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The patched signaling pathway in tumorigenesis and development: lessons from animal models
H Hahn1, L Wojnowski, G Miller
1Institute of Pathology, GSF Research Center of Environment and Health, Neuherberg, Germany. heidi.hahn@gsf.de
Abstract:
The identification of mutations in the human homolog of the Drosophila segment polarity gene Patched in basal cell carcinoma has sparked intense interest in the role of this gene in human disorders. The transmembrane protein Patched is a receptor for the morphogene Sonic Hedgehog. Sonic Hedgehog/Patched signaling involves another transmembrane protein, Smoothened, and its intracellular effectors, including the proto-oncogene GLI1. During the past 2 years it has become evident that mutations in Patched or in one of the components of its signaling pathway contribute to the formation of several common human tumors. It is now well established that Patched is a tumor suppressor gene. The Sonic Hedgehog/Patched/Smoothened signaling pathway is thus rapidly emerging as one of the most important regulators of oncogenic transformation. This pathway also plays an important role during mammalian embryonic development. This dual role is especially visible in humans with inherited Patched mutations. Such patients suffer from Gorlin, or nevoid basal cell carcinoma, syndrome and exhibit a variety of developmental defects accompanied by a predisposition to tumor formation. Activating mutations in Sonic Hedgehog and Smoothened lead to similar phenotypes as do loss-of function mutations in Patched. By means of transgenic and gene targeting technologies the respective mutations have been expressed in the mouse. Such mutant mouse strains exhibit many symptoms observed in humans. These strains are useful models to study the pathogenesis of several common human tumors and developmental defects. Furthermore they provide important tools to study the Sonic Hedgehog/Patched/Smoothened signaling at the molecular and biochemical level.
Insights
Mutations in the Patched gene and its Sonic Hedgehog pathway are linked to basal cell carcinoma and developmental defects. Mouse models of these mutations aid in studying cancer and development.
Area of Science:
- Developmental Biology
- Oncology
- Genetics
Background:
- The Patched gene, a receptor for Sonic Hedgehog, is implicated in basal cell carcinoma.
- Sonic Hedgehog/Patched signaling involves Smoothened and GLI1, crucial in cell development and cancer.
- Mutations in this pathway contribute to tumor formation and developmental abnormalities.
Purpose of the Study:
- To investigate the role of the Sonic Hedgehog/Patched/Smoothened signaling pathway in human disorders.
- To explore the dual role of this pathway in embryonic development and oncogenesis.
- To establish and utilize mouse models for studying related human diseases.
Main Methods:
- Identification of mutations in the Patched gene in human cancers.
- Analysis of Sonic Hedgehog/Patched/Smoothened signaling components.
- Generation of mutant mouse strains using transgenic and gene targeting technologies.
Main Results:
- Patched is confirmed as a tumor suppressor gene.
- Mutations in the pathway lead to Gorlin syndrome (nevoid basal cell carcinoma syndrome) with developmental defects and tumor predisposition.
- Mutant mouse models recapitulate human symptoms, aiding disease and pathway study.
Conclusions:
- The Sonic Hedgehog/Patched/Smoothened pathway is a key regulator of oncogenic transformation and embryonic development.
- Inherited Patched mutations cause Gorlin syndrome, highlighting the pathway's dual role.
- Mutant mouse strains are valuable tools for understanding cancer pathogenesis and developmental biology.