title: Protease inhibitors induce specific changes in protein tyrosine phosphorylation that correlate with inhibition of apoptosis in myeloid cells.
abstract: 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 Mr 42,000 substrate constitutes an important signaling event that may participate in regulation of the apoptotic response.
authors: Department of Medicine, Section of Hematology, University of Wisconsin, Madison, USA. lumelsky@facstaff.wisc.edu
authors: N L
authors: NL
authors: Lumelsky
authors: B S
authors: BS
authors: Schwartz
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002166:Camptothecin / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D009707:Nucleosomes; D011480:Protease Inhibitors; D059004:Topoisomerase I Inhibitors; D014108:Tosylphenylalanyl Chloromethyl Ketone; D014443:Tyrosine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D002166:Camptothecin