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

共 50 条

[11] Adrenal cortex tissue homeostasis and zonation: A WNT perspective [J].

Drelon, Coralie ;

Berthon, Annabel ;

Mathieu, Mickael ;

Martinez, Antoine ;

Val, Pierre .

MOLECULAR AND CELLULAR ENDOCRINOLOGY, 2015, 408 (0C) :156-164

[12] Analysis of the Role of Igf2 in Adrenal Tumour Development in Transgenic Mouse Models [J].

Drelon, Coralie ;

Berthon, Annabel ;

Ragazzon, Bruno ;

Tissier, Frederique ;

Bandiera, Roberto ;

Sahut-Barnola, Isabelle ;

de Joussineau, Cyrille ;

Batisse-Lignier, Marie ;

Lefrancois-Martinez, Anne-Marie ;

Bertherat, Jerome ;

Martinez, Antoine ;

Val, Pierre .

PLOS ONE, 2012, 7 (08)

[13] Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A [J].

Fang, XJ ;

Yu, SX ;

Lu, YL ;

Bast, RC ;

Woodgett, JR ;

Mills, GB .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (22) :11960-11965

[14] Adrenocortical Zonation Results from Lineage Conversion of Differentiated Zona Glomerulosa Cells [J].

Freedman, Bethany D. ;

Kempna, Petra Bukovac ;

Carlone, Diana L. ;

Shah, Manasvi S. ;

Guagliardo, Nick A. ;

Barrett, Paula Q. ;

Gomez-Sanchez, Celso E. ;

Majzoub, Joseph A. ;

Breault, David T. .

DEVELOPMENTAL CELL, 2013, 26 (06) :666-673

[15] Wnt/β-catenin and 3′,5′-cyclic adenosine 5′-monophosphate/protein kinase a signaling pathways alterations and somatic β-catenin gene mutations in the progression of adrenocortical tumors [J].

Gaujoux, Sebastien ;

Tissier, Frederique ;

Groussin, Lionel ;

Libe, Rossella ;

Ragazzon, Bruno ;

Launay, Pierre ;

Audebourg, Anne ;

Dousset, Bertrand ;

Bertagna, Xavier ;

Bertherat, Jerome .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2008, 93 (10) :4135-4140

[16] Localisation of the melanocortin-2-receptor and its accessory proteins in the developing and adult adrenal gland [J].

Gorrigan, Rebecca J. ;

Guasti, Leonardo ;

King, Peter ;

Clark, Adrian J. ;

Chan, Li F. .

JOURNAL OF MOLECULAR ENDOCRINOLOGY, 2011, 46 (03) :227-232

[17] Intestinal polyposis in mice with a dominant stable mutation of the β-catenin gene [J].

Harada, N ;

Tamai, Y ;

Ishikawa, T ;

Sauer, B ;

Takaku, K ;

Oshima, M ;

Taketo, MM .

EMBO JOURNAL, 1999, 18 (21) :5931-5942

[18] Wnt-4 deficiency alters mouse adrenal cortex function, reducing aldosterone production [J].

Heikkilä, M ;

Peltoketo, H ;

Leppäluoto, J ;

Ilves, M ;

Vuolteenaho, O ;

Vainio, S .

ENDOCRINOLOGY, 2002, 143 (11) :4358-4365

[19] Phosphorylation of β-catenin by cyclic AMP-dependent protein kinase stabilizes β-catenin through inhibition of its ubiquitination [J].

Hino, S ;

Tanji, C ;

Nakayama, KI ;

Kikuchi, A .

MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (20) :9063-9072

[20] Serial analysis of gene expression in adrenocortical hyperplasia caused by a germline PRKAR1A mutation [J].

Horvath, A ;

Mathyakina, L ;

Vong, Q ;

Baxendale, V ;

Pang, ALY ;

Chan, WY ;

Stratakis, CA .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2006, 91 (02) :584-596

← 1 2 3 4 5 →