Glioma oncoprotein Bcl2L12 inhibits the p53 tumor suppressor
Alexander H Stegh1, Cameron Brennan, John A Mahoney
1Belfer Institute for Applied Cancer Science, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. a-stegh@northwestern.edu
Abstract:
Glioblastoma multiforme (GBM) is a lethal brain tumor characterized by intense apoptosis resistance and extensive necrosis. Bcl2L12 (for Bcl2-like 12) is a cytoplasmic and nuclear protein that is overexpressed in primary GBM and functions to inhibit post-mitochondrial apoptosis signaling. Here, we show that nuclear Bcl2L12 physically and functionally interacts with the p53 tumor suppressor, as evidenced by the capacity of Bcl2L12 to (1) enable bypass of replicative senescence without concomitant loss of p53 or p19 (Arf), (2) inhibit p53-dependent DNA damage-induced apoptosis, (3) impede the capacity of p53 to bind some of its target gene promoters, and (4) attenuate endogenous p53-directed transcriptomic changes following genotoxic stress. Correspondingly, The Cancer Genome Atlas profile and tissue protein analyses of human GBM specimens show significantly lower Bcl2L12 expression in the setting of genetic p53 pathway inactivation. Thus, Bcl2L12 is a multifunctional protein that contributes to intense therapeutic resistance of GBM through its ability to operate on two key nodes of cytoplasmic and nuclear signaling cascades.
Insights
Bcl2L12 protein overexpression in glioblastoma (GBM) inhibits apoptosis by interacting with the p53 tumor suppressor. This interaction contributes to therapeutic resistance in GBM by disrupting p53
Area of Science:
- Oncology
- Molecular Biology
- Cellular Biology
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with high resistance to apoptosis and significant necrosis.
- Bcl2L12 (Bcl2-like 12) is a protein overexpressed in GBM, inhibiting apoptosis signaling pathways.
Purpose of the Study:
- To investigate the interaction between nuclear Bcl2L12 and the p53 tumor suppressor in GBM.
- To elucidate the functional consequences of this interaction on apoptosis and cellular signaling.
Main Methods:
- Physical and functional interaction assays between nuclear Bcl2L12 and p53.
- Analysis of p53-dependent apoptosis, senescence bypass, and gene promoter binding.
- Assessment of transcriptomic changes following genotoxic stress.
- Analysis of The Cancer Genome Atlas (TCGA) data and GBM tissue protein expression.
Main Results:
- Nuclear Bcl2L12 physically and functionally interacts with the p53 tumor suppressor.
- Bcl2L12 enables bypass of replicative senescence and inhibits p53-dependent apoptosis.
- Bcl2L12 impedes p53 binding to target gene promoters and attenuates p53-directed transcriptomic changes.
- GBM specimens with inactivated p53 pathways show significantly lower Bcl2L12 expression.
Conclusions:
- Bcl2L12 is a multifunctional protein contributing to GBM therapeutic resistance.
- Bcl2L12 impacts both cytoplasmic and nuclear signaling cascades involving p53.
- Targeting the Bcl2L12-p53 interaction may offer novel therapeutic strategies for GBM.
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