In earlier studies, we and others have established that activation of EGFR can promote survival in association with upregulation of Bcl-xL. However, the mechanism responsible for upregulation of Bcl-xL is unknown. For the current studies we have chosen pro-apoptotic, c-Myc-overexpressing murine mammary epithelial cells (MMECs) derived from MMTV-c-Myc transgenic mouse tumors. We now demonstrate that EGFR activation promotes survival through Akt and Erk1/2. Blockade of EGFR kinase activity and the PI3-K/Akt and MEK/Erk pathways with pharmacological inhibitors resulted in a significant induction of cellular apoptosis, paralleled by a downregulation of both Akt and Erk1/2 proteins. Consistent with a survival-promoting role of Akt, we observed that constitutively activated Akt (Myr-Akt) inhibited apoptosis of pro-apoptotic, c-Myc-overexpressing cells following the inhibition of EGFR tyrosine kinase activity. In addressing possible downstream effectors of EGFR through activated Akt, we detected significant upregulation of Bcl-xL protein, suggesting this pro-survival protein is a target of Akt in MMECs. By using pharmacological inhibitors of PI3-K/Akt and MEK/Erk together with dominant-negative Akt and Erk1 we observed the decrease in Bcl-xL protein. Our findings may be of importance for understanding the emerging role of Bcl-xL as a potential marker of poor prognosis in breast cancer.
|Original language||English (US)|
|Number of pages||14|
|Journal||Experimental Cell Research|
|State||Published - Jul 15 2003|
- Epidermal growth factor receptor
ASJC Scopus subject areas
- Cell Biology