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Endocrine Abstracts (2013) 31 PL3 | DOI: 10.1530/endoabs.31.PL3

University of Milan, Milan, Italy.


cAMP is implicated in the regulation of a variety of cell functions that are related to activation of multiple intracellular pathways. In addition to the control of differentiated functions, such as hormone secretion, cAMP inhibits or stimulates cell proliferation depending on the cell type. In particular, consistent with the frequent expression of somatic mutations constitutively activating Gs alpha subunit (gsp oncogene) in GH-secreting adenomas, the activation of cAMP dependent pathway generates proliferative signals in somatotrophs. Conversely, this stimulatory effect is not present, or even reverted in an inhibitory one, in pituitary cells of the lactotroph and gonadotroph lineages, such as human prolactinomas and non-functioning adenomas, as well as the corresponding cell lines (MMQ and HP75). The discrepant responsiveness to cAMP increase is restricted to cell proliferation and cell cycle protein induction, since the stimulatory effects on hormone secretion are maintained in all cell types. Although cAMP effects were initially attributed to protein phosphorylation through the activation of protein kinase A (PKA), other factors, such as the two cAMP-activated guanine nucleotide exchange factors (Epac one and two), have recently been identified as allosteric modulators of cAMP action. While the role of Epac induced activation of Rap1 has been investigated in other endocrine cell systems, such as the thyroid and the adrenal, the impact of this pathway on pituitary cells is still undefined. Recent data in the lab indicate that the stimulatory effect of cAMP on somatotrophs proliferation and the inhibitory effect on lactotrophs and gonadotrophs growth are mimicked by the PKA- and Epac-selective cAMP analogs. Moreover, these agents act synergistically in regulating cell proliferation and hormone secretion. These data rule out the involvement of Epac-generated signals on the divergent effects of cAMP in pituitary cells of different types, suggesting possible different expression and/or function of the cAMP and Ras-Raf-ERK cross-signalling components.

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