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Content archived on 2024-05-29

Analysis of AP-1 activation in T cells; new targets against T cell leukemias

Objective

Two critical events propel tumor cells and their progeny into uncontrolled expansion and invasion:

deregulated cell proliferation and suppression of apoptosis. The most critical issue is to identify how tumor cells

differ from normal cells and how those differences can be exploited therapeutically. Suppression of apoptosis is

one of the attributes of cancer cells, and proteins involved in survival pathways can be used as targets of

chemotherapeutic drugs.

During the past years my colleagues and me have extensively worked with two proteins that play an

essential role in T cell proliferation and apoptosis: Vav and Protein Kinase C 6 (PKC6). These two proteins are

essential components of the intracellular signaling pathway that leads from TCR engagement to interleukin 2

(IL-2) production, the essential marker of T cell activation. An essential component of this pathway is activating

protein -1 (AP-1), a transcription factor that binds to the IL-2 promoter. There is evidence supporting an

autocrine loop involving IL-2 and IL-2 receptor a (IL-2R d) that is constitutively expressed by the malignant

cells in an array of T cell leukemias. In this context, IL-2 gene regulation by AP-1 could be of therapeutical

interest. Besides the importance of AP-1 in T cell signaling, most of the intracellular pathway leading to its

activation is unknown. We propose to use Vav/PKC0 as a starting point to look for downstream signaling

pathways leading to AP-1 activation, with particular emphasis on MAPK cascades. In addition, we propose to

identify the components of AP-1 in TCR-activated T cells, using this as well to characterize the upstream

pathways that converge on this transcriptional regulator. We propose to dissect this pathway with the idea of

developing new drug targets for therapeutical interventions in leukemia, or different process in which the

immune system should be down regulated as autoimmunity or graft rejection.

As an example of the i

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Topic(s)

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Call for proposal

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FP6-2002-MOBILITY-12
See other projects for this call

Funding Scheme

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IRG - Marie Curie actions-International re-integration grants

Coordinator

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
EU contribution
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Total cost

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