Aberrant epidermal differentiation and disrupted ΔNp63/Notch regulatory axis in Ets1 transgenic mice

The transcription factor Ets1 is expressed at low levels in epidermal keratinocytes under physiological conditions, but is over-expressed in cutaneous squamous cell carcinoma (SCC). We previously showed that over-expression of Ets1 in differentiated keratinocytes of the skin leads to significant pro...

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Bibliographic Details
Published in:Biology open 2013-12, Vol.2 (12), p.1336-1345
Main Authors: Chin, Shu Shien, Romano, Rose-Anne, Nagarajan, Priyadharsini, Sinha, Satrajit, Garrett-Sinha, Lee Ann
Format: Article
Language:English
Subjects:
Differentiation
Embryogenesis
Embryonic growth stage
Epidermis
Ets-1 protein
Gene expression
Hyperplasia
Keratinocytes
Notch
Notch protein
Overexpression
Phenotypes
Physiological effects
Signal transduction
Signaling
Skin
Squamous cell carcinoma
Stem cell transplantation
Stem cells
Transcription
Transgenic mice
Tumorigenesis
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Summary:The transcription factor Ets1 is expressed at low levels in epidermal keratinocytes under physiological conditions, but is over-expressed in cutaneous squamous cell carcinoma (SCC). We previously showed that over-expression of Ets1 in differentiated keratinocytes of the skin leads to significant pro-tumorigenic alterations. Here, we further extend these studies by testing the effects of over-expressing Ets1 in the proliferative basal keratinocytes of the skin, which includes the putative epidermal stem cells. We show that induction of the Ets1 transgene in the basal layer of skin during embryogenesis results in epidermal hyperplasia and impaired differentiation accompanied by attenuated expression of spinous and granular layer markers. A similar hyper-proliferative skin phenotype was observed when the transgene was induced in the basal layer of the skin of adult mice leading to hair loss and open sores. The Ets1-mediated phenotype is accompanied by a variety of changes in gene expression including alterations in Notch signaling, a crucial mediator of normal skin differentiation. Finally, we show that Ets1 disrupts Notch signaling in part via its ability to upregulate ΔNp63, an established transcriptional repressor of several of the Notch receptors. Given the established tumor suppressive role for Notch signaling in skin tumorigenesis, the demonstrated ability of Ets1 to interfere with this signaling pathway may be important in mediating its pro-tumorigenic activities.
ISSN:2046-6390
2046-6390
DOI:10.1242/bio.20135397