Epidermal growth factor inhibition of c-Myc-mediated apoptosis through Akt and Erk involves Bcl-xL upregulation in mammary epithelial cells

Danica Ramljak, Christine M. Coticchia, Tagvor G. Nishanian, Motoyasu Saji, Matthew D. Ringel, Suzanne D. Conzen, Robert B. Dickson

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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 languageEnglish (US)
Pages (from-to)397-410
Number of pages14
JournalExperimental Cell Research
Volume287
Issue number2
DOIs
StatePublished - Jul 15 2003
Externally publishedYes

Keywords

  • Akt
  • Bcl-x
  • C-Myc
  • Epidermal growth factor receptor
  • Erk

ASJC Scopus subject areas

  • Cell Biology

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