A keratinocyte hypermotility/growth-arrest response involving laminin 5 and p16INK4A activated in wound healing and senescence

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

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 p16INK4A (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 gamma2 precursor form of laminin 5 (LN5') immediately induced directional hypermotility at approximately 125 microm/hour, followed by p16 expression and growth arrest. Cells deficient in p16 and either p14ARF 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) beta receptor I (TGFbetaRI) kinase inhibitor. In contrast, plating cells on collagen I triggered a TGFbetaRI kinase-independent hypermotility unaccompanied by smad translocation or growth arrest. Plating on control surfaces with TGFbeta induced hypermotility after a 1-day lag time and growth arrest by a p16-independent mechanism. Keratinocytes serially cultured with TGFbetaRI 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 culture.

Original languageEnglish
Pages (from-to)1821-37
Number of pages17
JournalThe American Journal of Pathology
Volume168
Issue number6
DOIs
Publication statusPublished - Jun 2006

Keywords / Materials (for Non-textual outputs)

  • Cell Adhesion Molecules
  • Cell Aging
  • Cell Culture Techniques
  • Cell Movement
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p16
  • Female
  • Humans
  • Keratinocytes
  • Male
  • Receptors, Transforming Growth Factor beta
  • Tumor Suppressor Protein p14ARF
  • Wound Healing

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