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Differential p53 Regulation of Neural Precursor Cell Death
Author(s) -
Geng Ying,
Akhtar Rizwan S.,
Roth Kevin A.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a12-c
Subject(s) - programmed cell death , staurosporine , puma , biology , dna damage , microbiology and biotechnology , dna laddering , transcription factor , neurodegeneration , apoptosis , phosphorylation , cancer research , protein kinase c , dna , gene , biochemistry , dna fragmentation , medicine , disease , pathology
Regulation of neural precursor cell (NPC) death is important for both normal nervous system development and brain tumor formation. We previously showed in primary cerebellar NPCs that genotoxin‐induced NPC death requires new protein synthesis and PUMA, a p53 transcriptionally‐regulated BH‐3 only molecule. In contrast, staurosporine (STS), a broad spectrum protein kinase inhibitor, induced NPC death without requiring new protein synthesis or PUMA expression. Similar to primary cerebellar NPCs, genotoxin‐induced death of the neural stem cell line C17.2 required new gene transcription, while STS induced NPC death did not. Genotoxic agents increased nuclear p53 immunoreactivity, while STS induced rapid cytoplasmic p53 accumulation. Total p53 protein levels were increased after both genotoxic injury and STS treatment. Immunocytochemical studies showed that the majority of cytoplasmic p53 after STS treatment did not colocalize with either mitochondrial markers or activated‐Bax. Phosphorylation of p53 on ser 18 was highly increased after genotoxic injury, but not STS treatment. Deficiency of ataxia‐telangiectaisa mutated (ATM), which phosphorylates p53 on ser 18 after DNA damage, decreased bleomycin‐induced, but not STS‐induced NPC death. Combined with our previous findings, these results suggest that genotoxic agents induce p53 transcription‐dependent NPC death, while STS induces p53 transcription‐independent NPC death. Whether differential post‐translational modification of p53 leads to its different subcellular localization after genotoxin or STS exposure and how cytosolic p53 induces p53‐dependent, transcription‐independent NPC death requires further investigation. Supported by NIH grants NS35107 and NS41962.