當傷口產生的時候，皮膚或組織會經過動態且複雜的癒合過程來修復受損的部分。研究發現，許多基因或細胞會參與傷口的癒合。其中p53是一個眾所皆知的抑癌基因，同時在傷口癒合中也扮演重要的角色。當短暫抑制p53的活性，能增加早期細胞增生的能力，這個時期對於傷口癒合是非常重要的。S100A2是一種鈣結合蛋白，不僅僅會與p53交互作用，並且也會調控其轉錄的活性。目前在老鼠身上並沒有找到S100A2基因的表現。因為S100A2主要表現在上皮，且具有調控角質細胞分化的功能，我們使用特定表現在上皮S100A2以及p53缺陷的基因轉殖鼠，研究傷口癒合中這兩種基因的功能以及參與的機制。經由我們實驗發現，S100A2會抑制傷口的癒合，然而p53的缺失則會促進傷口的復原。同時帶有S100A2的表達與p53缺失的基因轉殖鼠的傷口癒合能力與野生型的小鼠相同，這表示在傷口癒合的過程中，S100A2跟p53是參與在相似的機制中且扮演抑制傷口的角色。使用共同免疫沉澱以及鄰位接連技術的方式，我們證實S100A2和p53確實會形成複合體。S100A2抑制傷口的功能部分是透過降低表皮新生和角質細胞的移動與增生。另外，我們發現S100A2會抑制p53下游基因，VEGF-A、COX-2以及NF-kB mRNA的表現以及其promoter的活性。雖然還需要更多的實驗去證明，S100A2和p53確實可能會藉由之間的交互作用在傷口癒合中扮演相似的角色。了解之間的關係和調控的機制，對於有傷口問題的病人，可能可以提供一個治療的選擇與可能性。

Wound healing is a complicated and dynamic process by which skin or other tissues heals themselves after injury. Numerous factors have been shown to participate in wound healing process. P53, a well-known tumor suppressor, plays a curial role in wound regeneration. Consistent with the notion, transient inhibition of p53 promotes early cell proliferation required for rapid tissue repair. S100A2, a calcium binding protein, not only interacts with p53 but also modulates p53 transcriptional activity. No mouse S100A2 homolog was ever identified so far. Since S100A2 was mainly located in epidermis and has modulatory effect on keratinocyte differentiation, we used epithelial-specific S100A2 transgenic and p53 deficiency mice for studying the function and action mechanism of either gene alone and their interplay in puncture wound-induced healing process. We found that S100A2 transgene delayed wound repair while p53 deficiency promoted wound repair. S100A2 transgene together with p53 heterozygotes had comparable wound repair as those in wild type mice, suggesting that both genes may function in the same signaling axis for wound repair. Using co-immunopreicitation and proximity-ligation assays, S100A2 and p53 indeed formed a complex in vitro and in vivo. The negative effect of S100A2 on wound repair was partly through reduction of neo-epithelialization, as well as keratinocyte migration and proliferation. Consistent with a negative role of S100A2 in wound repair, we did detect the decrease in the mRNA expression of p53 targets, vascular endothelial growth factor A, cyclooxygenase 2 and NF-kappa B, and their promoter activities. Although more studies are needed, S100A2 may function in same signaling axis as p53 via direct interaction in regulating wound repair. Understanding the involvement of either protein in wound healing would facilitate the possible development of therapeutic targets for treating patients with healing problems.

Abdalla, S.I., Sanderson, I.R., and Fitzgerald, R.C. (2005). Effect of inflammation on cyclooxygenase (COX)-2 expression in benign and malignant oesophageal cells. Carcinogenesis 26, 1627-1633.
Bagchi, S., Fredriksson, R., and Wallen-Mackenzie, A. (2015). In Situ Proximity Ligation Assay (PLA). Methods Mol Biol 1318, 149-159.
Bao, P., Kodra, A., Tomic-Canic, M., Golinko, M.S., Ehrlich, H.P., and Brem, H. (2009). The role of vascular endothelial growth factor in wound healing. J Surg Res 153, 347-358.
Bensaude, O. (2011). Inhibiting eukaryotic transcription: Which compound to choose? How to evaluate its activity? Transcription 2, 103-108.
Brogi, E., Wu, T., Namiki, A., and Isner, J.M. (1994). Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only. Circulation 90, 649-652.
Buckley, N.E., D'Costa, Z., Kaminska, M., and Mullan, P.B. (2014). S100A2 is a BRCA1/p63 coregulated tumour suppressor gene with roles in the regulation of mutant p53 stability. Cell Death Dis 5, e1070.
Bukowiecki, A., Hos, D., Cursiefen, C., and Eming, S.A. (2017). Wound-Healing Studies in Cornea and Skin: Parallels, Differences and Opportunities. Int J Mol Sci 18.
