Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma

Alexander H. Stegh, Santosh Kesari, John E. Mahoney, Harry T. Jenq, Kristin L. Forloney, Alexei Protopopov, David N. Louis, Lynda Chin, Ronald A. DePinho

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)10703-10708
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number31
DOIs
StatePublished - Aug 5 2008

Fingerprint

Effector Caspases
Caspase 7
Crystallins
Glioblastoma
Caspase 3
Apoptosis
Oncogene Proteins
Glioma
Astrocytes
Necrosis
Small Heat-Shock Proteins
RNA Interference
Transcriptome
Brain Neoplasms
Cell Death

Keywords

  • Apoptosis/necrosis balance
  • Glial cells
  • Heat shock protein

ASJC Scopus subject areas

  • General

Cite this

Stegh, Alexander H. ; Kesari, Santosh ; Mahoney, John E. ; Jenq, Harry T. ; Forloney, Kristin L. ; Protopopov, Alexei ; Louis, David N. ; Chin, Lynda ; DePinho, Ronald A. / Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 31. pp. 10703-10708.
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Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma. / Stegh, Alexander H.; Kesari, Santosh; Mahoney, John E.; Jenq, Harry T.; Forloney, Kristin L.; Protopopov, Alexei; Louis, David N.; Chin, Lynda; DePinho, Ronald A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 31, 05.08.2008, p. 10703-10708.

Research output: Contribution to journalArticle

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

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