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

Nat Cell Biol. 2015 Jun;17(6):793-803. doi: 10.1038/ncb3164. Epub 2015 May 11.

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

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Cycle Proteins
  • Cell Differentiation / genetics
  • Cell Line
  • Cell Proliferation / genetics
  • Cell Transformation, Neoplastic / genetics*
  • Chromogranins
  • GTP-Binding Protein alpha Subunits, Gs / genetics*
  • GTP-Binding Protein alpha Subunits, Gs / metabolism
  • Gene Expression Regulation, Developmental
  • HEK293 Cells
  • Hair Follicle / cytology*
  • Hedgehog Proteins / metabolism
  • Humans
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Mice, Knockout
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Interference
  • RNA, Small Interfering
  • Stem Cells / cytology*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Zinc Finger Protein GLI1

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Chromogranins
  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Phosphoproteins
  • RNA, Small Interfering
  • Shh protein, mouse
  • Tumor Suppressor Proteins
  • Yap protein, mouse
  • Zinc Finger Protein GLI1
  • Lats1 protein, mouse
  • Hippo protein, mouse
  • LATS2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Gnas protein, mouse
  • GTP-Binding Protein alpha Subunits, Gs

Associated data

  • GEO/GSE58894