Genomic effects of the putative oncogene G alpha s. Chronic transcriptional activation of the c-fos proto-oncogene in endocrine cells.
Somatic mutations of the alpha subunit of Gs (G alpha s) have been detected in a variety of endocrine tumors. To test whether G alpha s is an oncogene, we investigated the genomic effects of G alpha s protein in which the GTPase activity had been inactivated. Results from transient transfection studies show that such proteins increase 1) transcription of a reporter gene driven by the minimal cAMP-responsive element (TGACGTCA) and 2) c-fos transcription in several endocrine cell lines (GH3, AtT20, and PC12). By promoter deletion analyses and genetic inactivation of cAMP-dependent protein kinase, we show that this transcriptional stimulation by G alpha s impinges on several regulatory elements within the c-fos promoter and operates within the protein kinase A pathways. Stable PC12 cell lines were established to analyze long-term effects of constitutively active G alpha s. Cell lines expressing mutated G alpha s have elevated cAMP levels and increased AP1 binding activity. Transcription of a variety of genes, including c-fos, c-jun, and junB, is increased in these cells. The strong and permanent effects of G alpha s on early immediate genes, and c-fos in particular, may be responsible for the oncogenic potential of G alpha s in endocrine cells.
Gaiddon
C
C
Institut de Physiologie et de Chimie Biologique, URA 1446 du CNRS, Strasbourg, France.
Boutillier
A L
AL
Monnier
D
D
Mercken
L
L
Loeffler
J P
JP
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D003001:Cloning, Molecular; D006224:Cricetinae; D003412:Cricetulus; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression; D016762:Genes, fos; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D016716:PC12 Cells; D010902:Pituitary Gland; D011519:Proto-Oncogenes; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D017384:Sequence Deletion; D014158:Transcription, Genetic
D046911:Macromolecular Substances; D011994:Recombinant Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins