A central role of Bcl-X-L in the regulation of keratinocyte survival by autocrine EGFR ligands

The epidermal growth factor receptor has multiple roles in epidermal biolog y relating to growth, migration, and, as shown recently, survival of kerati nocytes. In cultured keratinocytes activation of the epidermal growth facto r receptor upregulates expression of Bcl-X-L, an anti-apoptotic Bcl-2 homol og. The functional contribution of epidermal growth factor receptor-depende nt Bcl-x(L) expression to keratinocyte survival is poorly understood. Here we demonstrate that inhibition of the epidermal growth factor receptor tyro sine kinase activity with either an epidermal growth factor receptor antago nistic monoclonal antibody (MoAb 425) or an epidermal growth factor recepto r-selective tyrosine kinase inhibitor (AG 1478) downregulated Bcl-x(L) expr ession in normal human keratinocytes but had no effect on expression of the pro-apoptotic Bcl-2 homologs Bad, Bak, and Bar. Bovine pituitary extract a nd insulin partially alleviated both, downregulation of Bcl-x(L) expression and cell death upon epidermal growth factor receptor inhibition. Forced ex pression of Bcl-x(L) attenuated cell death of immortalized keratinocytes (H aCaT) induced by either forced suspension (anoikis) or by epidermal growth factor receptor blockade. These results demonstrate that epidermal growth f actor receptor-dependent signaling pathways control the balance of pro-apop totic and anti-apoptotic Bcl-2 family members expressed in normal keratinoc ytes. Inappropriate survival supported by aberrant signaling through the ep idermal growth factor receptor may contribute to the pathogenesis of psoria sis and of squamous cell carcinomas.