E2F-1 is essential for normal epidermal wound repair.
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(-/-) keratinocyte mRNA for genes differentially expressed in the two cell populations. We demonstrate the reduced expression of integrins alpha(5), alpha(6), beta(1), and beta(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-gamma1. E2F-1(-/-) keratinocytes, but not dermal fibroblasts, exhibit altered patterns of proliferation, including significant delays in transit through both G(1) 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.
D'Souza
Sudhir Jude Anthony
SJ
Department of Pharmacology, Child Health Research Institute, University of Western Ontario, London, Ontario N6A 5C1, Canada.
Vespa
Alisa
A
Murkherjee
Suranjana
S
Maher
Amy
A
Pajak
Agnieszka
A
Dagnino
Lina
L
D000818:Animals; D002448:Cell Adhesion; D018797:Cell Cycle Proteins; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology*; D016193:G1 Phase; D017403:In Situ Hybridization; D016023:Integrins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology*; D014945:Wound Healing
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D016023:Integrins; D014157:Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases