p38 MAPK-Mediated Bmi-1 Down-Regulation and Defective Proliferation in ATM-Deficient Neural Stem Cells Can Be Restored by Akt Activation

Abstract

A-T (ataxia telangiectasia) is a genetic disease caused by a mutation in the Atm (A-T mutated) gene that leads to neurodegeneration. Despite an increase in the numbers of studies in this area in recent years, the mechanisms underlying neurodegeneration in human A-T are still poorly understood. Previous studies demonstrated that neural stem cells (NSCs) isolated from the subventricular zone (SVZ) of Atm -/- mouse brains show defective self-renewal and proliferation, which is accompanied by activation of chronic p38 mitogen-activated protein kinase (MAPK) and a lower level of the polycomb protein Bmi-1. However, the mechanism underlying Bmi-1 down-regulation and its relevance to defective proliferation in Atm-/- NSCs remained unclear. Here, we show that over-expression of Bmi-1 increases self-renewal and proliferation of Atm-/- NSCs to normal, indicating that defective proliferation in Atm-/- NSCs is a consequence of down-regulation of Bmi-1. We also demonstrate that epidermal growth factor (EGF)-induced Akt phosphorylation renders Bmi-1 resistant to the proteasomal degradation, leading to its stabilization and accumulation in the nucleus. However, inhibition of the Akt-dependent Bmi-1 stabilizing process by p38 MAPK signaling reduces the levels of Bmi-1. Treatment of the Atm-/- NSCs with a specific p38 MAPK inhibitor SB203580 extended Bmi-1 posttranscriptional turnover and H2A ubiquitination in Atm-/- NSCs. Our observations demonstrate the molecular basis underlying the impairment of self-renewal and proliferation in Atm-/- NSCs through the p38 MAPK-Akt-Bmi-1-p21 signaling pathway.

BMI1 as a novel target for drug discovery in cancer

“…3pk is not the only kinase reported to phosphorylate BMI1. Kim et al [2011] recently demonstrated that epidermal growth factor (EGF)-induced Akt activation phosphorylated BMI1 and that this modification renders BMI1 resistant to proteasomal degradation, leading to its stabilization and accumulation in the nucleus. Quantitative analysis of the human spindle phosphoproteome revealed that three serine residues (S251, S253, and S255) at the C-terminal of the BMI1 protein were phosphorylated in extracts from HeLa cells [Malik et al, 2009].…”

Beyond transcription factors: how oncogenic signalling reshapes the epigenetic landscape

“…We and two other groups 6,65,66 have reported that BMI1 is phosphorylated by PI3K-AKT signaling, although the consequences of phosphorylation on BMI1 function varied between these reports. Kim et al .…”

Bmi1 inhibition enhances the sensitivity of pancreatic cancer cells to gemcitabine

“…50μM) of gemcitabine could inhibit Bmi1 expression (data not shown), which might account for the reduced Bmi1 staining of tumor tissues in nude mice received high gemcitabine chemotherapy. Gemcitabine has been proved to exert different effects on pancreatic cancer cells in a dose and time dependent manner by inducing different signaling pathways [21, 27], whereas Bmi1 expression can also be affected by such specific signaling molecules [28]. Thus, it is tempting to speculate that different signaling pathways induced by low or high concentrations of gemcitabine treatment may exert promoting or inhibiting role on Bmi1 expression in pancreatic cancer cells.…”