TY - JOUR
T1 - A keratinocyte hypermotility/growth-arrest response involving laminin 5 and p16INK4A activated in wound healing and senescence
AU - Natarajan, Easwar
AU - Omobono, John D.
AU - Guo, Zongyou
AU - Hopkinson, Susan
AU - Lazar, Alexander J.F.
AU - Brenn, Thomas
AU - Jones, Jonathan C.
AU - Rheinwald, James G.
N1 - Funding Information:
Supported by grants R01DE13178 and PO1DE12467 from National Institutes of Health to J.G.R., by the Harvard Skin Disease Research Center grant P30AR42689 , and by grants RO1DK60589 and PO1DE12328 to J.C.J.
PY - 2006/6
Y1 - 2006/6
N2 - 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 γ2 precursor form of laminin 5 (LNS′) immediately induced directional hypermotility at ∼125 μm/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) β receptor I (TGFβRI) kinase inhibitor. In contrast, plating cells on collagen I triggered a TGFβRI kinase-independent hypermotility unaccompanied by smad translocation or growth arrest. Plating on control surfaces with TGFβ induced hypermotility after a 1-day lag time and growth arrest by a p16-independent mechanism. Keratinocytes serially cultured with TGFβRI 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 hypermotility/growth-arrest response that is activated to wound healing, tumor suppression, and during serial cul-ture.
AB - 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 γ2 precursor form of laminin 5 (LNS′) immediately induced directional hypermotility at ∼125 μm/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) β receptor I (TGFβRI) kinase inhibitor. In contrast, plating cells on collagen I triggered a TGFβRI kinase-independent hypermotility unaccompanied by smad translocation or growth arrest. Plating on control surfaces with TGFβ induced hypermotility after a 1-day lag time and growth arrest by a p16-independent mechanism. Keratinocytes serially cultured with TGFβRI 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 hypermotility/growth-arrest response that is activated to wound healing, tumor suppression, and during serial cul-ture.
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U2 - 10.2353/ajpath.2006.051027
DO - 10.2353/ajpath.2006.051027
M3 - Article
C2 - 16723698
AN - SCOPUS:33744732501
SN - 0002-9440
VL - 168
SP - 1821
EP - 1837
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -