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Originally published In Press as doi:10.1074/jbc.M201001200 on March 11, 2002

J. Biol. Chem., Vol. 277, Issue 21, 19122-19130, May 24, 2002
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The Expression of Keratin K10 in the Basal Layer of the Epidermis Inhibits Cell Proliferation and Prevents Skin Tumorigenesis*

Mirentxu SantosDagger §, Jesús M. ParamioDagger §, Ana Bravo||, Angel RamirezDagger , and José L. JorcanoDagger

From the Dagger  Project on Cell and Molecular Biology and Gene Therapy, CIEMAT Av. Complutense 22, E-28040 Madrid, Spain and the || Department of Animal Pathology, Veterinary School, University of Santiago de Compostela, Lugo E-27002, Spain

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 hypoplasic 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.

* This work was partially funded by Grant PB94-1230 from the Spanish DGICYT (Dirección General de Investigación Científica y Tecnológica).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Both authors contributed equally to this work.

To whom correspondence should be addressed. Tel.: 34-91-3466598; Fax: 34-91-3466484; E-mail: jesusm.paramio@ciemat.es.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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