GLI1 protein is degraded by the proteasome in the absence of Hh signal. GLI1 levels are stabilized by treatment of cells with the proteasome inhibitor MG312, and GLI1 and beta-TrCP1 co-precipitate when expressed in NIH 3T3 cells.
Two SCF(beta-TrCP)-dependent degradation sites, Dn and Dc, have been identified in human GLI1. Removal of these sites abrogates the interaction with beta-TrCP, reduces the beta-TrCP-dependent ubiquitination of GLI1 and stabilizes the GLI1 protein levels. As is the case for GLI2 and GLI3, ubiquitination of GLI1 depends on the its prior phosphorylation by PKA, as GLI1 degradation is sensitive to PKA inhibitors and removal of the putative PKA sites abrogates the interaction with beta-TrCP and delays the kinetics of degradation (Huntzicker et al, 2006).