Impaired TNFalpha-induced A20 expression in E1A/Ras-transformed cells.

Br J Cancer

The Campbell Family Institute of Breast Cancer Research, Ontario Cancer Institute, University Health Network and Department of Medical Biophysics, University of Toronto, 620 University Avenue, Toronto, Ontario, Canada.

Published: November 2009

Background: Tumour necrosis factor (TNF) is capable of activating the cell death pathway, and has been implicated in killing transformed cells. However, TNF also activates survival signals, including NF-kappaB activation and the subsequent expression of anti-apoptotic genes, leading to protection against TNF toxicity.

Methods: In this study, we show that, although untransformed mouse embryonic fibroblasts (MEFs) were resistant to TNF killing, E1A/Ras-transformed MEFs were susceptible to extensive apoptosis induced by TNF. The key factors for determining TNF sensitivity were explored by comparing wild-type and E1A/Ras-transformed MEFs.

Results: TNF signalling to NF-kappaB and to its target genes such as IkappaBalpha seemed to be mostly intact in E1A/Ras-transformed cells. Instead, the induction of A20 was completely abolished in E1A/Ras-transformed MEFs, although A20 is known to be NF-kappaB dependent. Reintroduction of A20 into E1A/Ras-transformed MEFs rescued these cells from TNF-induced death and reduced the formation of the FADD/caspase-8 complex. This impaired A20 induction in E1A/Ras MEFs was not because of the stabilisation of p53 or a defective TNF-induced p38 and Jun N-terminal kinase (JNK) signalling. Consistently, we found a reduced A20 promoter activity but normal NF-kappaB activity in TNF-treated E1A/Ras MEFs. However, Bcl-3 seemed to have a role in the transactivation of the A20 promoter in E1A/Ras cells.

Conclusions: Our results suggest that specific inhibition of certain survival factors, such as A20, may determine the sensitivity to TNF-induced apoptosis in transformed cells such as E1A/Ras MEFs.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778522PMC
http://dx.doi.org/10.1038/sj.bjc.6605352DOI Listing

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Impaired TNFalpha-induced A20 expression in E1A/Ras-transformed cells.

Br J Cancer

November 2009

The Campbell Family Institute of Breast Cancer Research, Ontario Cancer Institute, University Health Network and Department of Medical Biophysics, University of Toronto, 620 University Avenue, Toronto, Ontario, Canada.

Background: Tumour necrosis factor (TNF) is capable of activating the cell death pathway, and has been implicated in killing transformed cells. However, TNF also activates survival signals, including NF-kappaB activation and the subsequent expression of anti-apoptotic genes, leading to protection against TNF toxicity.

Methods: In this study, we show that, although untransformed mouse embryonic fibroblasts (MEFs) were resistant to TNF killing, E1A/Ras-transformed MEFs were susceptible to extensive apoptosis induced by TNF.

View Article and Find Full Text PDF

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