CBP as a transcriptional organizer

The signal transduction events leading to the induction of cAMP-responsive genes constitute one of the best characterized transcriptional pathways. We have proposed that phosphorylation by PKA allows CREB to recruit a coactivator protein. CBP, that is responsible for transcriptional activation. This model has been extended by findings from other laboratories that many additional transcriptional activities also function through CBP. To date, most studies of CBP function have utilized cell culture models. To address the contribution of CBP to gene regulation in an intact system, we have examined its participation in the Drosophila hedgehog pathway. The transcription factor cubitus interruptus (ci) has been shown to depend on Drosophila CBP (dCBP) for activation. dCBP binds to the carboxy-terminal domain of ci, a portion that is removed by the proteolytic processing event that regulates ci function. PKA negatively regulates the hedgehog pathway, and we have shown that this modulation depends on ci phosphorylation. Phosphorylation of ci promotes proteolytic processing and removal of the dCBP interaction domain. Mutation of the PKA sites in ci prevents proteolytic processing and maintains the abil ity of ci to interact with dCBP. Thus, the negative regulation of transcription mediated by PKA in the Drosophila hedgehog pathway occurs indirectly by preventing dCBP recruitment to the promoters of ci-responsive genes.