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(American Journal of Pathology. 2006;168:1821-1837.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051027

A Keratinocyte Hypermotility/Growth-Arrest Response Involving Laminin 5 and p16^INK4A Activated in Wound Healing and Senescence

Easwar Natarajan^*, John D. Omobono, II^*, Zongyou Guo^*, Susan Hopkinson, Alexander J.F. Lazar, Thomas Brenn, Jonathan C. Jones and James G. Rheinwald^*

From the Departments of Dermatology^* and Pathology, Brigham and Women’s Hospital, Harvard Skin Disease Research Center, Harvard Medical School, Boston, Massachusetts; and the Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois

Keratinocytes become migratory to heal wounds, during early neoplastic invasion, and when undergoing telomere-unrelated senescence in culture. All three settings are associated with expression of the cell cycle inhibitor p16^INK4A (p16) and of the basement membrane protein laminin 5 (LN5). We have investigated cause-and-effect relationships among laminin 5, p16, hypermotility, and growth arrest. Plating primary human keratinocytes on the 2 precursor form of laminin 5 (LN5') immediately induced directional hypermotility at 125 µm/hour, followed by p16 expression and growth arrest. Cells deficient in p16 and either p14^ARF or p53 became hypermotile in response to LN5' but did not arrest growth. Plating on LN5' triggered smad nuclear translocation, and all LN5' effects were blocked by a transforming growth factor (TGF) ß receptor I (TGFßRI) kinase inhibitor. In contrast, plating cells on collagen I triggered a TGFßRI kinase-independent hypermotility unaccompanied by smad translocation or growth arrest. Plating on control surfaces with TGFß induced hypermotility after a 1-day lag time and growth arrest by a p16-independent mechanism. Keratinocytes serially cultured with TGFßRI kinase inhibitor exhibited an extended lifespan, and immortalization was facilitated following transduction to express the catalytic subunit of telomerase (TERT). These results reveal fundamental features of a keratinocyte hyper-motility/growth-arrest response that is activated in wound healing, tumor suppression, and during serial cul-ture.

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