Glioma oncoprotein Bc12L12 inhibits the p53 tumor suppressor

Alexander H Stegh, Cameron Brennan, John A. Mahoney, Kristin L. Forloney, Harry T. Jenq, Janina P. Luciano, Alexei Protopopov, Lynda Chin, Ronald A. DePinho

Research output: Contribution to journalArticle

62 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2194-2204
Number of pages11
JournalGenes and Development
Volume24
Issue number19
DOIs
StatePublished - Oct 1 2010

Fingerprint

Oncogene Proteins
Glioblastoma
Glioma
Apoptosis
DNA Damage
Neoplasms
Atlases
Cell Aging
Nuclear Proteins
Brain Neoplasms
Proteins
Necrosis
Genome
Genes
Therapeutics

Keywords

  • Bc12L12
  • Glioblastoma multiforme
  • p53

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Stegh, A. H., Brennan, C., Mahoney, J. A., Forloney, K. L., Jenq, H. T., Luciano, J. P., ... DePinho, R. A. (2010). Glioma oncoprotein Bc12L12 inhibits the p53 tumor suppressor. Genes and Development, 24(19), 2194-2204. https://doi.org/10.1101/gad.1924710
Stegh, Alexander H ; Brennan, Cameron ; Mahoney, John A. ; Forloney, Kristin L. ; Jenq, Harry T. ; Luciano, Janina P. ; Protopopov, Alexei ; Chin, Lynda ; DePinho, Ronald A. / Glioma oncoprotein Bc12L12 inhibits the p53 tumor suppressor. In: Genes and Development. 2010 ; Vol. 24, No. 19. pp. 2194-2204.
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Stegh, AH, Brennan, C, Mahoney, JA, Forloney, KL, Jenq, HT, Luciano, JP, Protopopov, A, Chin, L & DePinho, RA 2010, 'Glioma oncoprotein Bc12L12 inhibits the p53 tumor suppressor', Genes and Development, vol. 24, no. 19, pp. 2194-2204. https://doi.org/10.1101/gad.1924710

Glioma oncoprotein Bc12L12 inhibits the p53 tumor suppressor. / Stegh, Alexander H; Brennan, Cameron; Mahoney, John A.; Forloney, Kristin L.; Jenq, Harry T.; Luciano, Janina P.; Protopopov, Alexei; Chin, Lynda; DePinho, Ronald A.

In: Genes and Development, Vol. 24, No. 19, 01.10.2010, p. 2194-2204.

Research output: Contribution to journalArticle

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Stegh AH, Brennan C, Mahoney JA, Forloney KL, Jenq HT, Luciano JP et al. Glioma oncoprotein Bc12L12 inhibits the p53 tumor suppressor. Genes and Development. 2010 Oct 1;24(19):2194-2204. https://doi.org/10.1101/gad.1924710