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Sunderland Repository records the research produced by the University of Sunderland including practice-based research and theses.

Basal cancer cell survival involves JNK2 suppression of a novel JNK1/c-Jun/Bcl-3 apoptotic network

Ahmed, Shafiq and Milner, J (2009) Basal cancer cell survival involves JNK2 suppression of a novel JNK1/c-Jun/Bcl-3 apoptotic network. PLoS ONE, 4 (10).

Item Type: Article



The regulation of apoptosis under basal (non-stress) conditions is crucial for normal mammalian development and also for normal cellular turnover in different tissues throughout life. Deficient regulation of basal apoptosis, or its perturbation, can result in impaired development and/or disease states including cancer. In contrast to stress-induced apoptosis the regulation of apoptosis under basal conditions is poorly understood. To address this issue we have compared basal- and stress-induced apoptosis in human epithelial cells of normal and cancerous origins. For this purpose we focussed our study on the opposing pro-apoptotic JNK/anti-apoptotic NFkappaB pathways.

Combinatorial RNAi plus gene knockout were employed to access and map basal regulatory pathways of apoptosis. Follow-on, in-depth analyses included exogenous expression of phosphorylation mutants and chromatin immunoprecipitation. We demonstrate that basal apoptosis is constitutively suppressed by JNK2 in a range of human cancer cell lines. This effect was not observed in non-cancer cells. Silencing JNK2 by RNAi resulted in JNK1-dependent apoptosis of cancer cells via up-regulation of the AP-1 factor c-Jun. Unexpectedly we discovered that JNK1 and c-Jun promote basal apoptosis in the absence of "activating phosphorylations" typically induced by stress. Hypo-phosphorylated c-Jun accumulated to high levels following JNK2 silencing, auto-regulated its own expression and suppressed expression of Bcl-3, an unusual IkappaB protein and regulator of NFkappaB. Basal apoptosis was mediated by components of the TNFalpha response pathway but was mechanistically distinct from TNFalpha-induced apoptosis.

Our results demonstrate that mechanistically distinct pathways operate to regulate apoptosis in mammalian cells under basal (physiological) versus stress-induced conditions. We also describe a novel apoptotic network which governs the basal survival of cancer cells. Such information is crucial for understanding normal cellular turnover during mammalian development and subsequently throughout life. This information also opens new avenues for therapeutic intervention in human proliferative disease states including cancer.

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Depositing User: Paula Normington


Item ID: 6012
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Users with ORCIDS

ORCID for Shafiq Ahmed: ORCID iD

Catalogue record

Date Deposited: 17 Feb 2016 12:33
Last Modified: 18 Dec 2019 15:38


Author: Shafiq Ahmed ORCID iD
Author: J Milner

University Divisions

Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences



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