Role of AKT and CREB on EGF-dependent Bcl-X expression in mammary epithelial cells

GRINMAN, D; ROMORINI, L.; DAVIO, C; PECCI, A

Bariloche

Workshop; SISTAM 2012; 2012

Apoptosis is intrinsically regulated by Bcl-2 protein family members, among others. In HC11 mammary epithelial cells, EGF acts as a survival factor and blocks apoptosis of confluent and starved cells by increasing the expression of the antiapopotic Bcl-XL protein. This protective effect is due to the activation of the bcl-x gen’s promoter 1 (P1), being PI3K/AKT the main pathway involved in this process. In silico analysis of P1 and posterior over-expression of different transcription factors, reveal CREB as a potential mediator for the EGF-dependent expression of Bcl-XL. EGF increased phosphorylation levels of both AKT and CREB in HC11 cells growing in an apoptotic context. Bcl-XL mRNA induction was prevented when AKT activation was blocked by the comercial inhibitors B2311 and A6730, while CREB phosphorylation levels remained unaltered. Surprisingly, EGF treatment increased cAMP levels in a time-dependent way. Conclusions: AKT activity is relevant in the EGF-dependent Bcl-XL upregulation and consequently in the antiapoptotic effect. In addition, although preliminary, these results suggest that EGF can activate the PKA signaling pathway, by increasing cAMP levels throughout a still unknown mechanism. CREB activation by EGF may result in a parallel pathway modulating bcl-x P1 activation.