Beyond effector caspase inhibition: Bcl2L12 neutralizes p53 signaling in glioblastoma

Alexander H Stegh, Ronald A. DePinho

Research output: Contribution to journalReview article

55 Citations (Scopus)

Abstract

Malignant gliomas are the most common and lethal primary central nervous system cancer. Glioblastoma mutliforme (GBM), the most aggressive of these neoplasms, are generally lethal within two years of diagnosis due in part to the intense apoptosis resistance of its cancer cells, hence poor therapeutic response to conventional and targeted therapies. Twenty years of research has uncovered key genetic events involved in disease initiation and progression, foremost the Tp53 tumor suppressor that is mutated or deleted in 35% of GBM. The prime importance of p53 signaling for gliomapathogenesis is further evidenced by epistatic genetic events targeting additional pathway components including deletion of p14Arf (CDKN2A) and amplification of the p53-degrading ubiquitin ligases MDM2 and MDM4. Recent studies have identified and validated Bcl2-Like 12 (Bcl2L12) as a potent glioma oncoprotein with multiple strategic points in apoptosis regulatory networks, i.e. effector caspases and the p53 tumor suppressor. Bcl2L12 resides in both the cytoplasm and nucleus. In the cytoplasm, Bcl2L12 functions to inhibit caspases 3 and 7, in the nucleus, Bcl2L12 forms a complex with p53, modestly reduces p53 protein stability and prevents its binding to selected target gene promoters (e.g. p21, DR5, Noxa and PUMA), thereby inhibiting p53-directed transcriptomic changes upon DNA damage. Proteomic and multidimensional oncogenomic analyses confirmed a Bcl2L12-p53 signaling axis in GBM, as Bcl2L12 exhibited predominant genomic amplification, elevated mRNA and protein levels in GBM tumors with uncompromised p53 function. On the cell biological level, Bcl2L12 exerts robust inhibition of p53-dependent senescence and apoptosis processes in glioma cells. These multi-leveled studies establish Bcl2L12 as an important oncoprotein acting at the intersection of nuclear p53 and cytoplasmic caspase signaling and point to pharmacological disruption of the Bcl2L12:p53 complex as a promising novel therapeutic strategy for the enhanced treatment of GBM.

Original languageEnglish (US)
Pages (from-to)33-38
Number of pages6
JournalCell Cycle
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2011

Fingerprint

Effector Caspases
Glioblastoma
Glioma
Neoplasms
Oncogene Proteins
Apoptosis
Cytoplasm
Tumor Suppressor Protein p14ARF
Noxae
Caspase 7
Protein Stability
Ligases
Caspases
Ubiquitin
Caspase 3
Proteomics
DNA Damage
Disease Progression
Therapeutics
Central Nervous System

Keywords

  • Bcl2L12
  • Glioblastoma multiforme (GBM)
  • The Cancer Genome Atlas (TCGA) project
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

@article{a9db0b8301f74c018cd88297d29e2e1c,
title = "Beyond effector caspase inhibition: Bcl2L12 neutralizes p53 signaling in glioblastoma",
abstract = "Malignant gliomas are the most common and lethal primary central nervous system cancer. Glioblastoma mutliforme (GBM), the most aggressive of these neoplasms, are generally lethal within two years of diagnosis due in part to the intense apoptosis resistance of its cancer cells, hence poor therapeutic response to conventional and targeted therapies. Twenty years of research has uncovered key genetic events involved in disease initiation and progression, foremost the Tp53 tumor suppressor that is mutated or deleted in 35{\%} of GBM. The prime importance of p53 signaling for gliomapathogenesis is further evidenced by epistatic genetic events targeting additional pathway components including deletion of p14Arf (CDKN2A) and amplification of the p53-degrading ubiquitin ligases MDM2 and MDM4. Recent studies have identified and validated Bcl2-Like 12 (Bcl2L12) as a potent glioma oncoprotein with multiple strategic points in apoptosis regulatory networks, i.e. effector caspases and the p53 tumor suppressor. Bcl2L12 resides in both the cytoplasm and nucleus. In the cytoplasm, Bcl2L12 functions to inhibit caspases 3 and 7, in the nucleus, Bcl2L12 forms a complex with p53, modestly reduces p53 protein stability and prevents its binding to selected target gene promoters (e.g. p21, DR5, Noxa and PUMA), thereby inhibiting p53-directed transcriptomic changes upon DNA damage. Proteomic and multidimensional oncogenomic analyses confirmed a Bcl2L12-p53 signaling axis in GBM, as Bcl2L12 exhibited predominant genomic amplification, elevated mRNA and protein levels in GBM tumors with uncompromised p53 function. On the cell biological level, Bcl2L12 exerts robust inhibition of p53-dependent senescence and apoptosis processes in glioma cells. These multi-leveled studies establish Bcl2L12 as an important oncoprotein acting at the intersection of nuclear p53 and cytoplasmic caspase signaling and point to pharmacological disruption of the Bcl2L12:p53 complex as a promising novel therapeutic strategy for the enhanced treatment of GBM.",
keywords = "Bcl2L12, Glioblastoma multiforme (GBM), The Cancer Genome Atlas (TCGA) project, p53",
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Beyond effector caspase inhibition : Bcl2L12 neutralizes p53 signaling in glioblastoma. / Stegh, Alexander H; DePinho, Ronald A.

