A model system for screening and identification of compounds that interfere with Gli2 dependent tumorigenesis and provide potential use as anticancer agents is provided. In particular, the invention includes a Gli2 protein having an S662A point mutation that interferes with binding by the ubiquitin-ligase β-TrCP. The mutation inhibits Gli2 degradation by the ubiquitin pathway. Gli2 stability and half-life are increased in the host cell resulting in an increase in Gli2-dependent transcription and concomitant neoplasia and tumorigenesis. Expression of the Gli2 mutant allows for the high throughput screening of compounds that interfere with the tumorigenesis thereby identifying anticancer agents.