This Article Full Text Full Text (PDF) Supplemental Material Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Natarajan, E. Articles by Rheinwald, J. G. Search for Related Content PubMed PubMed Citation Articles by Natarajan, E. Articles by Rheinwald, J. G.

(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.

This article has been cited by other articles:

				S. Dabelsteen, P. Hercule, P. Barron, M. Rice, G. Dorsainville, and J. G. Rheinwald Epithelial Cells Derived from Human Embryonic Stem Cells Display P16INK4A Senescence, Hypermotility, and Differentiation Properties Shared by Many P63+ Somatic Cell Types Stem Cells, June 1, 2009; 27(6): 1388 - 1399. [Abstract] [Full Text] [PDF]

				E. A. Mroz, A. H. Baird, W. A. Michaud, and J. W. Rocco COOH-Terminal Binding Protein Regulates Expression of the p16INK4A Tumor Suppressor and Senescence in Primary Human Cells Cancer Res., August 1, 2008; 68(15): 6049 - 6053. [Abstract] [Full Text] [PDF]

				M. L. Usui, J. N. Mansbridge, W. G. Carter, M. Fujita, and J. E. Olerud Keratinocyte Migration, Proliferation, and Differentiation in Chronic Ulcers From Patients With Diabetes and Normal Wounds J. Histochem. Cytochem., July 1, 2008; 56(7): 687 - 696. [Abstract] [Full Text] [PDF]

				A. P. Petty, K. L. Garman, V. D. Winn, C. M. Spidel, and J. S. Lindsey Overexpression of Carcinoma and Embryonic Cytotrophoblast Cell-Specific Mig-7 Induces Invasion and Vessel-Like Structure Formation Am. J. Pathol., May 1, 2007; 170(5): 1763 - 1780. [Abstract] [Full Text] [PDF]