PKA inhibits WNT signalling in adrenal cortex zonation and prevents malignant tumour development

被引：85

作者：

Drelon, Coralie ^{[1
]}

Berthon, Annabel ^{[1
,2
]}

Sahut-Barnola, Isabelle ^{[1
]}

Mathieu, Mickael ^{[1
]}

Dumontet, Typhanie ^{[1
]}

Rodriguez, Stephanie ^{[1
]}

Batisse-Lignier, Marie ^{[1
,3
]}

Tabbal, Houda ^{[1
]}

Tauveron, Igor ^{[1
,3
]}

Lefrancois-Martinez, Anne-Marie ^{[1
]}

Pointud, Jean-Christophe ^{[1
]}

Gomez-Sanchez, Celso E. ^{[4
,5
]}

Vainio, Seppo ^{[6
]}

Shan, Jingdong ^{[6
]}

Sacco, Sonia ^{[7
]}

Schedl, Andreas ^{[7
]}

Stratakis, Constantine A. ^{[2
]}

Martinez, Antoine ^{[1
]}

Val, Pierre ^{[1
]}

机构：

[1] Clermont Univ, CNRS, UMR 6293, GReD,Inserm U1103, F-63171 Aubiere, France

[2] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dev Endocrine Oncol & Genet, Sect Genet & Endocrinol, Bethesda, MD 20892 USA

[3] Ctr Hosp Univ, Serv Endocrinol, Fac Med, F-63000 Clermont Ferrand, France

[4] GV Sonny Montgomery VA Med Ctr, Div Endocrinol, Jackson, MS 39216 USA

[5] Univ Mississippi, Dept Med Endocrinol, Med Ctr, Jackson, MS 39216 USA

[6] Univ Oulu, Bioctr Oulu, Dev Biol Lab, InfoTech Oulu,Ctr Cell Matrix Res,Fac Biochem & M, SF-90220 Oulu, Finland

[7] CNRS, Inst Biol Valrose, Inserm UMR1091, UMR 7277, F-06108 Nice, France

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

芬兰科学院;

关键词：

DEPENDENT PROTEIN-KINASE; TRANSGENIC MOUSE LINE; BETA-CATENIN GENE; ADRENOCORTICAL TUMORS; ALDOSTERONE PRODUCTION; WNT/BETA-CATENIN; PRKAR1A DEFECTS; PHOSPHORYLATION; SUPPRESSOR; CELLS;

D O I：

10.1038/ncomms12751

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 beta-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.

引用

页数：14

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