Effects of Endogenous Epidermal Growth Factor Receptor Signaling on DNA Synthesis and ERK Activation in a Cytokine-Dependent Hematopoietic Cell Line

Abstract

Epidermal growth factor (EGF) is commonly thought to affect the proliferation of many cells, especially epithelial cells. Aberrant expression of the receptor for EGF, (EGFR) or members of the EGFR family is often implicated in the etiology of many cancers. Ligation of the EGFR results in the activation of many downstream signaling pathways which have profound effects on cell cycle progression and the prevention of apoptosis. In general, the EGFR is thought to be either not expressed or expressed at low levels in hematopoietic cells. We determined that the EGFR was expressed at a low level in the murine cytokine-dependent hematopoietic cell line FDC-P1 but not in an additional murine IL-3 dependent cell line FL5. EGF induced a mild effect on DNA synthesis and ERK activation in EGFR positive FDC-P1 cells but not EGFR negative FL5.12 cells. Addition of suboptimal concentrations of IL-3 synergized with EGF in stimulating DNA synthesis in EGFR-positive FDC-P1 cells. Likewise, the EGFR inhibitor AG1478 induced apoptosis in EGFR positive FDC-P1 cells but not EGFR negative FL5.12 cells. Both cell lines can be directly transformed to cytokine independence by activated EGFR (v-ERBB) expression in the absence of autocrine growth factors indicating that they are poised to fully utilize EGFR mediated signal transduction pathways as a means for proliferation. These results document the functional importance of endogenous EGFR signaling pathway in some hematopoietic cells.

Targeting prostate cancer based on signal transduction and cell cycle pathways

“…[363][364][365][366][367][368][369] Recently, we reported that Akt activation can lead to inactivation of the MAPK pathway via Raf-1. 329 The results of these studies have importance in many arenas of prostatic research: disease progression and etiology, therapeutic efficacy and resistance to chemotoxic compounds.…”

Akt inactivates ERK causing decreased response to chemotherapeutic drugs in advanced CaP cells

“…In previous publications, we have reported that the PI3K/Akt/ PTEN and Raf/MEK/ERK signaling pathways have synergistic effects which lead to the transformation of hematopoietic cells. [45][46][47][48][49][50][51][52] Here, we report that Akt activation can lead to inactivation of the MAPK pathway via Raf-1. The results of these studies have importance in many arenas of prostatic research: disease progression and etiology, therapeutic efficacy and resistance to chemotoxic compounds.…”

EGF Induces Cell Motility and Multi-Drug Resistance Gene Expression in Breast Cancer Cells

“…13,14 The epidermal growth factor (EGF) receptor (EGFR) pathway is a clear example of a signal transduction pathway that has been associated with development, progression, and resistance to treatment with cytotoxic drugs of a number of human solid tumors including breast. [17][18][19][20][21][22][23][24][25][26] EGFR is part of the tyrosine kinase receptor family that also includes erbB2, erbB3, and erbB4. 20 EGFR are large proteins, which reside in the cell membrane and with the exception of erbB2 each has a specific extracellular ligand-binding domain, a transmembrane and intracellular domain, which has tyrosine kinase activity.…”