Glioma oncoprotein Bcl2L12 inhibits the p53 tumor suppressor

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 p19Arf, (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.

Bcl2L12 with a BH3-like domain in regulating apoptosis and TMZ-induced autophagy: A prospective combination of ABT-737 and TMZ for treating glioma

“…This finding is independent of the previously reported mechanisms of p53-dependent or caspase-3/7 inactivation (24,(38)(39)(40). Mutagenesis on either h1 or h2 residue of BH3-like domain within the hydrophobic groove of Bcl2L12 caused re-activation of apoptotic markers in U87MG cell line with or without treatment with STS or TMZ.…”

“…Expression of the full-length mRNA transcript has been observed in many tissues, including breast, thymus, prostate, fetal liver, colon, placenta, pancreas, small intestine, spinal cord, kidney and bone marrow, whereas the Bcl2L12A is mainly expressed in fetal liver, spinal cord and skeletal muscle (22). Previous studies showed that Bcl2L12 localized in both nucleus and the cytosol (23,24). The biological role of Bcl2L12 is yet completely understood.…”

“…Moreover, Bcl2L12 expression is an unfavorable and independent prognostic indicator of short-term relapse in nasopharyngeal carcinoma, indicating that Bcl2L12 mRNA expression may constitute a novel biomarker for the prediction of short-term relapse in nasopharyngeal carcinoma (?). In contrast, both two Bcl2L12 are ubiquitously overexpressed in primary human GBMs and may be associated with the resistance to chemotherapeutic agent-induced apoptosis that is an important hallmark of this disease (24). Furthermore, it has been reported that Bcl2L12 is an inhibitor of post-mitochondrial effector caspase activation, as it binds to and inhibits caspase-7 and upregulates the caspase-3-specific inhibitor αB-crystallin (CRYAB).…”

“…Furthermore, it has been reported that Bcl2L12 is an inhibitor of post-mitochondrial effector caspase activation, as it binds to and inhibits caspase-7 and upregulates the caspase-3-specific inhibitor αB-crystallin (CRYAB). Bcl2L12 attenuates endogenous p53-directed transcriptomic changes after genotoxic stress and inhibits p53-dependent DNA damage-induced apoptosis (24).…”

GSK3β regulates Bcl2L12 and Bcl2L12A anti-apoptosis signaling in glioblastoma and is inhibited by LiCl

“…[18][19][20] Besides that, BCL2L12 attenuates endogenous p53-directed transcriptomic changes after genotoxic stress and inhibits p53-dependent DNA damage-induced apoptosis. 21,22 The exact molecular mechanism by which GSK3b signaling supports the anti-apoptotic properties of GBM remains uncertain. Our lab is searching for possible GSK3b-interacting proteins.…”