Ets1 blocks terminal differentiation of keratinocytes and induces expression of matrix metalloproteases and innate immune mediators

Abstract

SummaryThe transcription factor Ets1 is normally expressed in the proliferative layer of stratified epithelium, but expression of Ets1 is significantly upregulated in squamous cell carcinomas. How elevated levels of Ets1 impact tumor initiation and progression is not well understood. To determine the biological consequences of overexpression of Ets1, we developed a transgenic mouse model that allows induction of Ets1 expression in keratinocytes of stratified epithelium in a regulatable fashion. Induction of Ets1 during embryonic development results in a dramatic alteration in epidermal structure and function by suppressing the expression of multiple stratum corneum constituents, while at the same time inducing expression of EGF ligands, AP1 transcription factors and matrix metalloproteases. Interestingly, expression of certain immune-related genes, including defensins, chemokines and cytokines was increased as well, suggesting a possible role for immune dysregulation in the promotion of squamous dysplasia. Experiments using cultured mouse keratinocytes indicate that Ets1 can induce expression of some of these mediators in a cell-intrinsic fashion. Collectively, our data reveal that elevated expression of Ets1 has a much broader array of pro-tumorigenic effects on epithelial cells than previously appreciated.

Review of Ets1 structure, function, and roles in immunity

“…Interestingly, myeloblasts harboring E26 do not spontaneously differentiate in culture [129], unlike those harboring AMV, suggesting a role for Ets1 in blocking differentiation of early hematopoietic progenitors. As described above, Ets1 blocks the terminal differentiation of squamous epithelial cells [121, 122] and of B lymphocytes [62]. Thus, together these data would suggest that Ets1 has a common activity of inhibiting cellular differentiation in a number of different contexts.…”

“…Using transgenic mouse models, where we are able to inducibly over-express Ets1 in stratified squamous epithelial cells, we have demonstrated that Ets1 induces a number of pro-oncogenic changes when it is expressed in epithelial cells including a block to terminal differentiation accompanied by high secretion of matrix metalloproteases (Mmps), epidermal growth factor ligands, and inflammatory mediators [121, 122]. It is likely that one or more of these activities of Ets1 contributes to its oncogenic activities in naturally arising tumors.…”

Increased retinoic acid levels through ablation of Cyp26b1 determine the processes of embryonic skin barrier formation and peridermal development

“…Abnormal CE assembly linked to defective barrier acquisition is seen in mouse models with targeted ablation of Arnt and loricrin, triple targeted deletion of involucrin, periplakin and envoplakin, and transgenic Ets1 overexpression in the suprabasal layer (Geng et al, 2006;Koch et al, 2000;Nagarajan et al, 2010;Sevilla et al, 2007). However, the phenotype of the CEs in these knockout mouse models is less severe than in Cyp26b1 -/-mice, suggesting that RA potentially regulates an encompassing group of effectors and structural proteins required for CE assembly.…”

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

“…Transcription factor activated downstream of the Ras-MAPK pathway, involved in homeostasis of squamous epithelia 58 . Involved in CD8 lineage differentiation and acts in part by promoting RUNX3 expression 59 .…”