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Papers In Press, published online ahead of print February 23, 2001
J. Biol. Chem, 10.1074/jbc.C100050200
Submitted on January 30, 2001
Revised on February 23, 2001
Accepted on February 23, 2001
Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115
Corresponding Author: donald_kufe{at}dfci.harvard.edu
The Abl family of mammalian nonreceptor tyrosine kinases consists of c-Abl and Arg (Abl-related gene). Certain insights are available regarding 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 Y48. 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 Y48 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.
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