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Dynamic regulation of Ras signaling – a novel way to attenuate PI3K activity in cancer and inflammation

Ziel

Ras genes take a center stage in signal transduction and molecular oncology, where Ras-driven signaling pathways control proliferation, differentiation, cell adhesion, apoptosis, and cell migration. Mutations in RAS are very common in cancer, and have been found in 20-30% of all human tumors. Moreover, constitutive Ras activation is known to trigger senescence in the absence of “second hit” mutations (e.g. loss of p53). Interestingly, both processes - cancer progression and oncogene-induced cellular senescence - were shown to be dependent on Ras interaction with phosphoinositide 3-kinase (PI3K), which points to a dominant role of Ras-mediated PI3K activation in proliferative disease.
Here we propose to investigate the possibility that Ras/PI3K interactions are dynamically regulated, which is supported by preliminary data: in certain cellular states, post-translational modification of Ras disrupts its binding to PI3K.
We aim to elucidate the importance of this process in physiology and disease. We assume that regulated Ras interactions with PI3Kalpha act in cancer progression, while Ras/PI3Kgamma complexes transiently regulate inflammatory processes. Along these lines, we aim to uncover cellular signaling networks that dynamically dissociate Ras from PI3K. When the above mechanism is validated, we plan to study the consequences of the abrogation of Ras/PI3K interactions in “in vivo” mouse models. These will elucidate if and how PI3K detachment from Ras acts as a a general and central mechanism to balance inflammatory cell recruitment, oncogen-mediated metastasis, proliferation and senescence.

Wissenschaftliches Gebiet (EuroSciVoc)

Programm/Programme

Thema/Themen

Aufforderung zur Vorschlagseinreichung

FP7-PEOPLE-2009-IIF
Andere Projekte für diesen Aufruf anzeigen

Finanzierungsplan

MC-IIF - International Incoming Fellowships (IIF)

Koordinator

UNIVERSITAT BASEL
EU-Beitrag
€ 172 065,20
Adresse
PETERSPLATZ 1
4051 Basel
Schweiz
Region
Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt
Aktivitätstyp
Higher or Secondary Education Establishments
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