Coope, Helen J.; (2001) Analysis of the regulation of NFkappaB by TPL-2 kinase. Doctoral thesis (Ph.D), UCL (University College London).

Text out.pdf Download (10MB)

Abstract

NFκB is a ubiquitously expressed transcription factor of particular importance in the immune system. Several signalling pathways regulate NFκB activation, which occurs following the degradation of inhibitory IκB proteins. One pathway of NFκB activation is the signal-induced degradation of NFκB1 p105, when this occurs, associated NFκB proteins transfer to the nucleus. TPL-2 is a proto-oncogene encoding a serine/threonine kinase, which interacts with NFκB1 p105 and regulates its degradation. The aims of the present study are to investigate the regulation of NFκB1 p105 degradation by TPL-2 and clarify the physiological circumstances in which this is important. Studies of NFκB knockout and transgenic animals reveal roles for NFKB in T cell development and function. TPL-2 is expressed in T cell rich organs. However, in the present study, transgenic mice expressing TPL-2 or dominant negative TPL-2 in the T cell lineage show no defects in thymocyte development, T cell proliferation, IL-2 and TNFα production or NFκB activation. Using stable cell lines, it is shown that TNFα stimulation but not CD3 and CD28 costimulation is a potent stimulus for NFKB1 p105 degradation in T cells. Expression of dominant negative TPL-2 inhibits NFκB1 p105 degradation in these cells, whereas ERK, JNK and P38 activation are unaffected. LPS is a potent inducer of NFKB1 p105 degradation in the monocyte-macrophage cell line THP-1, which coincides with the activation of the IKK kinases. Expression of dominant negative TPL-2 in these cells inhibits LPS induced NFκB1 p105 degradation, ERK activation and transcription of the TNFα gene. Taken together, these data suggest that TPL-2 may function in regulation of monocyte or macrophage responses to LPS.

Download activity - last month

Export as CSVXMLJSON

Download activity - last 12 months

Export as CSVXMLJSON

Downloads by country - last 12 months

Export as CSVXMLJSON

Archive Staff Only

View Item