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Tonic activation of Bax primes neural progenitors for rapid apoptosis through a mechanism preserved in medulloblastoma.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2013 Nov 13; Vol. 33 (46), pp. 18098-108. - Publication Year :
- 2013
-
Abstract
- Commitment to survival or apoptosis within expanding progenitor populations poses distinct risks and benefits to the organism. We investigated whether specialized mechanisms regulate apoptosis in mouse neural progenitors and in the progenitor-derived brain tumor medulloblastoma. Here, we identified constitutive activation of proapoptotic Bax, maintained in check by Bcl-xL, as a mechanism for rapid cell death, common to postnatal neural progenitors and medulloblastoma. We found that tonic activation of Bax in cerebellar progenitors, along with sensitivity to DNA damage, was linked to differentiation state. In cerebellar progenitors, active Bax localized to mitochondria, where it was bound to Bcl-xL. Disruption of Bax:Bcl-xL binding by BH3-mimetic ABT 737 caused rapid apoptosis of cerebellar progenitors and primary murine medulloblastoma cells. Conditional deletion of Mcl-1, in contrast, did not cause death of cerebellar progenitors. Our findings identify a mechanism for the sensitivity of brain progenitors to typical anticancer therapies and reveal that this mechanism persists in medulloblastoma, a malignant brain tumor markedly sensitive to radiation and chemotherapy.
- Subjects :
- Animals
Cells, Cultured
Female
Male
Medulloblastoma pathology
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Mice, Knockout
Neural Stem Cells pathology
Protein Binding physiology
Time Factors
Apoptosis physiology
Medulloblastoma metabolism
Neural Stem Cells metabolism
bcl-2-Associated X Protein metabolism
bcl-X Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 33
- Issue :
- 46
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 24227720
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.2602-13.2013