Abstract
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.
Highlights
The E2F family of transcription factors is pivotal in the control of cell proliferation and is involved in patterning during early embryogenesis [1,2,3]
Decreased Integrin Expression and Signaling in E2F-1Ϫ/Ϫ Keratinocytes—To confirm that the above described integrins are down-regulated in mutant keratinocytes, we isolated RNA from wild type and E2F-1Ϫ/Ϫ primary undifferentiated keratinocytes and epidermis and estimated integrin mRNA abundance using a quantitative reverse transcriptionPCR approach [21, 23]
The results of these experiments confirmed that the transcript levels of integrins ␣5, ␣6, 1, and 4 are 2–3-fold lower in mutant keratinocytes (Fig. 1A)
Summary
The E2F family of transcription factors is pivotal in the control of cell proliferation and is involved in patterning during early embryogenesis [1,2,3]. 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. As a consequence of altered integrin expression and function, E2F-1؊/؊ keratinocytes show impaired migration, adhesion to extracellular matrix proteins, and a blunted chemotactic response to transforming growth factor-␥1.
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