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.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Cell Cycle Proteins
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Cell Differentiation / genetics
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Cell Line
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Cell Proliferation / genetics
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Cell Transformation, Neoplastic / genetics*
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Chromogranins
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GTP-Binding Protein alpha Subunits, Gs / genetics*
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GTP-Binding Protein alpha Subunits, Gs / metabolism
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Gene Expression Regulation, Developmental
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HEK293 Cells
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Hair Follicle / cytology*
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Hedgehog Proteins / metabolism
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Humans
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Kruppel-Like Transcription Factors / metabolism
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Mice
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Mice, Knockout
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein-Serine-Threonine Kinases / antagonists & inhibitors
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Protein-Serine-Threonine Kinases / genetics
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Protein-Serine-Threonine Kinases / metabolism
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RNA Interference
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RNA, Small Interfering
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Stem Cells / cytology*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Zinc Finger Protein GLI1
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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Chromogranins
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Gli1 protein, mouse
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Hedgehog Proteins
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Kruppel-Like Transcription Factors
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Phosphoproteins
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RNA, Small Interfering
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Shh protein, mouse
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Tumor Suppressor Proteins
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Yap1 protein, mouse
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Zinc Finger Protein GLI1
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Lats1 protein, mouse
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Hippo protein, mouse
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LATS2 protein, mouse
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Protein-Serine-Threonine Kinases
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Gnas protein, mouse
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GTP-Binding Protein alpha Subunits, Gs