New insights in p38MAPK function and potential value as therapeutic target for high prevalence diseases
Author
Escós López, AlejandraAdvisor
Cuenda Méndez, Ana IsabelEntity
UAM. Departamento de Biología Molecular; CSIC. Centro Nacional de Biotecnología (CNB)Date
2019-07-26Subjects
Proteínas quinasas activadas por mitógenos - Tesis doctoral; Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 26-07-2019Esta tesis tiene embargado el acceso al texto completo hasta el 26-01-2021
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
Inflammation is a highly regulated process in which macrophages play a
fundamental role. These are activated through pattern-recognition
receptors that cause the secretion of cytokines by activating the TLR4-
Tpl2-ERK1/2 pathway. Our laboratory has shown that the absence of p38g
and p38d (p38g/p38d) caused a decrease in the protein levels of Tpl2 and
ABIN2. Consequently, ERK1/2 was not activated, thus blocking the
production of cytokines and decreasing the effects in the inflammatory
model of septic shock (Risco et al., 2012).
In this thesis we have described for the first time that, in macrophages in
response to Candida albicans infection, the signaling pathways TAK1-IKKTpl2-
ERK1/2 and Raf-1-ERK1/2 are activated under Dectin-1. We have also
described how the absence of p38g/p38d blocks the activation of ERK1/2
by decreasing the protein levels of Tpl2.
Due to the central role of Tpl2 in macrophages, we have studied the
molecular mechanism by which p38g/p38d regulate Tpl2 proteins levels.
We have described that p38g/p38d interact with the Tpl2/ABIN2/p105
complex through Tpl2 thus contributing to its stability. In this study we
observed that the translation of Tpl2 and ABIN2 decreases in the absence
of p38g/p38d, and that p38d could specifically regulate the translation of
the Tpl2 mRNA through its 3'UTR. In turn, p38g/p38d could be regulating
cap-independent translation of proteins.
Finally, we studied which signaling pathways downstream of the TLR4
receptor were modulated by p38g/p38d independently from Tpl2. For this,
we generated a new mouse line p38g171A/171A/p38d-/-, which is deficient in
p38d and expresses inactive p38g; it also expresses normal levels of Tpl2.
By the comparative study of RNA sequencing in p38g171A/171A/p38d-/-
macrophages stimulated with LPS we have discovered that they induce the
overproduction of proteins related to the interferon type I response.
Our results establish that p38g/p38d regulate the production of cytokines through gene transcription and translation processes.
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Google Scholar:Escós López, Alejandra
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