Sonic hedgehog-induced activation of the Gli1 promoter is mediated by GLI3

Drosophila transcription factor cubitus interruptus (Ci) and its co-activat or CRE (cAMP response element)binding protein (CBP) activate a group of tar get genes on the anterior-posterior border in response to hedgehog protein (Hh) signaling. In the anterior region, in contrast, the carboxyl-truncated form of Ci generated by protein processing represses Hh expression. In ver tebrates, three Ci-related transcription factors (glioblastoma gene product s (GLIs) 1, 2, and 3) were identified, but their functional difference in H h signal transduction is unknown. Here, we report distinct roles for GLI1 a nd GLIB in Sonic hedgehog (Shh) signaling. GLIB containing both repression and activation domains acts both as an activator and a repressor, as does C i, whereas GLI1 contains only the activation domain. Consistent with this, GLIB, but not GLI1, is processed to generate the repressor form. Transcript ional co-activator CBP binds to GLIB, but not to GLI1. The trans-activating capacity of GLIB is positively and negatively regulated by Shh and cAMP-de pendent protein kinase, respectively, through a specific region of GLI3, wh ich contains the CBP-binding domain and the phosphorylation sites of cAMP-d ependent protein kinase. GLI3 directly binds to the Gli1 promoter and induc es Gli1 transcription in response to Shh. Thus, GLI3 may act as a mediator of Shh signaling in the activation of the target gene Gli1.