title: The interleukin 1beta-converting enzyme inhibitor CrmA prevents Apo1/Fas- but not glucocorticoid-induced poly(ADP-ribose) polymerase cleavage and apoptosis in lymphoblastic leukemia cells.
abstract: Glucocorticoids (GC) induce programmed cell death (apoptosis) in immature lymphocytes and are an essential component in the therapy of acute lymphatic leukemia. The mechanism underlying GC-induced apoptosis particularly in leukemia cells is, however, not well understood. Most forms of apoptosis seem to employ a common final effector pathway characterized by specific proteolytic events mediated by interleukin 1beta-converting enzyme (ICE) and/or other ICE-like cysteine proteases. These events may result in the morphologic changes characteristic of apoptosis. To determine whether a similar proteolytic pathway is activated during GC-induced leukemia cell apoptosis, we investigated poly(ADP-ribose) polymerase (PARP), a typical target of ICE-like proteases, during GC-induced apoptosis of the human acute T-cell leukemic cell line CEM-C7H2. Our studies showed proteolytic PARP cleavage suggestive of activation of ICE-like proteases that preceeded morphologic signs of apoptosis. We further established stably transfected CEM-C7H2 sublines expressing the cowpox virus protein CrmA that inhibits some, but not all, ICE-like proteases. GC-induced PARP cleavage and apoptosis were neither inhibited nor delayed in crmA-expressing cell lines. In contrast, crmA expression rendered the same lines resistant to Apo1/Fas-induced PARP cleavage and apoptosis. Thus, different proteases might be activated during the effector phases of GC-and Apo1/Fas-induced apoptosis in human leukemia cells.
authors.affiliation: Institute for General and Experimental Pathology, University of Innsbruck, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Geley
authors.forename: B L
authors.initials: BL
authors.lastname: Hartmann
authors.forename: K
authors.initials: K
authors.lastname: Kapelari
authors.forename: A
authors.initials: A
authors.lastname: Egle
authors.forename: A
authors.initials: A
authors.lastname: Villunger
authors.forename: D
authors.initials: D
authors.lastname: Heidacher
authors.forename: R
authors.initials: R
authors.lastname: Greil
authors.forename: B
authors.initials: B
authors.lastname: Auer
authors.forename: R
authors.initials: R
authors.lastname: Kofler
mesh_terms: D017209:Apoptosis; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology / Q000473:pathology*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D015843:Serpins / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014764:Viral Proteins; D019014:fas Receptor / Q000276:immunology / Q000502:physiology
chemical_list: D005938:Glucocorticoids; D015843:Serpins; D014764:Viral Proteins; D019014:fas Receptor; D011064:Poly Adenosine Diphosphate Ribose; D003907:Dexamethasone; C074641:interleukin-1beta-converting enzyme inhibitor; D003546:Cysteine Endopeptidases; D020170:Caspase 1