Inactivation of a G?(s)-PKA tumour suppressor pathway in skin stem cells initiates basal-cell carcinogenesis.

ABSTRACT: Genomic alterations in GNAS, the gene coding for the G?s heterotrimeric G protein, are associated with a large number of human diseases. Here, we explored the role of G?s 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 G?s in the epidermis caused hair follicle stem cell exhaustion and hair loss. Mechanistically, we found that G?s-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 G?s-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.

SUBMITTER: Iglesias-Bartolome R 

PROVIDER: S-EPMC4449815 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature