Translational control of GATA-3

University Of Rochester, Rochester NY

Investigators

Abstract

DESCRIPTION (provided by applicant): The differentiation of CD4+ T cells into the Th2 subset is dependent on the transcription factor GATA-3, which promotes Th2 differentiation through multiple mechanisms. Both the expression and functional capacity of GATA-3 are tightly regulated processes and small changes in the level of functional GATA-3 protein can have significant effects on cellular differentiation. We have recently discovered that TCR signaling plays a critical role in the induction of GATA-3 expression and subsequent Th2 differentiation through the selective upregulation of GATA-3 translation rate. This translational upregulation of GATA-3 is dependent on TCR signaling through the PI3K/mTOR pathway and our preliminary data indicate that this is mediated through RNA secondary structure within the 5'UTR. These observations suggest a model of translational regulation where TCR signaling enhances the activity of the eIF2A helicase, which is required for ribosome scanning through 5'UTR with stable secondary structures. The overall aims of this proposal are to map the cis element in the GATA-3 5'UTR and to identify the downstream signaling pathways that regulate GATA-3 translation rate. The overall goal of these studies will be to identify specific molecular targets within GATA-3 that impact on the generation and stability of Th2 effectors cells and that could be developed into experimental modalities to control atopic diseases, including asthma.