C. Gaiddon et al., GENOMIC EFFECTS OF THE PUTATIVE ONCOGENE G-ALPHA-S - CHRONIC TRANSCRIPTIONAL ACTIVATION OF THE C-FOS PROTOONCOGENE IN ENDOCRINE-CELLS, The Journal of biological chemistry, 269(36), 1994, pp. 22663-22671
Somatic mutations of the a subunit of Gs (G alpha s) have been detecte
d in a variety of endocrine tumors. To test whether G alpha s is an on
cogene, we investigated the genomic effects of G alpha s protein in wh
ich the GTPase activity had been inactivated. Results from transient t
ransfection studies show that such proteins increase 1) transcription
of a reporter gene driven by the minimal cAMP-responsive element (TGAC
GTCA) and 2) c-fos transcription in several endocrine cell lines (GH3,
AtT20, and PC12). By promoter deletion analyses and genetic inactivat
ion of cAMP-dependent protein kinase, we show that this transcriptiona
l stimulation by G alpha s impinges on several regulatory elements wit
hin the c-fos promoter and operates within the protein kinase A pathwa
ys. Stable PC12 cell lines were established to analyze long-term effec
ts 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 a
lpha s on early immediate genes, and c-fos in particular, may be respo
nsible for the oncogenic potential of G alpha s in endocrine cells.