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Title: Regulation of interleukin-6 cytokine responses by mitogen activated protein kinases
Author: Bonito Monteiro, Nair Andreia
ISNI:       0000 0005 0734 2916
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Interleukin (IL)-6-type cytokines signal through glycoprotein (gp) 130, which is a key component of their receptor complex. Upon stimulation, gp130 mediates the activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs), extracellular signal-regulated kinase (ERK) 1 and ERK2, phosphoinositol-3 kinase (PI3K) and AKTs. Here, it is demonstrated that ERK2, but not ERK1, controls the expression and function of gp130. Silencing ERK2 in human osteosarcoma U2OS cells with short interfering (si) RNAs nearly obliterated gp130 expression, and this effect could be seen in cancer cell lines from different origins (e.g. breast, prostate, lung and cervix) that possess different mutational backgrounds, as well as in non-cancer cell lines (prostate and kidney). Interestingly, this regulation was not observed to the same extent in two mouse cell lines (MEF and NIH3T3) tested. Chemical inhibition of ERK1/2 did not have an impact on the receptor expression suggesting that the regulation of gp130 by ERK2 is independent of its canonical kinase activity. Importantly, ERK2 binds to the GP130 promoter, thereby decreasing gp130 expression, possibly by interacting with the transcriptional machinery. RNAi against ERK2 led to a reduction in RNA polymerase II activation, and luciferase reporter assays containing GP130 promoter and messenger RNA stability experiments also suggested that ERK2 has a transcriptional role important for the regulation of gp130 protein expression. Together, the data identity a new role for ERK2, not shared by ERK1, in the regulation of gp130 and that may be involved in cancer progression and inflammation. Additionally, genetic ablation of AKT2 and AKT3, two key components of the PI3K pathway that, under certain cellular backgrounds, are also activated downstream of the gp130 receptor, also impacts on gp130 expression. In this case, however, AKT enzymatic activation appears to be required. The precise mechanism that couples AKT to gp130 is currently unknown.
Supervisor: Costa-Pereira, Ana Paula ; Seckl, Michael Sponsor: Fundacao para a Ciencia e a Tecnologia
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral