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Protease Inhibitors Induce Specific Changes in Protein Tyrosine Phosphorylation That Correlate with Inhibition of Apoptosis in Myeloid Cells¹

Department of Medicine, Section of Hematology, University of Wisconsin, and William Middleton Veteran Affairs Hospital, Madison, Wisconsin 53706

To investigate early signaling events responsible for regulation of programmed cell death or apoptosis, we studied campothecin (a topoisomerase I inhibitor)-mediated apoptosis in the human promyelocytic leukemia cell line HL60. We demonstrate a tight correlation between protection of HL60 cells from apoptosis-associated internucleosomal DNA fragmentation by specific protease inhibitors or protein phosphatase inhibitors, with early tyrosine phosphorylation of a single protein substrate with a molecular weight of approximately 42,000. Exposure to protease inhibitors that did not protect HL60 cells from DNA fragmentation did not result in phosphorylation of this substrate. Likewise, a protein tyrosine kinase inhibitor that did not interfere with specific phosphorylation did not prevent DNA fragmentation. Taken together, these results suggest that phosphorylation of a M_r 42,000 substrate constitutes an important signaling event that may participate in regulation of the apoptotic response.

¹ This work was supported by a University of Wisconsin Medical School Research Committee Grant 161-9851 (to N. L. L.) and by USPHS Grant HL 43506 and a Veterans Administration merit review grant (to B. S. S.).

² To whom requests for reprints should be addressed, at Department of Medicine, Section of Hematology, 1300 University Ave., 2640 MSC, Madison, WI 53706. Phone: (608) 265-2700; Fax: (608) 263-4969; E-mail: lumelsky@facstaff.wisc.edu.

Received 3/12/96. Accepted 7/ 1/96.

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