Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues.

dc.contributor.author

Johnson, Carrie E

dc.contributor.author

Huang, Yolanda Y

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Parrish, Amanda B

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Smith, Michelle I

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Vaughn, Allyson E

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Zhang, Qian

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Wright, Kevin M

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Van Dyke, Terry

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Wechsler-Reya, Robert J

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Kornbluth, Sally

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Deshmukh, Mohanish

dc.coverage.spatial

United States

dc.date.accessioned

2014-03-06T18:28:24Z

dc.date.issued

2007-12-26

dc.description.abstract

Brain tumors are typically resistant to conventional chemotherapeutics, most of which initiate apoptosis upstream of mitochondrial cytochrome c release. In this study, we demonstrate that directly activating apoptosis downstream of the mitochondria, with cytosolic cytochrome c, kills brain tumor cells but not normal brain tissue. Specifically, cytosolic cytochrome c is sufficient to induce apoptosis in glioblastoma and medulloblastoma cell lines. In contrast, primary neurons from the cerebellum and cortex are remarkably resistant to cytosolic cytochrome c. Importantly, tumor tissue from mouse models of both high-grade astrocytoma and medulloblastoma display hypersensitivity to cytochrome c when compared with surrounding brain tissue. This differential sensitivity to cytochrome c is attributed to high Apaf-1 levels in the tumor tissue compared with low Apaf-1 levels in the adjacent brain tissue. These differences in Apaf-1 abundance correlate with differences in the levels of E2F1, a previously identified activator of Apaf-1 transcription. ChIP assays reveal that E2F1 binds the Apaf-1 promoter specifically in tumor tissue, suggesting that E2F1 contributes to the expression of Apaf-1 in brain tumors. Together, these results demonstrate an unexpected sensitivity of brain tumors to postmitochondrial induction of apoptosis. Moreover, they raise the possibility that this phenomenon could be exploited therapeutically to selectively kill brain cancer cells while sparing the surrounding brain parenchyma.

dc.identifier

https://www.ncbi.nlm.nih.gov/pubmed/18093951

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0709101105

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1091-6490

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https://hdl.handle.net/10161/8392

dc.language

eng

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Proceedings of the National Academy of Sciences

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Proc Natl Acad Sci U S A

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10.1073/pnas.0709101105

dc.subject

Apoptosis

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Apoptotic Protease-Activating Factor 1

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Astrocytoma

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Brain

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Brain Neoplasms

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Caspases

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Cytochromes c

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E2F1 Transcription Factor

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Gene Expression Regulation, Neoplastic

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Humans

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Medulloblastoma

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Neurons

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Oligonucleotide Array Sequence Analysis

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Promoter Regions, Genetic

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Transcription, Genetic

dc.title

Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues.

dc.type

Journal article

pubs.author-url

https://www.ncbi.nlm.nih.gov/pubmed/18093951

pubs.begin-page

20820

pubs.end-page

20825

pubs.issue

52

pubs.organisational-group

Biology

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Duke

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Duke Cancer Institute

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Institutes and Centers

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School of Medicine

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Trinity College of Arts & Sciences

pubs.publication-status

Published

pubs.volume

104

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