TY - JOUR
T1 - Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma
AU - Stegh, Alexander H.
AU - Kesari, Santosh
AU - Mahoney, John E.
AU - Jenq, Harry T.
AU - Forloney, Kristin L.
AU - Protopopov, Alexei
AU - Louis, David N.
AU - Chin, Lynda
AU - DePinho, Ronald A.
PY - 2008/8/5
Y1 - 2008/8/5
N2 - Glioblastoma multiforme (GBM) is a highly aggressive brain cancer that is characterized by the paradoxical features of intense apoptosis resistance yet a marked propensity to undergo necrosis. Bcl2L12 (for Bcl2-Like12) is a nuclear and cytoplasmic oncoprotein that is universally overexpressed in primary GBM and functions to block postmitochondrial apoptosis signaling by neutralizing effector caspase-3 and caspase-7 maturation. This postmitochondrial block in apoptosis engenders the alternate cell fate of cellular necrosis, thus providing a molecular explanation for GBM's classical features. Whereas Bcl2L12-mediated neutralization of caspase-7 maturation involves physical interaction, the mechanism governing Bcl2L12-mediated inhibition of caspase-3 activity is not known. The nuclear localization of Bcl2L12 prompted expression profile studies of primary astrocytes engineered to overexpress Bcl2L12. The Bcl2L12 transcriptome revealed a striking induction of the small heat shock protein α-basic-crystallin (αB-crystallin/HspB5), a link reinforced by robust αB-crystallin expression in Bcl2L12-expressing orthotopic glioma and strong coexpression of αB-crystallin and Bcl2L12 proteins in human primary GBMs. On the functional level, enforced αB-crystallin or Bcl2L12 expression enhances orthotopic tumor growth. Conversely, RNAi-mediated knockdown of αB-crystallin in Bcl2L12-expressing astrocytes and glioma cell lines with high endogenous B-crystallin showed enhanced apoptosis, yet decreased necrotic cell death with associated increased caspase-3 but not caspase-7 activation. Mirroring this specific effect on effector caspase-3 activation, αB-crystallin selectively binds procaspase-3 and its cleavage intermediates in vitro and in vivo. Thus, αB-crystallin is a Bcl2L12-induced oncoprotein that enables Bcl2L12 to block the activation of both effector caspases via distinct mechanisms, thereby contributing to GBM pathogenesis and its hallmark biological properties.
AB - Glioblastoma multiforme (GBM) is a highly aggressive brain cancer that is characterized by the paradoxical features of intense apoptosis resistance yet a marked propensity to undergo necrosis. Bcl2L12 (for Bcl2-Like12) is a nuclear and cytoplasmic oncoprotein that is universally overexpressed in primary GBM and functions to block postmitochondrial apoptosis signaling by neutralizing effector caspase-3 and caspase-7 maturation. This postmitochondrial block in apoptosis engenders the alternate cell fate of cellular necrosis, thus providing a molecular explanation for GBM's classical features. Whereas Bcl2L12-mediated neutralization of caspase-7 maturation involves physical interaction, the mechanism governing Bcl2L12-mediated inhibition of caspase-3 activity is not known. The nuclear localization of Bcl2L12 prompted expression profile studies of primary astrocytes engineered to overexpress Bcl2L12. The Bcl2L12 transcriptome revealed a striking induction of the small heat shock protein α-basic-crystallin (αB-crystallin/HspB5), a link reinforced by robust αB-crystallin expression in Bcl2L12-expressing orthotopic glioma and strong coexpression of αB-crystallin and Bcl2L12 proteins in human primary GBMs. On the functional level, enforced αB-crystallin or Bcl2L12 expression enhances orthotopic tumor growth. Conversely, RNAi-mediated knockdown of αB-crystallin in Bcl2L12-expressing astrocytes and glioma cell lines with high endogenous B-crystallin showed enhanced apoptosis, yet decreased necrotic cell death with associated increased caspase-3 but not caspase-7 activation. Mirroring this specific effect on effector caspase-3 activation, αB-crystallin selectively binds procaspase-3 and its cleavage intermediates in vitro and in vivo. Thus, αB-crystallin is a Bcl2L12-induced oncoprotein that enables Bcl2L12 to block the activation of both effector caspases via distinct mechanisms, thereby contributing to GBM pathogenesis and its hallmark biological properties.
KW - Apoptosis/necrosis balance
KW - Glial cells
KW - Heat shock protein
UR - http://www.scopus.com/inward/record.url?scp=49449083377&partnerID=8YFLogxK
U2 - 10.1073/pnas.0712034105
DO - 10.1073/pnas.0712034105
M3 - Article
C2 - 18669646
AN - SCOPUS:49449083377
SN - 0027-8424
VL - 105
SP - 10703
EP - 10708
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 31
ER -