GCOE Program Seminar(Global Education Seminar)"Stem Cell Regulation: Roles of Rheb2 and Sirt1"

Blood cell regulation is controlled by numerous cytokines, stromal cells and their impact on the functions of hematopoietic stem (HSCs) and progenitor (HPCs) cells. The functional actions of HSCs and HPCs are mediated by an interacting network of intracellular signaling molecules. This presentation will focus on two such molecules: Rheb2 and Sirt1. Rheb is a member of the ras homologue enriched in brain family of small ras-like GTPase molecules, and Rheb molecules are able to activate mammalian target of rapamycin (mTOR) signaling in mammalian cells. Using a bicistronic retroviral vector expressing enhanced green fluorescence protein and either Rheb2 or a control gene, it was determined that overexpression of Rheb2 enhances mouse HPC growth, while impairing HSC repopulation (Campbell, et al., Blood, In Press). Sirt1 (Silence Information Regulator 1) is a member of the Sirtuin family of deacetylases, which interacts with a number of pathways involved in differentiation, metabolism, chromatin remodeling, and survival. We recently reported that Sirt1 regulates apoptosis and nanog expression in mouse embryonic stem cells (mESCs) by controlling p53 subcellular localization (Han, et al., Cell Stem Cell, 2:241-251, 2008). We now report a role for Sirt1 on mESC differentiation towards the hematopoietic lineage, using Sirt1 null and parental mESC lines. Ultimately, it is hoped that information on signaling molecules in HSCs and HPCs will be able to used translationally for enhanced clinical benefit.