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

Shin-Chen Pan, Che Yu Li, Chia Yi Kuo, Yi Zih Kuo, Wei Yu Fang, Yu Hsuan Huang, Tzu Chin Hsieh, Hung Ying Kao, Yuan Kuo, Ya Rong Kang, Wan Chi Tsai, Sen-Tien Tsai, Li-Wha Wu

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Article number5458
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

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Wound Healing
Skin
Wounds and Injuries
Keratinocytes
Re-Epithelialization
Tumor Suppressor Protein p53
Messenger RNA
Collagen Type III
Collagen Type I
Transgenic Mice
Transcriptional Activation
Smooth Muscle
Actins
Biopsy
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • General

Cite this

Pan, Shin-Chen ; Li, Che Yu ; Kuo, Chia Yi ; Kuo, Yi Zih ; Fang, Wei Yu ; Huang, Yu Hsuan ; Hsieh, Tzu Chin ; Kao, Hung Ying ; Kuo, Yuan ; Kang, Ya Rong ; Tsai, Wan Chi ; Tsai, Sen-Tien ; Wu, Li-Wha. / The p53-S100A2 Positive Feedback Loop Negatively Regulates Epithelialization in Cutaneous Wound Healing. In: Scientific reports. 2018 ; Vol. 8, No. 1.
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title = "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.",
author = "Shin-Chen Pan and Li, {Che Yu} and Kuo, {Chia Yi} and Kuo, {Yi Zih} and Fang, {Wei Yu} and Huang, {Yu Hsuan} and Hsieh, {Tzu Chin} and Kao, {Hung Ying} and Yuan Kuo and Kang, {Ya Rong} and Tsai, {Wan Chi} and Sen-Tien Tsai and Li-Wha Wu",
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Pan, S-C, Li, CY, Kuo, CY, Kuo, YZ, Fang, WY, Huang, YH, Hsieh, TC, Kao, HY, Kuo, Y, Kang, YR, Tsai, WC, Tsai, S-T & Wu, L-W 2018, 'The p53-S100A2 Positive Feedback Loop Negatively Regulates Epithelialization in Cutaneous Wound Healing', Scientific reports, vol. 8, no. 1, 5458. https://doi.org/10.1038/s41598-018-23697-5

The p53-S100A2 Positive Feedback Loop Negatively Regulates Epithelialization in Cutaneous Wound Healing. / Pan, Shin-Chen; Li, Che Yu; Kuo, Chia Yi; Kuo, Yi Zih; Fang, Wei Yu; Huang, Yu Hsuan; Hsieh, Tzu Chin; Kao, Hung Ying; Kuo, Yuan; Kang, Ya Rong; Tsai, Wan Chi; Tsai, Sen-Tien; Wu, Li-Wha.

In: Scientific reports, Vol. 8, No. 1, 5458, 01.12.2018.

Research output: Contribution to journalArticle

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T1 - The p53-S100A2 Positive Feedback Loop Negatively Regulates Epithelialization in Cutaneous Wound Healing

AU - Pan, Shin-Chen

AU - Li, Che Yu

AU - Kuo, Chia Yi

AU - Kuo, Yi Zih

AU - Fang, Wei Yu

AU - Huang, Yu Hsuan

AU - Hsieh, Tzu Chin

AU - Kao, Hung Ying

AU - Kuo, Yuan

AU - Kang, Ya Rong

AU - Tsai, Wan Chi

AU - Tsai, Sen-Tien

AU - Wu, Li-Wha

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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