S02-05 Targeting tumor suppressor pathways to treat cancer

tion organelle. Primary cilia, immotile organelles found on most cells, have been implicated in several signaling pathways and we have observed direct binding of Hh protein to them. We find that the Ptc receptor protein is localized in cilia, where it prevents the accumulation of the Smo seven-transmembrane domain protein. Binding of Hh to Ptc causes departure of both from the cilium, allowing entrance of Smo. Smo in the cilium is able to activate Gli transcription factors which in turn control target gene expression. We have identified oxysterols as powerful agonists of Hh signaling in mammalian cells, and find that they also cause Smo to move into cilia. Using agonists and antagonists of Hh signaling, and mutants that affect primary cilia, we are exploring the mechanisms of protein trafficking and target gene activation. We are also characterizing Hh target genes in responsive cerebellum granule neuron precursors and in the medulloblastoma tumors that arise from these precursors when Ptc function is reduced.