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J. Biol. Chem., Vol. 276, Issue 35, 32844-32853, August 31, 2001
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From the Department of Dermatology, University of Rochester School
of Medicine and Dentistry, Rochester, New York 14642 and the Universite
du Droit et de la Sante, Faculte de Medecine, INSERM U 459, 1 Place de
Verdun, 59045 Lille Cedex, France
Keratinocyte proliferation and
differentiation result from expression of specific groups of genes
regulated by unique combinations of transcription factors. To better
understand these regulatory processes, we studied HOXA7
expression and its regulation of differentiation-specific keratinocyte
genes. We isolated the homeobox transcription factor HOXA7 from
keratinocytes through binding to a
differentiation-dependent viral enhancer and analyzed its
effect on endogenous differentiation-dependent genes,
primarily transglutaminase 1. HOXA7 overexpression
repressed transglutaminase 1-reporter activity. HOXA7
message markedly decreased, and transglutaminase RNA increased, upon
phorbol ester-induced differentiation, in a protein kinase
C-dependent manner. Overexpression of HOXA7 attenuated the
transglutaminase 1 induction by phorbol ester,
demonstrating that HOXA7 expression is inversely related to
keratinocyte differentiation, and to transglutaminase 1 expression. Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating
that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes. In keeping with these observations, epidermal growth factor receptor activation stimulated HOXA7
expression. HOX genes function in groups, and we found that
HOXA5 and HOXB7 were also down-regulated by
phorbol ester. These results provide the first example of protein
kinase C-mediated homeobox gene regulation in keratinocytes, and new
evidence that HOXA7, potentially in conjunction with HOXA5 and HOXAB7,
silences differentiation-specific genes during keratinocyte
proliferation, that are then released from inhibition in response to
differentiation signals.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF026397.
Human Homeobox HOXA7 Regulates Keratinocyte
Transglutaminase Type 1 and Inhibits Differentiation*
and
*
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.
To whom correspondence should be addressed: Dept. of Dermatology,
University of Rochester School of Medicine and Dentistry, Box 697, 601 Elmwood Ave., Rochester, NY 14642. Tel.: 716-275-9400; Fax:
716-273-1346; E-mail:
peter_lacelle@urmc.rochester.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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