Cell fate decisions rely on signaling pathways that integrate external signals to coordinate specific intracellular programs. One of these pathways leads to the activation of the protein kinase p38a, which plays key roles in cell responses to many types of stresses as well as chemotherapeutic
agents and oncogenes. Importantly, p38a acts in a cell context and cell type-specific manner to integrate signals that affect cell proliferation, differentiation and survival. There is good evidence indicating that p38a can negatively regulate tumor initiation at different levels. Intriguingly,
recent results suggest that p38a activation might sometimes contribute to tumorigenesis. The molecular basis for the different functions of p38a are not well understood but it is likely that the network of substrates phosphorylated by p38a plays a major role. This project proposes to investigate
mechanisms of signal integration by p38a with special emphasis on the re-wiring of this signaling pathway to serve oncogenic functions in cancer cells. An important part of the studies focuses on the mechanisms underlying pro-tumorigenic functions of p38a signaling, including the regulation
of survival, proliferation and spreading of cancer cells. Our experimental approach combines the genetic manipulation with the use of chemical inhibitors in different mouse models and human cancer cell lines. We will also use genetically modified mice that allow the deletion of p38a in a cell
type-specific manner to investigate in vivo functions of this signaling pathway during tumorigenesis, as well as how the p38a pathway regulates the interplay between tumor cells and different cell types in the tumor stroma. Taken together, this project is posed to open unique opportunities
for exploration of how complex signaling networks integrate during tumor development. The results of the proposed work should provide a rationale to develop novel cancer therapies based on the use of currently available drugs that target the p38a signaling network.
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