Aurintricarboxylic acid rescues PC12 cells and sympathetic neurons from cell death caused by nerve growth factor deprivation: correlation with suppression of endonuclease activity.
Past studies have shown that serum-free cultures of PC12 cells are a useful model system for studying the neuronal cell death which occurs after neurotrophic factor deprivation. In this experimental paradigm, nerve growth factor (NGF) rescues the cells from death. It is reported here that serum-deprived PC12 cells manifest an endonuclease activity that leads to internucleosomal cleavage of their cellular DNA. This activity is detected within 3 h of serum withdrawal and several hours before any morphological sign of cell degeneration or death. NGF and serum, which promote survival of the cells, inhibit the DNA fragmentation. Aurintricarboxylic acid (ATA), a general inhibitor of nucleases in vitro, suppresses the endonuclease activity and promotes long-term survival of PC12 cells in serum-free cultures. This effect appears to be independent of macromolecular synthesis. In addition, ATA promotes long-term survival of cultured sympathetic neurons after NGF withdrawal. ATA neither promotes nor maintains neurite outgrowth. It is hypothesized that the activation of an endogenous endonuclease could be responsible for neuronal cell death after neurotrophic factor deprivation and that growth factors could promote survival by leading to inhibition of constitutively present endonucleases.
Batistatou
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A
Department of Pathology and Center for Neurobiology and Behavior, Columbia University, College of Physicians and Surgeons, New York 10032.
Greene
L A
LA
D000818:Animals; D001312:Aurintricarboxylic Acid / Q000494:pharmacology*; D015152:Blotting, Northern; D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D004587:Electrophoresis, Agar Gel; D004720:Endonucleases / Q000378:metabolism; D008858:Microscopy, Phase-Contrast; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D016716:PC12 Cells; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D013564:Sympathetic Nervous System / Q000166:cytology
D009414:Nerve Growth Factors; D016760:Proto-Oncogene Proteins c-fos; D001312:Aurintricarboxylic Acid; D004720:Endonucleases