Co-expression of p16INK4A and laminin 5 by keratinocytes: a wound-healing response coupling hypermotility with growth arrest that goes awry during epithelial neoplastic progression.
The replicative lifespan of human keratinocytes in culture is restricted by a telomere-unrelated induction of p16INK4A (p16) and p14ARF. We have found that, in vivo, p16 is expressed by epidermal and oral keratinocytes at the migrating fronts of healing wounds and at the stromal interface of severely dysplastic and early invasive lesions and that such cells also invariably display increased expression of Laminin 5 (Lam5). In culture, p16 and Lam5 are coexpressed in keratinocytes at senescence, at the edges of wounds made in confluent cultures, and when cells are plated on dishes coated with the gamma2 precursor form of Lam5 (Lam5gamma2pre). Lam5/p16 coexpression in all three in vitro settings is associated with directional hypermotility and growth arrest. Hypermotility and growth arrest are uncoupled in p16- and p14ARF/p53-deficient keratinocytes and squamous cell carcinoma (SCC) cells; such cells become hypermotile is response to Lam5gamma2pre but do not growth arrest. Thus, the Lam5/p16 response is activated in normal wound healing, causing growth arrest of migratory keratinocytes that lead wound reepithelialization. This response also becomes activated at a critical stage of neoplastic progression, acting as a tumor suppressor mechanism. Rare premalignant cells that lose p16 remain motile and proliferative, thereby resulting in invasive growth as SCC.
Natarajan
Easwar
E
Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Omobono
John D
JD
Jones
Jonathan C
JC
Rheinwald
James G
JG
D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis* / Q000502:physiology; D018450:Disease Progression; D006801:Humans; D015603:Keratinocytes / Q000737:chemistry* / Q000502:physiology; D007797:Laminin / Q000032:analysis* / Q000502:physiology; D009375:Neoplasms, Glandular and Epithelial / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D014945:Wound Healing
D019941:Cyclin-Dependent Kinase Inhibitor p16; C400567:LAMC2 protein, human; D007797:Laminin; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53