Membrane-Tethered Intracellular Domain of Amphiregulin Promotes Keratinocyte Proliferation
Copyright policy )Membrane-Tethered Intracellular Domain of Amphiregulin Promotes Keratinocyte Proliferation
The epidermal growth factor receptor (EGFR) and its ligands are essential regulators of epithelial biology, which are often amplified in cancer cells. We have previously shown that shRNA-mediated silencing of one of these ligands, amphiregulin (AREG), results in keratinocyte growth arrest that cannot be rescued by soluble extracellular EGFR ligands. To further explore the functional importance of specific AREG domains, we stably transduced keratinocytes expressing tetracycline-inducible AREG-targeted shRNA with lentiviruses expressing silencing-proof, membrane-tethered AREG cytoplasmic and extracellular domains (AREG-CTD and AREG-ECD), as well as full-length AREG precursor (proAREG). Here we show that growth arrest of AREG-silenced keratinocytes occurs in G2/M and is significantly restored by proAREG and AREG-CTD but not by AREG-ECD. Moreover, the AREG-CTD was sufficient to normalize cell cycle distribution profiles and expression of mitosis-related genes. Our findings uncover an important role of the AREG-CTD in regulating cell division, which may be relevant to tumor resistance to EGFR-directed therapies.
- Instituto de Investigación Marqués de Valdecilla Spain
- University of Michigan–Ann Arbor United States
- University of Michigan–Flint United States
Keratinocytes, EGF Family of Proteins, Blotting, Western, Fluorescent Antibody Technique, Enzyme-Linked Immunosorbent Assay, Dermatology, Real-Time Polymerase Chain Reaction, Biochemistry, Amphiregulin, Mice, Animals, Humans, Gene Silencing, RNA, Messenger, RNA, Small Interfering, Molecular Biology, Cells, Cultured, Cell Proliferation, Mice, Knockout, Cell Biology, Flow Cytometry, ErbB Receptors, Gene Expression Regulation, Signal Transduction
Keratinocytes, EGF Family of Proteins, Blotting, Western, Fluorescent Antibody Technique, Enzyme-Linked Immunosorbent Assay, Dermatology, Real-Time Polymerase Chain Reaction, Biochemistry, Amphiregulin, Mice, Animals, Humans, Gene Silencing, RNA, Messenger, RNA, Small Interfering, Molecular Biology, Cells, Cultured, Cell Proliferation, Mice, Knockout, Cell Biology, Flow Cytometry, ErbB Receptors, Gene Expression Regulation, Signal Transduction
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