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J. Biol. Chem., Vol. 277, Issue 12, 10626-10632, March 22, 2002
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From the Departments of E2F factors are involved in proliferation and
apoptosis. To understand the role of E2F-1 in the epidermis, we
screened wild type and E2F-1
E2F-1 Is Essential for Normal Epidermal Wound Repair*
§¶,,,,§, and§
Pharmacology and Toxicology,
and § Paediatrics, Child Health Research Institute and
Lawson Health Research Institute, University of Western Ontario,
London, Ontario N6A 5C1, Canada
/ keratinocyte
mRNA for genes differentially expressed in the two cell
populations. We demonstrate the reduced expression of integrins 
5, 6, 
1, and
4 in E2F-1/ keratinocytes associated
with reduced activation of Jun terminal kinase and Erk upon integrin
stimulation. As a consequence of altered integrin expression and
function, E2F-1/ keratinocytes also show impaired
migration, adhesion to extracellular matrix proteins, and a blunted
chemotactic response to transforming growth factor-
1.
E2F-1/ keratinocytes, but not dermal
fibroblasts, exhibit altered patterns of proliferation, including
significant delays in transit through both G1 and
S phases of the cell cycle. Recognizing that proliferation and
migration are key for proper wound healing in vivo, we
postulated that E2F-1/ mice may exhibit abnormal
epidermal repair upon injury. Consistent with our hypothesis,
E2F-1/ mice exhibited impaired cutaneous wound healing.
This defect is associated with substantially reduced local inflammatory
responses and rates of re-epithelialization. Thus, we demonstrate
that E2F-1 is indispensable for a hitherto unidentified cell
type-specific and unique role in keratinocyte proliferation, adhesion,
and migration as well as in proper wound repair and epidermal
regeneration in vivo.
*
This work was supported by funds from the Canadian
Institutes of Health Research (CIHR) and, in part, by the J. P. Bickell Foundation and the Lawson Health Research Institute.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.
Recipient of a Cancer Research Society Inc./Canadian
Institutes of Health Research Scholarship. To whom correspondence
should be addressed: Dept. of Pharmacology and Toxicology, Medical
Sciences Bldg., University of Western Ontario, London, ON N6A 5C1,
Canada. Tel.: 519-661-4264; Fax: 519-661-4051; E-mail:
ldagnino@uwo.ca.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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