Role of 3′-5′-cyclic adenosine monophosphate on the epidermal growth factor dependent survival in mammary epithelial cells

• EGF prevents apoptosis of starved and confluent murine mammary epithelial cells.
• An unexpected raise of cAMP levels was found upon EGFR activation by EGF treatment.
• PI3K/AKT and cAMP/PKA pathways are required for EGF dependent cell survival.
• Both pathways also trigger bcl-XL transcription by activating bcl-X Promoter 1.

Epidermal growth factor (EGF) has been suggested to play a key role in the maintenance of epithelial cell survival during lactation. Previously, we demonstrated that EGF dependent activation of PI3K pathway prevents apoptosis in confluent murine HC11 cells cultured under low nutrient conditions. The EGF protective effect is associated with increased levels of the antiapoptotic protein Bcl-XL. Here, we identify the EGF-dependent mechanism involved in cell survival that converges in the regulation of bcl-X expression by activated CREB. EGF induces Bcl-XL expression through activation of a unique bcl-X promoter, the P1; being not only the PI3K/AKT signaling pathway but also the increase in cAMP levels and the concomitant PKA/CREB activation necessary for both bcl-XL upregulation and apoptosis avoidance. Results presented in this work suggest the existence of a novel connection between the EGF receptor and the adenylate cyclase that would have an impact in preventing apoptosis under low nutrient conditions.

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