EGFR enhances Survivin expression through the phosphoinositide 3 (PI-3) kinase signaling pathway.
The ErbB family of receptor tyrosine kinases includes the epidermal growth factor receptor (EGFR), p185/neu/c-erbB2, ErbB3, and ErbB4. Many of these receptors are overexpressed or amplified in various forms of cancers. Previous studies have indicated that activation of erbB molecules contributes to malignant transformation both by promoting cell proliferation through the mitogen-activated protein kinase (MAP kinase) signaling pathway and by preventing apoptosis through the Phosphoinositide 3 kinase (PI-3 kinase) pathway. Disabling erbB receptors converts malignant cells that were resistant to cell death caused by irradiation to cells that are sensitive to apoptosis. Here, we report that an activated form of EGFR can elevate the levels of Survivin, a member of the Inhibitor of Apoptosis Protein (IAP) family implicated in mitotic checkpoint control. Conversely, inactivation of the ErbB receptors reduces the expression levels of Survivin. Furthermore, we found that upregulation of Survivin by EGFR is dependent on the PI-3 kinase pathway but not on the MAP kinase pathway. Indeed, inhibition of PI-3 kinase can diminish Survivin at both the mRNA and the protein levels. Combined with previous findings that Survivin plays a role in control of chromosome segregation and that it is overexpressed in various cancers, our results suggest that EGFR may cause transformation by directly affecting mitosis and increasing chromosome instability.
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Qiang
Q
Wang
Mark I
MI
Greene
D017209:Apoptosis / Q000502:physiology; D015152:Blotting, Northern; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000077022:Survivin
D066246:ErbB Receptors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077022:Survivin; C107489:BIRC5 protein, human