Glioma oncoprotein Bcl2L12 inhibits the p53 tumor suppressor.
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.
Stegh
Alexander H
AH
Belfer Institute for Applied Cancer Science, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. a-stegh@northwestern.edu
Brennan
Cameron
C
Mahoney
John A
JA
Forloney
Kristin L
KL
Jenq
Harry T
HT
Luciano
Janina P
JP
Protopopov
Alexei
A
Chin
Lynda
L
Depinho
Ronald A
RA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D004249:DNA Damage; D005786:Gene Expression Regulation; D005910:Glioma / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D055550:Protein Stability; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C543826:Bcl2l12 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53