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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
Author(s) -
Stefanis Leonidas,
Troy Carol M.,
Qi Haiqing,
Greene Lloyd A.
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.69041425.x
Subject(s) - proteases , caspase , programmed cell death , apoptosis , serine , trypsin , microbiology and biotechnology , chemistry , pharmacology , tosyl , biology , biochemistry , phosphorylation , enzyme , stereochemistry
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 α ‐ 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.