John Blenis, Ph.D.
Department of Cell Biology
Harvard Medical School
240 Longwood Avenue

Tuberous Sclerosis results from the loss of function of the TSC1 or TSC2 gene products. Loss of TSC1 or TSC2 results in inappropriate phosphorylation and activation of the 40S ribosomal S6 protein kinases. This results in enhanced translation of a specific pool of mRNAs. Other functions of the S6 kinases remain to be defined. In addition, the eIF-4E inhibitors proteins, 4E-BPs, are also inappropriately phosphorylated resulting in constitutive activation of eIF-4E and enhanced translation of another pool of mRNAs. Combined it is thought that these contribute to the improper regulation of cell size and cell proliferation that is the foundation of the TSC phenotype. In order to identify candidate targets for therapeutic intervention, we propose to fully define the molecular basis of how TSC1/2 up-regulate S6 kinase and 4E-BP1 phosphorylation, and to use this information as a starting point in the development of high-throughput assays designed to identify reagents that might inhibit, either or both, of these pathways.

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