Gli genes in development and cancer

With the realization that many proto-oncogenes and tumor suppressor genes a re expressed and have important functions during mammalian development, it is clear that cancer often involves the inappropriate activation of genetic pathways used during normal development. A signaling cascade that has been of considerable interest to both developmental and cancer biologists invol ves the Hedgehog (Hh) family of secreted proteins. To date, the only transc ription factors shown to be directly downstream of Hh are the zinc-finger c ontaining proteins Cubitus interruptus (Ci) and Gli, in flies and vertebrat es, respectively, The identification of many of the genes and proteins invo lved in Hh signaling has come largely from genetic and biochemical studies in Drosophila. Ci mediates Hh signaling through a Hh-dependent set of prote in modifications that alter the activity of Ci on Hh target genes, Recent e vidence suggests vertebrate Gli proteins may be similarly regulated. The in terest in this pathway has taken on added importance with the identificatio n of mutations in Hh pathway genes, including Gli genes, in several human d evelopmental disorders and cancers. We discuss models for how Gli proteins mediate Hh signaling in both vertebrate development and cancers.