Journal article
Evidence for involvement of Bax and p53, but not caspases, in radiation‐induced cell death of cultured postnatal hippocampal neurons
Journal of neuroscience research, Vol.54(6), pp.721-733
12/15/1998
DOI: 10.1002/(SICI)1097-4547(19981215)54:6<721::AID-JNR1>3.0.CO;2-1
PMID: 9856857
Abstract
Bax (a death‐promoting member of the bcl‐2 gene family), the tumor suppressor gene product p53, and the ICE/ced‐3‐related proteases (caspases) have all been implicated in programmed cell death in a wide variety of cell types. However, their roles in radiation‐induced neuronal cell death are poorly understood. In order to further elucidate the molecular mechanisms underlying radiation‐induced neuronal cell death, we have examined the ability of ionizing radiation to induce cell death in primary cultured hippocampal neurons obtained from wild‐type, p53‐deficient and Bax‐deficient newborn mice. Survival in neuronal cultures derived from wild‐type mice decreased in a dose‐dependent manner 24 hr after a single 10 Gy to 30 Gy dose of ionizing radiation. In contrast, neuronal survival in irradiated cultures derived from p53‐deficient or Bax‐deficient mice was equivalent to that observed in control, nonirradiated cultures. Western blot analyses indicated that neuronal p53 protein levels increased after irradiation in wild‐type cells. However, Bax protein levels did not change, indicating that other mechanisms exist for regulating Bax activity. Adenovirus‐mediated overexpression of p53 also caused neuronal cell death without increasing Bax protein levels. Irradiation resulted in a significant induction in caspase activity, as measured by increased cleavage of fluorogenic caspase substrates. However, specific inhibitors of caspase activity (zVAD‐fmk, zDEVD‐fmk and BAF) failed to protect postnatal hippocampal neurons from radiation‐induced cell death. Staurosporine (a potent inducer of apoptosis in many cell types) effectively induced neuronal cell death in wild‐type, p53‐deficient and Bax‐deficient hippocampal neurons, indicating that all were competent to undergo programmed cell death. These results demonstrate that both p53 and Bax are necessary for radiation‐induced cell death in postnatal cultured hippocampal neurons. The fact that cell death occurred despite caspase inhibition suggests that radiation‐induced neuronal cell death may occur in a caspase‐independent manner. J. Neurosci. Res. 54:721–733, 1998. © 1998 Wiley‐Liss, Inc.
Details
- Title: Subtitle
- Evidence for involvement of Bax and p53, but not caspases, in radiation‐induced cell death of cultured postnatal hippocampal neurons
- Creators
- Mark D JohnsonHong XiangSusan LondonYoshito KinoshitaMichael KnudsonMarc MaybergStanley J KorsmeyerRichard S Morrison
- Resource Type
- Journal article
- Publication Details
- Journal of neuroscience research, Vol.54(6), pp.721-733
- Publisher
- John Wiley & Sons, Inc; New York
- DOI
- 10.1002/(SICI)1097-4547(19981215)54:6<721::AID-JNR1>3.0.CO;2-1
- PMID
- 9856857
- ISSN
- 0360-4012
- eISSN
- 1097-4547
- Number of pages
- 13
- Grant note
- National Institutes of Health (NS31775; AG10917; DK47754)
- Language
- English
- Date published
- 12/15/1998
- Academic Unit
- Pathology; Radiation Oncology
- Record Identifier
- 9984047980102771
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