Nature communications · 2016
PKA inhibits WNT signalling in adrenal cortex zonation and prevents malignant tumour development.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Drelon Coralie, Berthon Annabel, Sahut-Barnola Isabelle, Mathieu Mickaël, Dumontet Typhanie, Rodriguez Stéphanie, Batisse-Lignier Marie, Tabbal Houda, Tauveron Igor, Lefrançois-Martinez Anne-Marie, Pointud Jean-Christophe, Gomez-Sanchez Celso E, Vainio Seppo, Shan Jingdong, Sacco Sonia, Schedl Andreas, Stratakis Constantine A, Martinez Antoine, Val Pierre
Аннотация
Adrenal cortex physiology relies on functional zonation, essential for production of aldosterone by outer zona glomerulosa (ZG) and glucocorticoids by inner zona fasciculata (ZF). The cortex undergoes constant cell renewal, involving recruitment of subcapsular progenitors to ZG fate and subsequent lineage conversion to ZF identity. Here we show that WNT4 is an important driver of WNT pathway activation and subsequent ZG differentiation and demonstrate that PKA activation prevents ZG differentiation through WNT4 repression and WNT pathway inhibition. This suggests that PKA activation in ZF is a key driver of WNT inhibition and lineage conversion. Furthermore, we provide evidence that constitutive PKA activation inhibits, whereas partial inactivation of PKA catalytic activity stimulates β-catenin-induced tumorigenesis. Together, both lower PKA activity and higher WNT pathway activity lead to poorer prognosis in adrenocortical carcinoma (ACC) patients. These observations suggest that PKA acts as a tumour suppressor in the adrenal cortex, through repression of WNT signalling.