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Trafficking of Nuclear Heparin-Binding Epidermal Growth Factor–like Growth Factor into an Epidermal Growth Factor Receptor–Dependent Autocrine Loop in Response to Oxidative Stress

The Urological Diseases Research Center, Childrens Hospital, and Departments of Surgery and Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Michael R. Freeman Enders Research Laboratories, Room 1161, 300 Longwood Avenue, Boston, MA 02115. Phone: 617-919-2644; Fax: 617-730-0238; E-mail: michael.freeman{at}childrens.harvard.edu.

Heparin-binding epidermal growth factor (EGF)–like growth factor (HB-EGF) accumulates in the nucleus in aggressive transitional cell carcinoma (TCC) cells and this histologic feature is a marker of poor prognosis in human bladder cancer tissues. Here we report that HB-EGF can be exported from the nucleus during stimulated processing and secretion of the growth factor. Production of reactive oxygen species (ROS) resulted in mobilization of the HB-EGF precursor, proHB-EGF, from the nucleus of TCCSUP bladder cancer cells to a detergent-resistant membrane compartment, where the growth factor was cleaved by a metalloproteinase-mediated mechanism and shed into the extracellular space. Inhibition of nuclear export suppressed HB-EGF shedding. Production of ROS resulted in EGF receptor (EGFR) and Akt1 phosphorylation in HB-EGF–expressing cells. HB-EGF also stimulated cell proliferation and conferred cytoprotection when cells were challenged with cisplatin. These findings show that the nucleus can serve as an intracellular reservoir for a secreted EGFR ligand and, thus, can contribute to an autocrine loop leading to cell proliferation and protection from apoptotic stimuli.

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