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

Author

Listed:
  • Coralie Drelon

    (CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université)

  • Annabel Berthon

    (CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université
    Developmental Endocrine Oncology and Genetics, Section on Genetics and Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development)

  • Isabelle Sahut-Barnola

    (CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université)

  • Mickaël Mathieu

    (CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université)

  • Typhanie Dumontet

    (CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université)

  • Stéphanie Rodriguez

    (CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université)

  • Marie Batisse-Lignier

    (CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université
    Centre Hospitalier Universitaire, Service d’Endocrinologie, Faculté de Médecine)

  • Houda Tabbal

    (CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université)

  • Igor Tauveron

    (CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université
    Centre Hospitalier Universitaire, Service d’Endocrinologie, Faculté de Médecine)

  • Anne-Marie Lefrançois-Martinez

    (CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université)

  • Jean-Christophe Pointud

    (CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université)

  • Celso E. Gomez-Sanchez

    (G.V. (Sonny) Montgomery VA Medical Center
    University of Mississippi Medical Center)

  • Seppo Vainio

    (Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu)

  • Jingdong Shan

    (Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu)

  • Sonia Sacco

    (Inserm UMR1091, CNRS UMR 7277, Institute of Biology Valrose)

  • Andreas Schedl

    (Inserm UMR1091, CNRS UMR 7277, Institute of Biology Valrose)

  • Constantine A. Stratakis

    (Developmental Endocrine Oncology and Genetics, Section on Genetics and Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development)

  • Antoine Martinez

    (CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université)

  • Pierre Val

    (CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université)

Abstract

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.

Suggested Citation

  • Coralie Drelon & Annabel Berthon & Isabelle Sahut-Barnola & Mickaël Mathieu & Typhanie Dumontet & Stéphanie Rodriguez & Marie Batisse-Lignier & Houda Tabbal & Igor Tauveron & Anne-Marie Lefrançois-Mar, 2016. "PKA inhibits WNT signalling in adrenal cortex zonation and prevents malignant tumour development," Nature Communications, Nature, vol. 7(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12751
    DOI: 10.1038/ncomms12751
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    Cited by:

    1. Damien Dufour & Typhanie Dumontet & Isabelle Sahut-Barnola & Aude Carusi & Méline Onzon & Eric Pussard & James Jr Wilmouth & Julie Olabe & Cécily Lucas & Adrien Levasseur & Christelle Damon-Soubeyrand, 2022. "Loss of SUMO-specific protease 2 causes isolated glucocorticoid deficiency by blocking adrenal cortex zonal transdifferentiation in mice," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Zachary T. Spencer & Victoria H. Ng & Hassina Benchabane & Ghalia Saad Siddiqui & Deepesh Duwadi & Ben Maines & Jamal M. Bryant & Anna Schwarzkopf & Kai Yuan & Sara N. Kassel & Anant Mishra & Ashley P, 2023. "The USP46 deubiquitylase complex increases Wingless/Wnt signaling strength by stabilizing Arrow/LRP6," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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