Inhibitors of trypsin-like serine proteases inhibit processing of the caspase Nedd-2 and protect PC12 cells and sympathetic neurons from death evoked by withdrawal of trophic support.
Rat pheochromocytoma (PC12) cells and sympathetic neurons undergo apoptotic cell death upon withdrawal of trophic support. We have shown previously that selective cysteine aspartase (caspase) inhibitors protect PC12 cells and sympathetic neurons from such death, and that the caspase Nedd-2 is required for this type of death to occur. We now show that 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) and N(alpha)-p-tosyl-L-lysine chloromethyl ketone (TLCK), agents that inhibit another class of proteases, the trypsin-like serine proteases, also suppress cell death in this paradigm. The site of action of these agents is upstream of the caspases, because the CPP32-like and Nedd-2-cleaving activities that are induced upon withdrawal of trophic support in PC12 cells are inhibited when AEBSF and TLCK are applied to the cells. Both agents inhibit thymidine incorporation in PC12 cells at concentrations similar to those that promote survival, raising the possibility that they may promote survival in neuronal cells through inhibition of aberrant activation of cell cycle components.
Stefanis
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Department of Pathology, Taub Center for Alzheimer's Disease Research and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032, U.S.A.
Troy
C M
CM
Qi
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Greene
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D000818:Animals; D001790:Blood Physiological Phenomena; D053143:Caspase 2; D053148:Caspase 3; D020169:Caspases; D016923:Cell Death / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism; D009414:Nerve Growth Factors / Q000008:administration & dosage; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells / Q000187:drug effects* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000166:cytology / Q000187:drug effects*; D013936:Thymidine / Q000037:antagonists & inhibitors; D014107:Tosyllysine Chloromethyl Ketone / Q000494:pharmacology; D014361:Trypsin Inhibitors / Q000494:pharmacology
D009414:Nerve Growth Factors; D011506:Proteins; D015842:Serine Proteinase Inhibitors; D013450:Sulfones; D014361:Trypsin Inhibitors; D014107:Tosyllysine Chloromethyl Ketone; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; C505410:Casp3 protein, rat; D053143:Caspase 2; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D013936:Thymidine