The activating mutation R201C in GNAS promotes intestinal tumourigenesis in Apc(Min/+) mice through activation of Wnt and ERK1/2 MAPK pathways.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE

Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-

MAP Kinase Signaling System*; Adenomatous Polyposis Coli Protein/*metabolism ; Colorectal Neoplasms/*genetics ; Colorectal Neoplasms/*pathology ; GTP-Binding Protein alpha Subunits, Gs/*metabolism ; Mutant Proteins/*metabolism ; Wnt Proteins/*metabolism; Adenoma/enzymology ; Adenoma/genetics ; Adenoma/metabolism ; Adenoma/pathology ; Alleles ; Animals ; Cell Differentiation/genetics ; Cell Proliferation ; Chromogranins ; Colorectal Neoplasms/enzymology ; Colorectal Neoplasms/metabolism ; Cyclic AMP/metabolism ; Disease Progression ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Female ; GTP-Binding Protein alpha Subunits, Gs/genetics ; Gene Expression Regulation, Neoplastic ; Genetic Loci/genetics ; Humans ; Intestinal Mucosa/metabolism ; Intestinal Mucosa/pathology ; Male ; Membrane Glycoproteins/genetics ; Mice ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Mutant Proteins/genetics ; Mutation ; Organ Specificity ; Phosphoric Diester Hydrolases/metabolism ; Promoter Regions, Genetic/genetics ; Stem Cells/metabolism ; Stem Cells/pathology ; Substrate Specificity ; Up-Regulation

Somatically acquired, activating mutations of GNAS, the gene encoding the stimulatory G-protein Gsalpha subunit, have been identified in kidney, thyroid, pituitary, leydig cell, adrenocortical and, more recently, in colorectal tumours, suggesting that mutations such as R201C may be oncogenic in these tissues. To study the role of GNAS in intestinal tumourigenesis, we placed GNAS R201C under the control of the A33-antigen promoter (Gpa33), which is almost exclusively expressed in the intestines. The GNAS R201C mutation has been shown to result in the constitutive activation of Gsalpha and adenylate cyclase and to lead to the autonomous synthesis of cyclic adenosine monophosphate (cAMP). Gpa33(tm1(GnasR201C)Wtsi/+) mice showed significantly elevated cAMP levels and a compensatory upregulation of cAMP-specific phosphodiesterases in the intestinal epithelium. GNAS R201C alone was not sufficient to induce tumourigenesis by 12 months, but there was a significant increase in adenoma formation when Gpa33(tm1(GnasR201C)Wtsi/+) mice were bred onto an Apc(Min/+) background. GNAS R201C expression was associated with elevated expression of Wnt and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK1/2 MAPK) pathway target genes, increased phosphorylation of ERK1/2 MAPK and increased immunostaining for the proliferation marker Ki67. Furthermore, the effects of GNAS R201C on the Wnt pathway were additive to the inactivation of Apc. Our data strongly suggest that activating mutations of GNAS cooperate with inactivation of APC and are likely to contribute to colorectal tumourigenesis.

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United Kingdom WT_ Wellcome Trust; 082356 United Kingdom WT_ Wellcome Trust; A6997 United Kingdom CRUK_ Cancer Research UK; A8784 United Kingdom CRUK_ Cancer Research UK

Indexing Agency: NLM Local ID #: UKMS30064.

0 (Adenomatous Polyposis Coli Protein)
0 (Chromogranins)
0 (Gpa33 protein, mouse)
0 (Membrane Glycoproteins)
0 (Mutant Proteins)
0 (Wnt Proteins)
E0399OZS9N (Cyclic AMP)
EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
EC 3.1.4.- (Phosphoric Diester Hydrolases)
EC 3.6.1.- (GNAS protein, human)
EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gs)

Date Created: 20100610 Date Completed: 20100903 Latest Revision: 20230523

20231215

PMC2923080

10.1038/onc.2010.202

20531296