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

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

doi:10.1073/pnas.0712034105

Cited by 133 publications

(132 citation statements)

References 30 publications

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“…1, left), while other heat shock proteins, caspases, and their (post-mitochondrial) inhibitors, such as members of the IAP family, are not differentially expressed. 6,17 In addition, primary human GBM tumor specimens revealed striking co-expression of Bcl2L12 and αB-crystallin, and Bcl2L12-driven (U87MG) xenografts showed significant upregulation of αB-crystallin, confirming a Bcl2L12-aB-crystallin signaling axis axis not only in glial cells in vitro, but also in GBM tumors in vivo. 17 The induction of αB-crystallin expression by Bcl2L12 appears to be highly relevant.…”

Section: αB-crystallin Is a Novel Gliomagenic Oncoproteinmentioning

confidence: 79%

“…6,17 In addition, primary human GBM tumor specimens revealed striking co-expression of Bcl2L12 and αB-crystallin, and Bcl2L12-driven (U87MG) xenografts showed significant upregulation of αB-crystallin, confirming a Bcl2L12-aB-crystallin signaling axis axis not only in glial cells in vitro, but also in GBM tumors in vivo. 17 The induction of αB-crystallin expression by Bcl2L12 appears to be highly relevant. αB-crystallin is a molecular chaperon with a plethora of highly diverse activities, ranging from cyto-protective effects against misfolded/denatured proteins or oxidative-inflammatory conditions to tumorigenic functions.…”

Section: αB-crystallin Is a Novel Gliomagenic Oncoproteinmentioning

confidence: 79%

“…Alternatively, the modulation of upstream signaling components that impact the activity of αB-crystallin, most importantly through phosphorylation, might represent another approach for its pharmacologic inactivation. Along these lines, we could demonstrate that a phospho-mimetic phosphorylation triple point mutant of αB-crystallin (Ser19, 45, 59→Glu19, 45, 59; termed "3XSE") showed loss of tumorigenicity upon expression in human glioma cell lines followed by orthotopic intracerebral implantation, 17 whereas a phosphorylation-deficient protein (3XSA) exhibited enhanced tumorigenic potential (ID50 values [days]: pBabe: n.d.; αB-crystallin WT: 167; αB-crystallin 3XSA: 118; αB-crystallin 3XSE: n.d.; Bcl2L12: 157; EGFRvIII: 46). 17 In Bcl2L12-expressing astrocytes, αB-crystallin is weakly phosphorylated on Ser59 (Stegh AH and DePinho RA, unpublished observation), a known target residue of p38α/β-activated MAPKAP kinase-2 (MK2).…”

Section: αB-crystallin Is a Novel Gliomagenic Oncoproteinmentioning

confidence: 99%

“…Along these lines, we could demonstrate that a phospho-mimetic phosphorylation triple point mutant of αB-crystallin (Ser19, 45, 59→Glu19, 45, 59; termed "3XSE") showed loss of tumorigenicity upon expression in human glioma cell lines followed by orthotopic intracerebral implantation, 17 whereas a phosphorylation-deficient protein (3XSA) exhibited enhanced tumorigenic potential (ID50 values [days]: pBabe: n.d.; αB-crystallin WT: 167; αB-crystallin 3XSA: 118; αB-crystallin 3XSE: n.d.; Bcl2L12: 157; EGFRvIII: 46). 17 In Bcl2L12-expressing astrocytes, αB-crystallin is weakly phosphorylated on Ser59 (Stegh AH and DePinho RA, unpublished observation), a known target residue of p38α/β-activated MAPKAP kinase-2 (MK2). 42 Consequently, the enhancement of its phosphorylation status in glial cells through (re-) activation of the p38 pathway and/or modulation of additional kinase or phosphatase activities might represent another avenue for therapeutic intervention.…”

Section: αB-crystallin Is a Novel Gliomagenic Oncoproteinmentioning

confidence: 99%

“…17 RNAi-mediated knockdown of αB-crystallin in Bcl2L12-expressing Ink4a/Arf-deficient cortical astrocytes and human glioma cell lines provoked robust sensitization towards drug-induced apoptosis through enhancement of effector caspase-3, but not caspase-7. 17 Mirroring this selective effect on caspase-3 activation, GST binding assays and co-association studies in astrocytes revealed highly specific binding of αB-crystallin to caspase-3 and its cleavage intermediates, but not to caspase-7 in vitro and on endogenous protein levels in vivo. Three mechanisms of caspase-3 inhibition by αB-crystallin are conceivable: (1) αB-crystallin occupies the active site of caspase-3 resulting in a blockage of substrate entry comparable to inhibition of active effector caspase-3/7 by XIAP or covalent peptide inhibitors.…”

Section: αB-crystallin Is a Novel Gliomagenic Oncoproteinmentioning

confidence: 99%

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What drives intense apoptosis resistance and propensity for necrosis in glioblastoma? A role for Bcl2L12 as a multifunctional cell death regulator

