ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2007) 14 S19.3

Oncogene gsp and Gsα overexpression in pituitary cell biology

Anne Barlier2, Corinne Gérard1 & Enjalbert Alain1

1Laboratory ICNE UMR6544 CNRS Université de la Méditérranée, Marseille, France; 2Laboratory of Biochemistry anf Molecular Biology, CHU Conception, Marseille, France.

Somatic mutations of the αs subunit of G proteins were initially reported by Landis and collaborators in 1989 in somatotroph tumors characterized by markedly high cAMP levels. These mutations are localized at two critical sites concerning the intrinsic guanosine triphosphatase activity of the protein leading to a constitutive activation of the adenylyl cyclase. The mutated protein has been named the gsp oncogene. On the other hand, Gsα mRNA level varied among human somatotroph adenomas, the highest expression being observed in gsp- tumors (not bearing the active Gsα mutant). We previously showed that gsp oncogene impacted tumoral phenotype, gsp+ tumors being smaller and more sensitive to octreotide treatment. We have recently showed that high Gsα expression impacted also tumoral phenotype of gsp- tumors.

Gsα is coded from GNAS gene which is imprinted in a tissue-specific manner. Gsα is paternally silenced in normal pituitary, but a Gsα imprinting relaxation is found in some tumoral tissue. Unexpectedly, we found that the loss of Gsα imprinting did not induce the expected Gsα overexpression and was not associated with a modification of methylation status of exon1A DMR (a differentially methylated region controling the Gsα imprinting) in human pituitary tumors.

To explore the impact on transduction pathways of mutated or overexpressed Gsα protein, we obtained somatolactotroph GH4C1 cell lines by performing doxycycline-dependent conditional overexpression of the wild type Gsa protein and expression of the gsp oncogene. Although the resulting adenylyl cyclase and cAMP levels were ten-fold lower in the wild type Gsa overexpressing cell line, a sustained MAPKinase ERK1/2 activation was observed in both cell lines. Overexpression of the wild type Gsα protein as the gsp oncogene initiated chronic activation of endogenous PRL synthesis and secretion, as well as chronic activation of ERK1/2-sensitive human PRL and GH promoters.

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