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The Journal of Neuroscience, February 1, 1998, 18(3):830-840
Multiple Pathways of Neuronal Death Induced by DNA-Damaging
Agents, NGF Deprivation, and Oxidative Stress
David S.
Park1,
Erick
J.
Morris3,
Leonidas
Stefanis1, 2,
Carol M.
Troy1,
Michael L.
Shelanski1,
Herbert M.
Geller3, and
Lloyd A.
Greene1
1 Department of Pathology, Taub Center for Alzheimer's
Disease Research, and 2 Neurology and Center for
Neurobiology and Behavior, Columbia University College of Physicians
and Surgeons, New York, New York 10032, and 3 Department of
Pharmacology, University of Medicine and Dentistry of New Jersey
(UMDNJ)-Robert Wood Johnson Medical School, Piscataway, New Jersey
08854
Here, we compare the pathways by which DNA-damaging agents,
NGF deprivation, and superoxide dismutase 1 (SOD1) depletion evoke apoptosis of sympathetic neurons. Previous work raised the hypothesis that cell cycle signaling plays a required role in neuronal apoptosis elicited by NGF deprivation and the DNA-damaging agent camptothecin. To
test this hypothesis, we extended our investigation of DNA-damaging agents to cytosine arabinoside (AraC) and UV irradiation. As with NGF
deprivation and camptothecin treatment, the cyclin-dependent kinase
inhibitors flavopiridol and olomoucine protected neurons from apoptosis
induced by AraC and UV treatment. These observations support the model
that camptothecin, AraC, and UV treatment cause DNA damage, which leads
to apoptosis by a mechanism that, as in the case of NGF deprivation,
includes activation of cell cycle components. Flavopiridol and
olomoucine, however, had no effect on death induced by SOD1 depletion,
suggesting that CDKs do not play a role in this paradigm of neuronal
death. To compare further the mechanisms of death evoked by NGF
withdrawal, SOD1 depletion, and DNA-damaging agents, we investigated
their responses to inhibitors of cysteine aspartases, elements of
apoptotic pathways. The V-ICEinh and BAF, two peptide
inhibitors of cysteine aspartases, protected neurons in all three death
paradigms. In contrast, the cysteine aspartase inhibitory peptide
zVAD-fmk conferred protection from NGF withdrawal and SOD1 depletion,
but not DNA-damaging agents, whereas acYVAD-cmk protected only from
SOD1 depletion. Taken together, these findings indicate that three
different apoptotic stimuli activate separate pathways of death in the
same neuron type.
Key words:
CDK; cell cycle; DNA damage; caspase; apoptosis; cytosine
arabinoside
Copyright © 1998 Society for Neuroscience 0270-6474/98/183830-11$05.00/0
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