In its resting state, the Patched receptor prevents activation of the Hedgehog pathway by inhibiting Smoothened. When secreted the Hedgehog ligand binds to and inactivates Patched, that results in activation of Smoothened. This triggers a cascade of signaling events that result in gene transcription of Hedgehog target genes through the Gli family of transcription factors. Direct targets of Hedgehog pathway activity include genes involved in cell proliferation, development, and tissue maintenance.
However, reactivation of the Hedgehog pathway in adult tissues may be linked to the development of cancer. This may occur by genetic alterations in Hedgehog pathway components or excessive secretion of Hedgehog ligands. Basal cell carcinoma (BCC) and medulloblastoma are 2 types of cancer that exhibit mutation-driven Hedgehog signaling. The most frequent genetic aberrations are inactivating mutations in PTCH, the gene for the Patched protein, and activating mutations in SMO, the gene for the Smoothened protein.
Hedgehog signaling was initially linked to cancer with the discovery of Gorlin syndrome (also known as basal cell nevus syndrome or nevoid basal cell carcinoma syndrome). Gorlin syndrome is a rare hereditary disorder characterized by multiple BCCs and an increased risk of medulloblastoma. Discovering that inherited loss-of-function mutations in the PTCH gene was the underlying cause of Gorlin syndrome firs,t established a connection between the Hedgehog pathway and cancer. Activation of the pathway through such mutations was subsequently identified in sporadic BCC and medulloblastoma.
The following link is an article from the New England Journal of Medicine explaining the connection between Hedgehog malfunction and BCC
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