects of Siva-1 are accentuated in cells stably expressing ARG and
are inhibited in ARG-deficient cells. Moreover, the proapoptotic
effects of Siva-1 are abrogated by mutation of the Tyr48
site. We also show that the apoptotic response to oxidative stress is
attenuated in ARG-deficient cells and that this defect is corrected by
reconstituting ARG expression. These findings support a model in which
the activation of ARG by oxidative stress induces apoptosis by a
Siva-1-dependent mechanism.
ACCELERATED PUBLICATION
The ARG Tyrosine Kinase Interacts with Siva-1 in the
Apoptotic Response to Oxidative Stress*
,
Department of Molecular Biophysics and
Biochemistry, Yale University, New Haven, Connecticut 06520, and
§ Department of Microbiology and Immunology, University of Illinois at
Chicago, Chicago, Illinois 60612
*
This investigation was supported by Grant CA42802 awarded by
the NCI, National Institutes of Health.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.
To whom correspondence should be addressed: Dana-Farber
Cancer Institute, Harvard Medical School, 44 Binney St., Boston, MA 02115. Tel.: 617-632-3141; Fax: 617-632-2934; E-mail:
donald_kufe@dfci.harvard.edu.
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