TY - JOUR
T1 - ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes
AU - Liu, Na
AU - Stoica, George
AU - Yan, Mingshan
AU - Scofield, Virginia L.
AU - Qiang, Wenan
AU - Lynn, William S.
AU - Wong, Paul K.Y.
N1 - Funding Information:
We thank Vanessa Edwards, Shawna Johnson, David Galloway, and Cynthia Kim for their assistance in preparing the manuscript and Lifang Zhang, Shoufeng Wang, and Amy Reid for their technical support. We thank Dr Jiangjun Shen of the Molecular Biology Core and Kent Claypool of the Cell and Tissue Analysis Facility Core at Science Park. We are also most grateful to the support of Robert Howard and the Longevity Foundation (formerly A-T Project, Austin, TX). This work was also supported by Center Grant ES07784 and Core Grant CA 16672, both from the National Institutes of Health.
PY - 2005/12
Y1 - 2005/12
N2 - ATM kinase, the product of the ataxia telangiectasia mutated (Atm) gene, is activated by genomic damage. ATM plays a crucial role in cell growth and development. Here we report that primary astrocytes isolated from ATM-deficient mice grow slowly, become senescent, and die in culture. However, before reaching senescence, these primary Atm-/- astrocytes, like Atm-/- lymphocytes, show increased spontaneous DNA synthesis. These astrocytes also show markers of oxidative stress and endoplasmic reticulum (ER) stress, including increased levels of heat shock proteins (HSP70 and GRP78), malondialdehyde adducts, Cu/Zn superoxide dismutase, procaspase 12 cleavage, and redox-sensitive phosphorylation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2). In addition, HSP70 and ERK1/2 phosphorylation are upregulated in the cerebella of ATM-deficient mice. This increase in ERK1/2 phosphorylation is seen primarily in cerebellar astrocytes, or Bergmann glia, near degenerating Purkinje cells. ERK1/2 activation and astrogliosis are also found in other parts of the brain, for example, the cortex. We conclude that ATM deficiency induces intrinsic growth defects, oxidative stress, ER stress, and ERKs activation in astrocytes.
AB - ATM kinase, the product of the ataxia telangiectasia mutated (Atm) gene, is activated by genomic damage. ATM plays a crucial role in cell growth and development. Here we report that primary astrocytes isolated from ATM-deficient mice grow slowly, become senescent, and die in culture. However, before reaching senescence, these primary Atm-/- astrocytes, like Atm-/- lymphocytes, show increased spontaneous DNA synthesis. These astrocytes also show markers of oxidative stress and endoplasmic reticulum (ER) stress, including increased levels of heat shock proteins (HSP70 and GRP78), malondialdehyde adducts, Cu/Zn superoxide dismutase, procaspase 12 cleavage, and redox-sensitive phosphorylation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2). In addition, HSP70 and ERK1/2 phosphorylation are upregulated in the cerebella of ATM-deficient mice. This increase in ERK1/2 phosphorylation is seen primarily in cerebellar astrocytes, or Bergmann glia, near degenerating Purkinje cells. ERK1/2 activation and astrogliosis are also found in other parts of the brain, for example, the cortex. We conclude that ATM deficiency induces intrinsic growth defects, oxidative stress, ER stress, and ERKs activation in astrocytes.
KW - Astrocyte
KW - Ataxia telangiectasia mutated
KW - Cerebellar Bergmann glia
KW - Endoplasmic reticulum stress
KW - Extracellular signal-regulated protein kinases
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=27944476980&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=27944476980&partnerID=8YFLogxK
U2 - 10.1038/labinvest.3700354
DO - 10.1038/labinvest.3700354
M3 - Article
C2 - 16189515
AN - SCOPUS:27944476980
VL - 85
SP - 1471
EP - 1480
JO - Laboratory Investigation
JF - Laboratory Investigation
SN - 0023-6837
IS - 12
ER -