Stegh¹,

Chin²,

Louis³

et al. 2008

Cell Cycle

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Glioblastoma (GBM) is the most common type of primary brain cancer and carries a dismal prognosis primarily due to the emergence of resistance towards extant radiation, conventional and targeted chemotherapies. Although GBM resists therapy-induced apoptosis, tumors show a seemingly paradoxical propensity for florid intratumoral necrogenesis. This necrosis manifests pathologically as microscopic foci or confluent expanses of necrotic tumor. While it is now well recognized that necrosis is an active cell death process and that apoptosis and necrosis death modalities are intertwined on multiple levels, the precise molecular mechanisms and genetic elements underlying these forms of cell death in GBM remain areas of active investigation. In recent oncogenomic studies, we identified a novel GBM oncoprotein, Bcl2-Like 12 (Bcl2L12), which is significantly expressed in the majority of primary GBM tumor specimens and distantly related to canonical Bcl-2 proteins. Due to its distinctive impact on cell death signaling, Bcl2L12 phenocopies pro-necrotic and anti-apoptotic propensities of highgrade glioma: Mechanistically, we determined that unlike prototypic Bcl-2 family members, Bcl2L12 does not safeguard mitochondrial membrane integrity, but instead potently inhibits apoptosis at the level of post-mitochondrial effector caspase-3/7 activation. A combination of enforced expression, RNAi-mediated extinction, co-localization and protein interaction studies revealed that Bcl2L12 inhibits caspases 3 and 7 via distinct mechanisms. Direct physical interaction underlies Bcl2L12's inhibition of caspase-7 processing, whereas Bcl2L12-induced transcriptional upregulation of the small heat shock protein αB-crystallin is instrumental to neutralization of caspase-3 activation. Mirroring the cellular phenotype elicited by energy depletion, genetic or pharmacologic inhibition of post-mitochondrial apoptosis signaling molecules, Bcl2L12 promotes necrogenesis in glial cells in the context of a proapoptotic stimulus establishing that it represents a novel regulator of the balance between apoptosis and necrosis in GBM.

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Section: αB-crystallin Is a Novel Gliomagenic Oncoproteinmentioning

confidence: 79%

Section: αB-crystallin Is a Novel Gliomagenic Oncoproteinmentioning

confidence: 79%

Section: αB-crystallin Is a Novel Gliomagenic Oncoproteinmentioning

confidence: 99%

Section: αB-crystallin Is a Novel Gliomagenic Oncoproteinmentioning

confidence: 99%

Section: αB-crystallin Is a Novel Gliomagenic Oncoproteinmentioning

confidence: 99%

See 3 more Smart Citations

What drives intense apoptosis resistance and propensity for necrosis in glioblastoma? A role for Bcl2L12 as a multifunctional cell death regulator

Stegh¹,

Chin²,

Louis³

et al. 2008

Cell Cycle

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Multi‐omics‐based analysis of high grade serous ovarian cancer subtypes reveals distinct molecular processes linked to patient prognosis

et al. 2023

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Despite advancements in treatment, high‐grade serous ovarian cancer (HGSOC) is still characterized by poor patient outcomes. To understand the molecular heterogeneity of this disease, which underlies the challenge in selecting optimal treatments for HGSOC patients, we have integrated genomic, transcriptomic, and epigenetic information to identify seven new HGSOC subtypes using a multiscale clustering method. These subtypes not only have significantly distinct overall survival, but also exhibit unique patterns of gene expression, microRNA expression, DNA methylation, and copy number alterations. As determined by our analysis, patients with similar clinical outcomes have distinct profiles of activated or repressed cellular processes, including cell cycle, epithelial‐to‐mesenchymal transition, immune activation, interferon response, and cilium organization. Furthermore, we performed a multiscale gene co‐expression network analysis to identify subtype‐specific key regulators and predicted optimal targeted therapies based on subtype‐specific gene expression. In summary, this study provides new insights into the cellular heterogeneity of the HGSOC genomic, epigenetic, and transcriptomic landscapes and provides a basis for future studies into precision medicine for HGSOC patients.

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Targeting CXCR4 to suppress glioma‐initiating cells and chemoresistance in glioma

Tang

Yin

et al. 2022

Cell Biology International

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Glioma initiating cells (GICs), also known as glioma stem cells, display the capacity to recapitulate the functional diversity within the tumor. Despite the great progress achieved over the last decades, defining the key molecular regulators of GICs has represented a major obstacle in this field. In our study, data from The Cancer Genome Atlas database illustrated a relationship between C‐X‐C motif chemokine receptor 4 (CXCR4) expression and the survival of glioma patients. Mechanistically, we further indicated that CXCR4 mediated the upregulation of Kruppel like factor 5 (KLF5), a zinc‐finger‐containing transcription factor, to facilitate the proliferation of GICs. What's more, CXCR4 also enhanced the chemoresistance through KLF5/Bcl2‐like 12 (BCl2L12) in glioma. The elevated expression of KLF5 and BCL2L12 induced by CXCR4 was dependent on phosphoinositide 3‐kinases (PI3K)/serine/threonine kinase (AKT) signaling. Importantly, combined application of temozolomide and a CXCR4 inhibitor efficiently reversed CXCR4 mediated drugs resistance and improved anticancer effects in vivo. Collectively, our findings confirmed that CXCR4 promoted GICs proliferation via the KLF5/BCL2L12 dependent pathway, which may enrich the understanding of GICs and help drive the design of efficacious therapeutic strategies.

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

Cited by 133 publications

References 30 publications

What drives intense apoptosis resistance and propensity for necrosis in glioblastoma? A role for Bcl2L12 as a multifunctional cell death regulator

What drives intense apoptosis resistance and propensity for necrosis in glioblastoma? A role for Bcl2L12 as a multifunctional cell death regulator

Multi‐omics‐based analysis of high grade serous ovarian cancer subtypes reveals distinct molecular processes linked to patient prognosis

Targeting CXCR4 to suppress glioma‐initiating cells and chemoresistance in glioma

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