title: The expression of keratin k10 in the basal layer of the epidermis inhibits cell proliferation and prevents skin tumorigenesis.
abstract: Forced expression of K10, a keratin normally expressed in postmitotic, terminally differentiating epidermal keratinocytes, inhibits the progression of the cell cycle in cultured cells (Paramio, J. M., Casanova, M. Ll., Segrelles, C., Mittnacht, S., Lane, E. B., and Jorcano, J. L. (1999) Mol. Cell. Biol. 19, 3086-3094). This process requires a functional retinoblastoma (pRb) gene product and is mediated by K10-induced inhibition of Akt and PKCzeta, two signaling intermediates belonging to the phosphoinositide (PI) 3-kinase signal transduction pathway (Paramio, J. M., Segrelles, C., Ruiz, S., and Jorcano, J. L. (2001) Mol. Cell. Biol. 21, 7449-7459). Extending earlier in vitro studies to the in vivo situation, this work analyzes the alterations found in transgenic mice that ectopically express K10 in the proliferative basal cells of the epidermis. Increased expression of K10 led to a hypoplastic and hyperkeratotic epidermis due to a dramatic decrease in skin keratinocyte proliferation in association with the inhibition of Akt and PKCzeta activities. The inhibition of cell proliferation and Akt and PKCzeta activities was also observed although to a minor extent in low hK10-expressing mice. These animals displayed no overt epidermal phenotype nor overexpression of K10. In these non-phenotypic mice, ectopic K10 expression also resulted in decreased skin tumorigenesis. Collectively, these data demonstrate that keratin K10 in vivo functions include the control of epithelial proliferation in skin epidermis.
authors.affiliation: Project on Cell and Molecular Biology and Gene Therapy, CIEMAT Av. Complutense 22, E-28040 Madrid, Spain.
authors.forename: Mirentxu
authors.initials: M
authors.lastname: Santos
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Paramio
authors.forename: Ana
authors.initials: A
authors.lastname: Bravo
authors.forename: Angel
authors.initials: A
authors.lastname: Ramirez
authors.forename: José L
authors.initials: JL
authors.lastname: Jorcano
mesh_terms: D000818:Animals; D002455:Cell Division; D000078404:Epidermal Cells; D004817:Epidermis / Q000201:enzymology / Q000378:metabolism*; D007633:Keratins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012878:Skin Neoplasms / Q000517:prevention & control*
chemical_list: D011518:Proto-Oncogene Proteins; D007633:Keratins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt