Lack of activation induced cell death in human T blasts despite CD95L up‐regulation: protection from apoptosis by MEK signalling

Walker, Lucy; McLeod, Julie; Boulougouris, George; Patel, Yusuf; Ellwood, Claire N.; Hall, N. D.; Sansom, David M.

doi:10.1046/j.1365-2567.1999.00925.x

Cited by 11 publications

(5 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most of these early studies, however, were done in T cell lines or T cell clones and not in human primary T cells (32-35). Interestingly, T cells have been shown to also die in a DR-independent and caspase independent manner (36-38). Towards understanding the mechanism of epitope specific AICD in CD8+ human primary CTL, we have also recently shown that the AICD in human melanoma associated antigen specific CD8+ primary CTL is a JNK activation driven, DR-independent, caspase-independent, mitochondria-centric process (10, 13, 14).…”

Section: Discussionmentioning

confidence: 99%

Death Receptor–Independent Activation-Induced Cell Death in Human Melanoma Antigen–Specific MHC Class I–Restricted TCR-Engineered CD4 T Cells

Chhabra

Mukherji

2013

The Journal of Immunology

View full text Add to dashboard Cite

Engaging CD4 T cells in anti-tumor immunity has been quite challenging, especially in an antigen specific manner, since most human solid tumors usually do not express MHC class II molecules. We have recently shown that human CD4 T cells engineered to express a human melanoma associated antigenic epitope, MART-127-35, specific MHC class I restricted transgenic T cell receptor (TCR) function as polyfunctional effectors that can exhibit a helper as well as cytolytic effector function, in an epitope specific and MHC class I restricted manner (Chhabra et al., JI, 2008, Ray et al., J. Clin. Immunol., 2010). TCR engineered (TCReng) CD4 T cells therefore have translational potential and clinical trials with MHC class I TCR engineered CD4 T cells are underway. We here show that while TCReng CD4 T cells could be useful in cancer immunotherapy, they are also susceptible to epitope specific AICD. We also show that the AICD in TCReng CD4 T cells is a death receptor (DR)-independent process, and that JNK andp53 play critical roles in this process as pharmacological inhibitors targeting JNK activation and p-53 mediated transcription-independent mitochondria-centric death cascade rescued a significant fraction of TCReng CD4 T cells from undergoing AICD without affecting their effector function. Our data offer novel insights towards AICD in TCReng CD4 T cells and identify several potential targets to interfere with this process.

show abstract

Section: Discussionmentioning

confidence: 99%

Death Receptor–Independent Activation-Induced Cell Death in Human Melanoma Antigen–Specific MHC Class I–Restricted TCR-Engineered CD4 T Cells

Chhabra

Mukherji

2013

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…It is therefore likely that ERK-dependent apoptosis in these cells does not require the mitochondrial amplification loop and thus would not be sensitive to an inhibition of the mitochondrial pathway. Nevertheless, ERK activation has been shown to prevent Fas-and TRAIL-mediated apoptosis in Jurkat T cells [48][49][50] and in 3T3 fibroblasts ectopically expressing Fas. 51 In Jurkat cells, however, ERK did not affect caspase 8 cleavage at the level of the DISC but rather prevented downstream cleavage of Bid and the onset of mitochondrial amplification by caspase 9.…”

Section: Discussionmentioning

confidence: 99%

Prolonged activation of ERK1,2 induces FADD-independent caspase 8 activation and cell death

2006

View full text Add to dashboard Cite

Prolonged ERK/MAPK activation has been implicated in neuronal cell death in vitro and in vivo. We found that HEK293 cells, recently reported to express neuronal markers, are exquisitely sensitive to long term ERK stimulation. Activation of an inducible form of Raf-1 (Raf-1:ER) in HEK293 cells induced massive apoptosis characterized by DNA degradation, loss of plasma membrane integrity and PARP cleavage. Cell death required MEK activity and protein synthesis and occurred via the death receptor pathway independently of the mitochondrial pathway. Accordingly, prolonged ERK stimulation activated caspase 8 and strongly potentiated Fas signaling. The death receptor adaptator FADD was found to be rapidly induced upon ERK activation. However using RNA interference and ectopic expression, we demonstrated that neither FADD nor Fas were necessary for caspase 8 activation and cell death. These findings reveal that prolonged ERK/MAPK stimulation results in caspase 8 activation and cell death.

show abstract

“…Finally, the cells were washed once in PBS with 1% bovine serum albumin and analyzed quantitatively for fluorescein isothiocyanate incorporation using a Becton-Dickinson FACSCalibur flow cytometer and data analyzed using CellQuest software. TUNEL-positive staining was established by setting a gate at the highest staining 5% of the population of untreated cells as previously outlined (25).…”

Section: Methodsmentioning

confidence: 99%

ATM Is Activated in Response toN-Methyl-N′-nitro- N-nitrosoguanidine-induced DNA Alkylation

Adamson¹,

Kim²,

Shangary³

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

p53 plays an important role in response to ionizing radiation by regulating cell cycle progression and triggering apoptosis. These activities are controlled, in part, by the phosphorylation of p53 by the protein kinase ATM. Recent evidence indicates that the monofunctional DNA alkylating agent N-methyl-N -nitro-Nnitrosoguanidine (MNNG) also triggers up-regulation and phosphorylation of p53; however, the mechanism(s) responsible for this are unknown. We observed that in MNNG-treated normal human fibroblasts, up-regulation and phosphorylation of p53 was sensitive to the ATM kinase inhibitor wortmannin. ATM-deficient fibroblasts exhibited a delay in p53 up-regulation indicating a role for ATM in triggering the MNNG-induced response. Likewise, a mismatch repair (MMR)-deficient colorectal tumor line failed to show rapid up-regulation of p53. However, unlike ATM-deficient cells, these MMR-deficient cells displayed rapid phosphorylation of the p53 residue serine 15 after MNNG. In vitro kinase assays indicate that ATM is rapidly activated in both normal and MMR-deficient cells in response to MNNG. Using a number of morphological and biochemical approaches, we failed to observe MNNG-induced apoptosis in normal human fibroblasts, suggesting that apoptosis-induced DNA strand breaks are not required for the activation of ATM in response to MNNG. Comet assays indicated that strand breaks accumulated, and p53 up-regulation/ phosphorylation occurred quite rapidly (within 30 min) after MNNG treatment, suggesting that DNA strand breaks that arise during the repair process activate ATM. These findings indicate that ATM activation is not limited to the ionizing radiation-induced response and potentially plays an important role in response to DNA alkylation.

show abstract

Lack of activation induced cell death in human T blasts despite CD95L up‐regulation: protection from apoptosis by MEK signalling

Cited by 11 publications

References 46 publications

Death Receptor–Independent Activation-Induced Cell Death in Human Melanoma Antigen–Specific MHC Class I–Restricted TCR-Engineered CD4 T Cells

Death Receptor–Independent Activation-Induced Cell Death in Human Melanoma Antigen–Specific MHC Class I–Restricted TCR-Engineered CD4 T Cells

Prolonged activation of ERK1,2 induces FADD-independent caspase 8 activation and cell death

ATM Is Activated in Response toN-Methyl-N′-nitro- N-nitrosoguanidine-induced DNA Alkylation

Contact Info

Product

Resources

About

Lack of activation induced cell death in human T blasts despite CD95L up‐regulation: protection from apoptosis by MEK signalling

Cited by 11 publications

References 46 publications

Death Receptor–Independent Activation-Induced Cell Death in Human Melanoma Antigen–Specific MHC Class I–Restricted TCR-Engineered CD4 T Cells

Death Receptor–Independent Activation-Induced Cell Death in Human Melanoma Antigen–Specific MHC Class I–Restricted TCR-Engineered CD4 T Cells

Prolonged activation of ERK1,2 induces FADD-independent caspase 8 activation and cell death

ATM Is Activated in Response toN-Methyl-N′-nitro- N-nitrosoguanidine-induced DNA Alkylation

Contact Info

Product

Resources

About

Lack of activation induced cell death in human T blasts despite CD95L up‐regulation: protection from apoptosis by MEK signalling