The research focus of my laboratory is on the molecular mechanism that drives the self-renewal of stem cells and cancer cells, with the hope that we can use this knowledge to enhance the endogenous regenerative process to repair damaged tissues caused by diseases or injuries, particularly in the central nervous system, or to reduce the uncontrolled proliferation seen in metastatic and high-grade tumors. The biological systems we use are ES, primary neural stem cell culture, mammary cancer stem cells, and cancer cell lines, as well as mouse genetic models. The molecular target of our present studies is a family of nucleolar GTPases, one of which, nucleostemin (NS), confers a unique nucleolar state in the stem cells. NS was previously identified as enriched in the stem cell population, and shown to play important roles in maintaining the self-renewal of stem and cancer cells and inducing pluripotency. The activity of NS is to provide a unique genome-protecting mechanism against replicative DNA damage and is regulated by a small molecule in the cells (GTP) that serves as a molecular switch controlling the on and off states. Our work suggests a model in which continuously dividing cells use NS as a sensor to control their rate of division in response to changes that take place in their microenvironment. The mechanism by which NS and NS-related genes control tissue homeostasis in adult animals is being addressed in the following directions: 1) defining the unique nucleolar state in stem cells; 2) determining the signaling pathway that regulates the expression and activity of NS in stem cells and during adult tissue regeneration; and 3) establishing the role of NS-expressing cells in the tumorigenic process, with an emphasis on the brain, breast, and prostate tumors.