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Experimental Therapeutics

Specific Proteolytic Cleavage of Poly(ADP-ribose) Polymerase: An Early Marker of Chemotherapy-induced Apoptosis

Scott H. Kaufmann, Serge Desnoyers, Yvonne Ottaviano, Nancy E. Davidson and Guy G. Poirier
Scott H. Kaufmann
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Serge Desnoyers
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Yvonne Ottaviano
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Nancy E. Davidson
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Guy G. Poirier
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DOI:  Published September 1993
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Abstract

Apoptosis is a morphologically and biochemically distinct form of cell death that occurs under a variety of physiological and pathological conditions. In the present study, the proteolytic cleavage of poly(ADP-ribose) polymerase (pADPRp) during the course of chemotherapy-induced apoptosis was examined. Treatment of HL-60 human leukemia cells with the topoisomerase II-directed anticancer agent etoposide resulted in morphological changes characteristic of apoptosis. Endonucleolytic degradation of DNA to generate nucleosomal fragments occurred simultaneously. Western blotting with epitope-specific monoclonal and polyclonal antibodies revealed that these characteristic apoptotic changes were accompanied by early, quantitative cleavage of the Mr 116,000 pADPRp polypeptide to an Mr ∼25,000 fragment containing the amino-terminal DNA-binding domain of pADPRp and an Mr ∼85,000 fragment containing the automodification and catalytic domains. Activity blotting revealed that the Mr ∼85,000 fragment retained basal pADPRp activity but was not activated by exogenous nicked DNA. Similar cleavage of pADPRp was observed after exposure of HL-60 cells to a variety of chemotherapeutic agents including cis-diaminedichloroplatinum (II), colcemid, 1-β-d-arabinofuranosylcytosine, and methotrexate; to γ-irradiation; or to the protein synthesis inhibitors puromycin or cycloheximide. Similar changes were observed in MDA-MB-468 human breast cancer cells treated with trifluorothymidine or 5-fluoro-2′-deoxyuridine and in γ-irradiated or glucocorticoid-treated rat thymocytes undergoing apoptosis. Treatment with several compounds (tosyl-l-lysine chloromethyl ketone, tosyl-l-phenylalanine chloromethyl ketone, N-ethylmaleimide, iodoacetamide) prevented both the proteolytic cleavage of pADPRp and the internucleosomal fragmentation of DNA. The results suggest that proteolytic cleavage of pADPRp, in addition to being an early marker of chemotherapy-induced apoptosis, might reflect more widespread proteolysis that is a critical biochemical event early during the process of physiological cell death.

Footnotes

  • ↵1 Supported in part by grants from the NIH (CA50435, CA55642, CA57545), Canadian Medical Research Council (MT6128), and Natural Sciences and Engineering Research Council of Canada (AO415). S. H. K. was supported by a Clinical Oncology Career Development Award from the American Cancer Society. S. D. received a predoctoral fellowship from the Fonds pour la Formation de Chercheurs et l'Aide à la Recherche. Y. O. was supported by a Stetler Research Fund fellowship.

  • ↵2 To whom reprint requests should be addressed, at Oncology 1-127, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, MD 21287.

  • Received March 3, 1993.
  • Accepted June 21, 1993.
  • ©1993 American Association for Cancer Research.
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September 1993
Volume 53, Issue 17
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Specific Proteolytic Cleavage of Poly(ADP-ribose) Polymerase: An Early Marker of Chemotherapy-induced Apoptosis
Scott H. Kaufmann, Serge Desnoyers, Yvonne Ottaviano, Nancy E. Davidson and Guy G. Poirier
Cancer Res September 1 1993 (53) (17) 3976-3985;

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Specific Proteolytic Cleavage of Poly(ADP-ribose) Polymerase: An Early Marker of Chemotherapy-induced Apoptosis
Scott H. Kaufmann, Serge Desnoyers, Yvonne Ottaviano, Nancy E. Davidson and Guy G. Poirier
Cancer Res September 1 1993 (53) (17) 3976-3985;
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