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The Journal of Neuroscience, May 1, 1998, 18(9):3224-3232
High Constitutive NF- B Activity Mediates Resistance to
Oxidative Stress in Neuronal Cells
Frank
Lezoualc'h1,
Yutaka
Sagara2,
Florian
Holsboer1, and
Christian
Behl1
1 Max-Planck-Institute of Psychiatry, 80804 Munich,
Germany, and 2 The Salk Institute for Biological
Studies, San Diego, California 90370
Selected clones of the sympathetic precursor-like cell line PC12
(rCl8) are resistant to oxidative cell death induced by the Alzheimer's disease-associated amyloid protein (A ) and hydrogen peroxide (H2O2). Here, we show that the
transcriptional activity and DNA binding activity of the
redox-sensitive transcription factor NF- B and its nuclear expression
are constitutively increased in rCl8 cells compared with their
nonresistant parental PC12 cell (PC12p) counterpart. Suppression of the
transcriptional activity of NF- B in rCl8 cells with the synthetic
glucocorticoid dexamethasone or by direct overexpression of a
super-repressor mutant form of I B , a specific inhibitor of
NF- B, reversed the oxidative stress resistance phenotype of these
cells and ultimately led to increased cell death after the challenge
with H2O2. Dexamethasone treatment also caused
an increase in the protein level of I B . Our data show that an
increased baseline of NF- B activity may mediate the resistance of
these cells of neuronal origin to oxidative stress. Therefore, the
presented model may help to identify possible neuronal target genes of
NF- B and to further elucidate the molecular basis of the
differential sensitivity of neurons in neurodegenerative conditions
associated with an increased oxidative burden, such as in Alzheimer's
disease.
Key words:
NF- B; Alzheimer's disease; amyloid protein; oxidative stress; antioxidant enzymes; glucocorticoids; neuroprotection
Copyright © 1998 Society for Neuroscience 0270-6474/98/1893224-09$05.00/0
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