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J. Biol. Chem., Vol. 280, Issue 33, 29904-29911, August 19, 2005

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Hoxb13 Up-regulates Transglutaminase Activity and Drives Terminal Differentiation in an Epidermal Organotypic Model^*

Judith A. Mack¶, Ling Li||, Nobuyuki Sato, Vincent C. Hascall, and Edward V. Maytin

From the Departments of Biomedical Engineering and Dermatology, Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, Ohio 44195 and the ^||College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, Florida 33328

Hox genes act to differentiate and pattern embryonic structures by promoting the proliferation of specific cell types. An exception is Hoxb13, which functions as a proapoptotic and antiproliferative protein during development of the caudal spinal cord and tail vertebrae and has also been implicated in adult cutaneous wound repair. The adult epidermis, which expresses several Hox genes including Hoxb13, is continually renewed in a program of growth arrest, differentiation, and a specialized form of apoptosis (cornification). Yet little is known about the function(s) of these genes in skin. Based on its role during embryogenesis, Hoxb13 is an attractive candidate to be involved in the regulation of epidermal differentiation. Here, we demonstrate that Hoxb13 overexpression in an adult organotypic epidermal model recapitulates actions of Hoxb13 reported in embryonic development. Epidermal cell proliferation is decreased, apoptosis increased, and excessive terminal differentiation observed, as characterized by enhanced transglutaminase activity and excessive cornified envelope formation. Overexpression of Hoxb13 also produces abnormal phenotypes in the epidermal tissue that resemble certain pathological features of dysplastic skin diseases. Our results suggest that Hoxb13 functions to promote epidermal differentiation, a critical process for skin regeneration and for the maintenance of normal barrier function.

Received for publication, May 12, 2005 , and in revised form, June 16, 2005.

^* This work was supported by National Institutes of Health Grants K01 AR51076-01 (to J. A. M.), R01 AR049249-01 (to E. V. M.), and P01 CA84203-4 (to E. V. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Cleveland Clinic Foundation, Lerner Research Institute, Dept. of Biomedical Engineering ND-20, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-445-9308; Fax: 216-444-9198; E-mail: mackj{at}ccf.org.

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