Brain Tumours

The Hedgehog (Hh) Pathway

 Hh signaling pathway is essential in mammalian embryonic development and adult tissue homeostasis 1  Mechanism: 2,3 • PTCH inhibits SMO • Hh ligand binding to PTCH relieves inhibition of SMO • SMO signaling, via SUFU, activates GLI transcription factors  Constitutive activation can result from mutations ( PTCH , SMO or SUFU ) or overexpression of the ligands 4–8

SMO

Target Genes

• Hypermethylation of PTCH and the negative regulator HIP1 can lead to pathway activation 9,10

COS, conserved ortholog set; GLI, glioma-associated oncogene; Hh, hedgehog; HIP1, hedgehog interating protein 1; PTCH, patched; SMO, smoothened; SUFU, suppressor of fused 1. Jiang J, Hui C. Dev Cell 2008; 2. Epstein EH. Nat Rev Cancer 2008; 3. Xie J. Acta Biochim Biophys Sin (Shanghai) 2008; 4. Slade I , et al. Fam Cancer 2011; 5. Lee Y , et al. Cancer Res 2003; 6. Scott DK , et al. Cell Cycle 2006; 7. Zurawel RH, et al. Genes Chromosomes Cancer 2000; 8. Thompson MC, et al. JCO 2006; 9. Shahi MH, et al. BMC Cancer 2010; 10. Shahi MH, et al. J Neurooncol 2011.