Inactivation of a Gα(s)-PKA tumour suppressor pathway in skin stem cells initiates basal-cell carcinogenesis.
Inactivation of a Gα(s)-PKA tumour suppressor pathway in skin stem cells initiates basal-cell carcinogenesis.
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DOI：
10.1038/ncb3164
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发表时间：
2015-06
影响因子：
21.3
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中科院分区：
文献类型：
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编码GαS异源三聚体G蛋白的基因GNAS的基因组变化与人类的许多疾病有关。在这里，我们以小鼠表皮为模型系统，探索GαS在干细胞命运决定中的作用。表皮条件性缺失GNAS或抑制PKA信号导致干细胞室显著扩张，导致基底细胞癌的快速形成。相反，真皮中活性GαS的诱导表达可导致毛囊干细胞耗竭和脱发。从机制上，我们发现G-αS-PKA的破坏促进了细胞自主的音速刺激性通路的刺激和河马信号的抑制，导致了GLI和YAP1的非规范激活。我们的研究强调了G-αS-PKA的一个重要的肿瘤抑制功能，它限制了上皮干细胞的增殖，并维持了适当的毛囊动态平衡。这些发现可能对包括癌症在内的多种病理生理状况有广泛的影响。
Genomic alterations in GNAS, the gene coding for the Gαs heterotrimeric G-protein, are associated with a large number human of 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 signaling 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 signaling inhibition, resulting in the non-canonical activation of GLI and YAP1. Our study highlights an important tumor suppressive function of Gαs-PKA, limiting the proliferation of epithelial stem cells and maintaining proper hair follicle homeostasis. These findings can have broad implications in multiple pathophysiological conditions, including cancer.