In: Cell Cycle, Vol. 10, No. 1, 01.01.2011, p. 33-38.

Research output: Contribution to journalReview article

TY - JOUR

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T2 - Bcl2L12 neutralizes p53 signaling in glioblastoma

AU - Stegh, Alexander H

AU - DePinho, Ronald A.

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N2 - Malignant gliomas are the most common and lethal primary central nervous system cancer. Glioblastoma mutliforme (GBM), the most aggressive of these neoplasms, are generally lethal within two years of diagnosis due in part to the intense apoptosis resistance of its cancer cells, hence poor therapeutic response to conventional and targeted therapies. Twenty years of research has uncovered key genetic events involved in disease initiation and progression, foremost the Tp53 tumor suppressor that is mutated or deleted in 35% of GBM. The prime importance of p53 signaling for gliomapathogenesis is further evidenced by epistatic genetic events targeting additional pathway components including deletion of p14Arf (CDKN2A) and amplification of the p53-degrading ubiquitin ligases MDM2 and MDM4. Recent studies have identified and validated Bcl2-Like 12 (Bcl2L12) as a potent glioma oncoprotein with multiple strategic points in apoptosis regulatory networks, i.e. effector caspases and the p53 tumor suppressor. Bcl2L12 resides in both the cytoplasm and nucleus. In the cytoplasm, Bcl2L12 functions to inhibit caspases 3 and 7, in the nucleus, Bcl2L12 forms a complex with p53, modestly reduces p53 protein stability and prevents its binding to selected target gene promoters (e.g. p21, DR5, Noxa and PUMA), thereby inhibiting p53-directed transcriptomic changes upon DNA damage. Proteomic and multidimensional oncogenomic analyses confirmed a Bcl2L12-p53 signaling axis in GBM, as Bcl2L12 exhibited predominant genomic amplification, elevated mRNA and protein levels in GBM tumors with uncompromised p53 function. On the cell biological level, Bcl2L12 exerts robust inhibition of p53-dependent senescence and apoptosis processes in glioma cells. These multi-leveled studies establish Bcl2L12 as an important oncoprotein acting at the intersection of nuclear p53 and cytoplasmic caspase signaling and point to pharmacological disruption of the Bcl2L12:p53 complex as a promising novel therapeutic strategy for the enhanced treatment of GBM.

AB - Malignant gliomas are the most common and lethal primary central nervous system cancer. Glioblastoma mutliforme (GBM), the most aggressive of these neoplasms, are generally lethal within two years of diagnosis due in part to the intense apoptosis resistance of its cancer cells, hence poor therapeutic response to conventional and targeted therapies. Twenty years of research has uncovered key genetic events involved in disease initiation and progression, foremost the Tp53 tumor suppressor that is mutated or deleted in 35% of GBM. The prime importance of p53 signaling for gliomapathogenesis is further evidenced by epistatic genetic events targeting additional pathway components including deletion of p14Arf (CDKN2A) and amplification of the p53-degrading ubiquitin ligases MDM2 and MDM4. Recent studies have identified and validated Bcl2-Like 12 (Bcl2L12) as a potent glioma oncoprotein with multiple strategic points in apoptosis regulatory networks, i.e. effector caspases and the p53 tumor suppressor. Bcl2L12 resides in both the cytoplasm and nucleus. In the cytoplasm, Bcl2L12 functions to inhibit caspases 3 and 7, in the nucleus, Bcl2L12 forms a complex with p53, modestly reduces p53 protein stability and prevents its binding to selected target gene promoters (e.g. p21, DR5, Noxa and PUMA), thereby inhibiting p53-directed transcriptomic changes upon DNA damage. Proteomic and multidimensional oncogenomic analyses confirmed a Bcl2L12-p53 signaling axis in GBM, as Bcl2L12 exhibited predominant genomic amplification, elevated mRNA and protein levels in GBM tumors with uncompromised p53 function. On the cell biological level, Bcl2L12 exerts robust inhibition of p53-dependent senescence and apoptosis processes in glioma cells. These multi-leveled studies establish Bcl2L12 as an important oncoprotein acting at the intersection of nuclear p53 and cytoplasmic caspase signaling and point to pharmacological disruption of the Bcl2L12:p53 complex as a promising novel therapeutic strategy for the enhanced treatment of GBM.

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KW - The Cancer Genome Atlas (TCGA) project

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