Obiettivo
Wnt signaling is important in many developmental processes and has been implicated in tumorigenesis and in degenerative diseases. In normal cells, Wnt family proteins act through the well characterized canonical or less well understood non-canonical signaling pathways. While the canonical pathways proceed through the stabilization of beta-catenin, the non-canonical ones involve several effectors including protein kinases such as JNK, a member of the Stress Activated Protein Kinases family, which is activated by a variety of extracellular stimuli (Weston et al.). The Brisken laboratory has recently shown that increased Wnt signaling in primary human breast epithelial cells (HBECs) triggers a cascade of events resulting in oncogenic conversion of these cells (Ayyanan, A., et al). They found that an early event triggered by ectopic Wnt-1 expression is the activation of the DNA Damage Response (DDR). A hallmark of DDR is the phosphorylation state of the histone H2AX since phosphorylation of H2AX is induced in response to DSBs (double stranded breaks) originating from diverse origins including external damage (E.P. Rogakou et al.; T.T. Paull et al.), replication fork collision (T. Furuta, et al.; I.M. Ward et al.), apoptosis (E.P. Rogakou, et al.), and dysfunctional telomeres (F. d’Adda di Fagagna et al.;.H. Takai et al.). Recently, it has been shown that H2AX could be phosphorylated by JNK. The goal of this project is to determine which signaling cascades are activated by Wnt-1 in primary HBECs, and to test the hypothesis that activation of JNK leads to phosphorylation of H2AX thereby triggering the DDR. This will help to uncover the nature of molecular mechanisms activated by Wnt that could be targets of molecular or pharmacological therapies to breast cancers where Wnt signaling plays a role.
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FP7-PEOPLE-2007-4-2-IIF
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MC-IIF - International Incoming Fellowships (IIF)Coordinatore
1015 Lausanne
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