The p53-S100A2 Positive Feedback Loop Negatively Regulates Epithelialization in Cutaneous Wound Healing

Abstract

The S100A2 protein is an important regulator of keratinocyte differentiation, but its role in wound healing remains unknown. We establish epithelial-specific S100A2 transgenic (TG) mice and study its role in wound repair using punch biopsy wounding assays. In line with the observed increase in proliferation and migration of S100A2-depleted human keratinocytes, mice expressing human S100A2 exhibit delayed cutaneous wound repair. This was accompanied by the reduction of re-epithelialization as well as a slow, attenuated response of Mcp1, Il6, Il1β, Cox2, and Tnf mRNA expression in the early phase. We also observed delayed Vegfa mRNA induction, a delayed enhancement of the Tgfβ1-mediated alpha smooth muscle actin (α-Sma) axis and a differential expression of collagen type 1 and 3. The stress-activated p53 tumor suppressor protein plays an important role in cutaneous wound healing and is an S100A2 inducer. Notably, S100A2 complexes with p53, potentiates p53-mediated transcription and increases p53 expression both transcriptionally and posttranscriptionally. Consistent with a role of p53 in repressing NF-κB-mediated transcriptional activation, S100A2 enhanced p53-mediated promoter suppression of Cox2, an early inducible NF-κB target gene upon wound injury. Our study thus supports a model in which the p53-S100A2 positive feedback loop regulates wound repair process.

Exploring the wound healing, anti-inflammatory, anti-pathogenic and proteomic effects of lactic acid bacteria on keratinocytes

“…It enhances cellular migration 51 , chemotaxis, and skin cancer metastasis 52 , by interacting with components of the motility apparatus such as tropomyosin and actin cytoskeleton 53 . Although mice expressing human S100A2 exhibited delayed wound repair 54 , it has been showed that S100A2 knockdown reduces the TGF-β1-induced cell migration 52 . Other proteins strongly induced in keratinocytes after treatment with SGL07, such as casein kinase II subunit alpha 3 and ribosome-binding protein 1, or after treatment with SGL19, such as actin aortic smooth muscle, are directly implicated in cell migration 55 – 57 .…”

Friend or Foe: S100 Proteins in Cancer

“…Additionally, it was shown that some S100 proteins, namely S100A2, S100A4, S100A14, and S100B interact with p53 [51][52][53][54]. The transcription factor p53 is an important tumour suppressor, and among other functions also regulates DNA replication and induces the transcription of pro-apoptotic proteins such as phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) and p53 upregulated modulator of apoptosis (PUMA) [55].…”

USP15 Enhances Re-epithelialization Through Deubiquitinating EIF4A1 During Cutaneous Wound Repair

“…Previous studies have demonstrated that keratinocyte function is essential in wound repair. For example, mice expressing human S100A2 exhibited delayed cutaneous wound repair, and the p53-S100A2 feedback loop impairs re-epithelialization in wound healing ( Pan et al, 2018 ). Therapeutically, adipose stem cell-derived exosomes combined with hyaluronic acid significantly accelerated wound healing through promoting epithelialization and angiogenesis ( Liu et al, 2019 ).…”