Plates-Formes de Recherche en Neurosciences

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Équipe A. Barlier

Accueil > Recherche > Équipe A. Barlier > Annonces > PhD défense : Morgane PERTUIT

PhD défense : Morgane PERTUIT

PhD défense :L12/22/2009 ’la salle des thèses de la Faculté de Médecine, Secteur Nord.

ABSTRACT

The aim of this work was to investigate (i) the proteins of the intracellular signaling network involved in cross-talk mechanisms which are crucial for the control of somatotroph physiology (ii) alterations of those proteins in somatotroph physiopathology. In the somatolactotroph GH4C1 cell line, we show that the MAPK ERK1/2 cascade, which dialogues with the cAMP pathway, also dialogues with the PI3K pathway. The PI3K/Akt/Rap1/Raf-1 cascade exerts dual regulatory effects on both the MAPK pathway and prolactin (PRL) release : negative effects in unstimulated cells and positive ones in IGF-1-stimulated cells. Alterations of the cAMP pathway (gsp oncogene and wild-type Gsα over-expression) are associated with somatotroph pathology. Using GH4C1 cell lines with conditional Gsα expression, we show for the first time that wild-type Gsα over-expression as the gsp oncogene expression initiates a chronic ERK activation correlated with a chronic activation of PRL and GH promoters. We show that such disorders induced by the gsp oncogene expression disrupt the cellular response sensitivity to VIP but not to EGF, are PKA/cAMP dependent and involve the Src kinases. The gsp oncogene expression initiates the activation of the Ras and Rap1 proteins which are both recruited for the ERK hyperactivation and the chronic activation of PRL promoter. Interestingly the Ras GTPase, which is a negative regulator in the physiological control of PRL activation by the cAMP pathway, becomes a positive regulator in a physiopathological context when the gsp oncogene is expressed. Those findings provide evidence that the ERK cascade take centre stage in the regulation of somatotroph physiology and physiopathology.

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