PKA inhibits WNT signalling in adrenal cortex zonation and prevents malignant tumour development.
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.
CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université, F-63171 Aubière Cedex, France.
Coralie
C
Drelon
CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université, F-63171 Aubière Cedex, France.|Developmental Endocrine Oncology and Genetics, Section on Genetics and Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland 20892-1103, USA.
Annabel
A
Berthon
CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université, F-63171 Aubière Cedex, France.
Isabelle
I
Sahut-Barnola
CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université, F-63171 Aubière Cedex, France.
Mickaël
M
Mathieu
CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université, F-63171 Aubière Cedex, France.
Typhanie
T
Dumontet
CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université, F-63171 Aubière Cedex, France.
Stéphanie
S
Rodriguez
CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université, F-63171 Aubière Cedex, France.|Centre Hospitalier Universitaire, Service d'Endocrinologie, Faculté de Médecine, F-63000 Clermont-Ferrand, France.
Marie
M
Batisse-Lignier
CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université, F-63171 Aubière Cedex, France.
Houda
H
Tabbal
CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université, F-63171 Aubière Cedex, France.|Centre Hospitalier Universitaire, Service d'Endocrinologie, Faculté de Médecine, F-63000 Clermont-Ferrand, France.
Igor
I
Tauveron
CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université, F-63171 Aubière Cedex, France.
Anne-Marie
AM
Lefrançois-Martinez
CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université, F-63171 Aubière Cedex, France.
Jean-Christophe
JC
Pointud
Division of Endocrinology, G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi 39216, USA.|Department of Medicine-Endocrinology, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Celso E
CE
Gomez-Sanchez
Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90220 Oulu, Finland.
Seppo
S
Vainio
Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90220 Oulu, Finland.
Jingdong
J
Shan
Inserm UMR1091, CNRS UMR 7277, Institute of Biology Valrose, F-06108 Nice, France.
Sonia
S
Sacco
Inserm UMR1091, CNRS UMR 7277, Institute of Biology Valrose, F-06108 Nice, France.
Andreas
A
Schedl
Developmental Endocrine Oncology and Genetics, Section on Genetics and Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland 20892-1103, USA.
Constantine A
CA
Stratakis
CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université, F-63171 Aubière Cedex, France.
Antoine
A
Martinez
CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université, F-63171 Aubière Cedex, France.
Pierre
P
Val
D000310:Adrenal Gland Neoplasms / Q000209:etiology*; D000818:Animals; D063646:Carcinogenesis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D060449:Wnt Signaling Pathway; D015383:Zona Fasciculata / Q000166:cytology / Q000378:metabolism*; D015384:Zona Glomerulosa / Q000166:cytology / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D051176:beta Catenin; D017868:Cyclic AMP-Dependent Protein Kinases