Tonic activation of Bax primes neural progenitors for rapid apoptosis through a mechanism preserved in medulloblastoma.
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.
Departments of Neurology, Radiation Oncology, and Radiology, Neuroscience Center, Lineberger Comprehensive Cancer Center, and Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
Andrew J
AJ
Crowther
Vivian
V
Gama
Ariana
A
Bevilacqua
Sha X
SX
Chang
Hong
H
Yuan
Mohanish
M
Deshmukh
Timothy R
TR
Gershon
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D008297:Male; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000502:physiology; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein