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Molecular Tuning Of Telomerase Activity In Senescent Human T Cells

Lanna, A; (2016) Molecular Tuning Of Telomerase Activity In Senescent Human T Cells. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Telomerase, a RNA-dependent DNA polymerase that adds telomeric DNA at the ends of eukaryotic chromosomes, is essential for the lifelong preservation of the proliferative potential of antigen specific T lymphocytes. However, senescent T cells that have low telomerase activity, short telomeres and lack of replicative capacity accumulate in old humans, patients with chronic viral infections and cancer. The mechanisms inhibiting telomerase in these cells are poorly understood. Here I investigated the molecular pathways causing telomerase dysfunction and defined an unrecognized mode of p38 MAPK activation in T cells. To identify mechanisms involved in telomerase down-regulation, I activated T cells in the presence of IFN-α, an inflammatory cytokine that inhibits telomerase. Telomerase down-regulation was mediated in part by p38 activation. I further investigated the upstream regulatory network of p38 MAPK in senescent T cells. Unexpectedly, spontaneous p38 activation in these cells was not regulated by either the ‘canonical’ MAPK cascade or the ‘alternative’ pathway downstream of the T cell receptor, in contrast to the current paradigm of how this pathway is activated in T cells. Instead, the senescence-related DNA damage response pathway activates the low nutrient sensor AMPK, which in turn induces p38 auto-phosphorylation through the scaffold molecule TAB1. These findings establish a third, ‘intrasensory’ pathway for p38 activation in T cells in which low nutrient and genotoxic signalling converge to inhibit proliferative responses. This can be reversed by blocking AMPK/TAB1 mediated activation of p38, which may represent a selective way for boosting T cell activity during ageing.

Type: Thesis (Doctoral)
Title: Molecular Tuning Of Telomerase Activity In Senescent Human T Cells
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1476231
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