Hedgehog signal path

The gene that codes for Hedgehog in the fruit fly Drosophila melanogaster was first described by researchers Christiane Nüsslein-Volhard and Eric F. Wieschaus (both were awarded a Nobel Prize in 1995 "for their fundamental insights into the genetic control of early embryo development"), who used a genetic screen to discover various mutations that influence embryonic development in Drosophila.

Hedgehog proteins are signaling proteins that play an important role in cell growth and differentiation during animal embryogenesis. The Hedgehog signaling pathway appeared very early in evolutionary history. A malfunction of this signaling pathway leads to massive malformations in the course of embryonic development and can cause carcinomas in adults. Three hedgehog proteins are currently known in mammals (sonic hedgehog, indian hedgehog and desert hedgehog).

The Hedgehog signaling pathway is based on proteolysis. It becomes active when the hedgehog protein binds to the receptor Patched (see PTCH 1 gene below). This removes the (physiological) inhibition of the receptor(SMO = Smoothened) by PTCH1.

When the Hedgehog signaling pathway is active and transmits a signal, the protein Ci can no longer be degraded, diffuses into the cell nucleus and regulates gene expression there. It has been shown that the Hedgehog signaling pathway plays a decisive role in the pathogenesis of basal cell carcinomas. Most sporadic basal cell carcinomas have mutations in this signaling pathway. In addition, mutations of the p-53 tumor suppressor gene are also found. A mutation in the PTCH1 gene has been identified for autosomal dominant Gorlin-Goltz syndrome.

Inhibitors of the Hedgehog signaling pathway (GDC-0449/Fa. Gentech; see also Itraconazole) represent a new drug approach in the treatment of advanced basal cell carcinoma. GDC-0449 is a small molecule that binds to SMO and thus inhibits signal transduction (see basal cell carcinoma below).

1. Hafner C (2010) Targeted drug therapy of basal cell carcinoma by inhibition of the hedgehog signaling pathway. dermatologist 61: 356-358
2. Ruby AL et al (2005) Basal-cell carcinoma. N Engl J Med 353: 2262-2269
3. Van Hoff et al (2009) Inhibition of the hedgehog pathway in advanced basal cell carcinoma. N Engl J Med 361: 1164-1172
4. Zugasti O et al (2005) The function and expansion of the Patched- and Hedgehog-related homologs in C. elegans. Genome Research 15: 1402-1410