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- Title
Inactivation of a Gα<sub>s</sub>-PKA tumour suppressor pathway in skin stem cells initiates basal-cell carcinogenesis.
- Authors
Iglesias-Bartolome, Ramiro; Torres, Daniela; Marone, Romina; Feng, Xiaodong; Martin, Daniel; Simaan, May; Chen, Min; Weinstein, Lee S.; Taylor, Susan S.; Molinolo, Alfredo A.; Gutkind, J. Silvio
- Abstract
Genomic alterations in GNAS, the gene coding for the Gαs heterotrimeric G protein, are associated with a large number of human diseases. Here, we explored the role of Gαs on stem cell fate decisions by using the mouse epidermis as a model system. Conditional epidermal deletion of Gnas or repression of PKA signalling caused a remarkable expansion of the stem cell compartment, resulting in rapid basal-cell carcinoma formation. In contrast, inducible expression of active Gαs in the epidermis caused hair follicle stem cell exhaustion and hair loss. Mechanistically, we found that Gαs-PKA disruption promotes the cell autonomous Sonic Hedgehog pathway stimulation and Hippo signalling inhibition, resulting in the non-canonical activation of GLI and YAP1. Our study highlights an important tumour suppressive function of Gαs-PKA, limiting the proliferation of epithelial stem cells and maintaining proper hair follicle homeostasis. These findings could have broad implications in multiple pathophysiological conditions, including cancer.
- Subjects
TUMOR suppressor proteins; TUMOR suppressor genes; CARCINOGENESIS; BASAL cell carcinoma; STEM cells; CELL proliferation
- Publication
Nature Cell Biology, 2015, Vol 17, Issue 6, p793
- ISSN
1465-7392
- Publication type
Article
- DOI
10.1038/ncb3164