Cancer accounts for nearly one quarter of the deaths in the U.S. each year. Treatment options include radiation, chemotherapy and surgery, among others. However, these treatments often cause debilitating side effects and are not always efficacious. New ways of treating cancer are needed.

The glioma-associated (GLI) proteins may provide a new drug target for cancer treatment. These proteins are a family of transcription factors involved in the activation of the highly conserved Hedgehog (Hh) signaling pathway in mammals. In particular, Gli2 appears to be the major nuclear effector of Hh signaling. Because activation of this pathway in adult tissues has been implicated in tumorigenesis, agents that inhibit Gli2 may reduce tumor growth.

UW-Madison researchers have developed a mutant form of Gli2 that results in a constitutively active Hh signaling pathway. They identified a point mutation that inhibits the first step in the degradation of Gli2 and makes the protein more stable.

Because the mutation increases the half-life of Gli2, it results in an increase in Gli2-dependent transcription. This in turn leads to an increase in tumorigenesis, which enables high throughput screening for potential anti-cancer compounds that interfere with Gli2-mediated tumor growth.
 

File Number: P07243US 

Other Information:
Bhatia N., Thiyagarajan S., Elcheva I., Saleem M., Dlugosz A., Mukhtar H. and Spiegelman V.S. 2006. Gli2 Is Targeted for Ubiquitination and Degradation by β-TrCP Ubiquitin Ligase. J. Biol. Chem. 281, 19320-19326.

See WARF reference number P08215US for a method of treating prostate cancer by inhibiting the expression of Gli2.