HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 29, 20530-20541, July 21, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/29/20530    most recent M602712200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gazel, A. Articles by Blumenberg, M. Search for Related Content PubMed PubMed Citation Articles by Gazel, A. Articles by Blumenberg, M. Social Bookmarking                      What's this?

Inhibition of JNK Promotes Differentiation of Epidermal Keratinocytes^*

Alix Gazel, Tomohiro Banno, Rebecca Walsh, and Miroslav Blumenberg^¶||1

From the Departments of Dermatology, ^¶Biochemistry, and ^||The Cancer Institute, New York University School of Medicine, New York, New York, 10016 and the Dermatology Department, Institute of Clinical Medicine, Tsukuba University, 1-1-1 Tennodai, Ibaraki 305-8575, Japan

In inflamed tissue, normal signal transduction pathways are altered by extracellular signals. For example, the JNK pathway is activated in psoriatic skin, which makes it an attractive target for treatment. To define comprehensively the JNK-regulated genes in human epidermal keratinocytes, we compared the transcriptional profiles of control and JNK inhibitor-treated keratinocytes, using DNA microarrays. We identified the differentially expressed genes 1, 4, 24, and 48 h after the treatment with SP600125. Surprisingly, the inhibition of JNK in keratinocyte cultures in vitro induces virtually all aspects of epidermal differentiation in vivo: transcription of cornification markers, inhibition of motility, withdrawal from the cell cycle, stratification, and even production of cornified envelopes. The inhibition of JNK also induces the production of enzymes of lipid and steroid metabolism, proteins of the diacylglycerol and inositol phosphate pathways, mitochondrial proteins, histones, and DNA repair enzymes, which have not been associated with differentiation previously. Simultaneously, basal cell markers, including integrins, hemidesmosome and extracellular matrix components, are suppressed. Promoter analysis of regulated genes finds that the binding sites for the forkhead family of transcription factors are over-represented in the SP600125-induced genes and c-Fos sites in the suppressed genes. The JNK-induced proliferation appears to be secondary to inhibition of differentiation. The results indicate that the inhibition of JNK in epidermal keratinocytes is sufficient to initiate their differentiation program and suggest that augmenting JNK activity could be used to delay cornification and enhance wound healing, whereas attenuating it could be a differentiation therapy-based approach for treating psoriasis.

Received for publication, March 22, 2006 , and in revised form, April 24, 2006.

^* This work was supported by a grant from the Dystrophic epidermolysis bullosa Research Association (DebRA) UK Foundation with additional support from DebRA of America. 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.

¹ To whom correspondence should be addressed: Dept. of Dermatology, New York University School of Medicine, 550 First Ave., New York, NY 10016. Tel.: 212-263-5924; Fax: 212-263-8752; E-mail: blumem01{at}med.nyu.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Yoshida, N. Kajitani, A. Satsuka, H. Nakamura, and H. Sakai Ras Modifies Proliferation and Invasiveness of Cells Expressing Human Papillomavirus Oncoproteins J. Virol., September 1, 2008; 82(17): 8820 - 8827. [Abstract] [Full Text] [PDF]

				P. Bayo, A. Sanchis, A. Bravo, J. L. Cascallana, K. Buder, J. Tuckermann, G. Schutz, and P. Perez Glucocorticoid Receptor Is Required for Skin Barrier Competence Endocrinology, March 1, 2008; 149(3): 1377 - 1388. [Abstract] [Full Text] [PDF]

				A. T. Black, J. P. Gray, M. P. Shakarjian, D. L. Laskin, D. E. Heck, and J. D. Laskin Distinct effects of ultraviolet B light on antioxidant expression in undifferentiated and differentiated mouse keratinocytes Carcinogenesis, January 1, 2008; 29(1): 219 - 225. [Abstract] [Full Text] [PDF]