Carvalho, L., Jacinto, A., and Matova, N. (2014). The Toll/NF-kappaB signaling pathway is required for epidermal wound repair in Drosophila. Proc Natl Acad Sci U S A 111, E5373-5382.
Choi, E.M., Heo, J.I., Oh, J.Y., Kim, Y.M., Ha, K.S., Kim, J.I., and Han, J.A. (2005). COX-2 regulates p53 activity and inhibits DNA damage-induced apoptosis. Biochem Biophys Res Commun 328, 1107-1112.
Coffill, C.R., Lee, A.P., Siau, J.W., Chee, S.M., Joseph, T.L., Tan, Y.S., Madhumalar, A., Tay, B.H., Brenner, S., Verma, C.S., et al. (2016). The p53-Mdm2 interaction and the E3 ligase activity of Mdm2/Mdm4 are conserved from lampreys to humans. Genes Dev 30, 281-292.
Deshayes, N., Bloas, F., Boissout, F., Lecardonnel, J., and Paris, M. (2017). A 3D in vitro model of the re-epithelialization phase in the wound healing process. Exp Dermatol.
Donehower, L.A., Harvey, M., Slagle, B.L., McArthur, M.J., Montgomery, C.A., Jr., Butel, J.S., and Bradley, A. (1992). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215-221.
Eckert, R.L. (1989). Structure, function, and differentiation of the keratinocyte. Physiol Rev 69, 1316-1346.
Eckert, R.L., Broome, A.M., Ruse, M., Robinson, N., Ryan, D., and Lee, K. (2004). S100 proteins in the epidermis. J Invest Dermatol 123, 23-33.
Eming, S.A., Hammerschmidt, M., Krieg, T., and Roers, A. (2009). Interrelation of immunity and tissue repair or regeneration. Semin Cell Dev Biol 20, 517-527.
Eming, S.A., Werner, S., Bugnon, P., Wickenhauser, C., Siewe, L., Utermohlen, O., Davidson, J.M., Krieg, T., and Roers, A. (2007). Accelerated wound closure in mice deficient for interleukin-10. Am J Pathol 170, 188-202.
Ettenson, D.S., and Gotlieb, A.I. (1994). Endothelial wounds with disruption in cell migration repair primarily by cell proliferation. Microvasc Res 48, 328-337.
Futagami, A., Ishizaki, M., Fukuda, Y., Kawana, S., and Yamanaka, N. (2002). Wound Healing Involves Induction of Cyclooxygenase-2 Expression in Rat Skin. Laboratory Investigation 82, 1503-1513.
Giatromanolaki, A., Koukourakis, M.I., Kakolyris, S., Turley, H., O'Byrne, K., Scott, P.A., Pezzella, F., Georgoulias, V., Harris, A.L., and Gatter, K.C. (1998). Vascular endothelial growth factor, wild-type p53, and angiogenesis in early operable non-small cell lung cancer. Clin Cancer Res 4, 3017-3024.
Halawi, A., Abbas, O., and Mahalingam, M. (2014). S100 proteins and the skin: a review. J Eur Acad Dermatol Venereol 28, 405-414.
Joray, M.B., Villafanez, F., Gonzalez, M.L., Crespo, M.I., Laiolo, J., Palacios, S.M., Bocco, J.L., Soria, G., and Carpinella, M.C. (2017). P53 tumor suppressor is required for efficient execution of the death program following treatment with a cytotoxic limonoid obtained from Melia azedarach. Food Chem Toxicol.
Karamercan, A., Ercan, S., and Bozkurt, S. (2006). Nitric oxide synthase inhibitors appear to improve wound healing in endotoxemic rats: An investigator-blinded, controlled, experimental study. Curr Ther Res Clin Exp 67, 378-385.
Kennedy Crispin, M., Fuentes-Duculan, J., Gulati, N., Johnson-Huang, L.M., Lentini, T., Sullivan-Whalen, M., Gilleaudeau, P., Cueto, I., Suarez-Farinas, M., Lowes, M.A., et al. (2013). Gene profiling of narrowband UVB-induced skin injury defines cellular and molecular innate immune responses. J Invest Dermatol 133, 692-701.
Keyes, B.E., Liu, S., Asare, A., Naik, S., Levorse, J., Polak, L., Lu, C.P., Nikolova, M., Pasolli, H.A., and Fuchs, E. (2016). Impaired Epidermal to Dendritic T Cell Signaling Slows Wound Repair in Aged Skin. Cell 167, 1323-1338 e1314.
Koh, T.J., and DiPietro, L.A. (2011). Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med 13, e23.
Kuwano, T., Nakao, S., Yamamoto, H., Tsuneyoshi, M., Yamamoto, T., Kuwano, M., and Ono, M. (2004). Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis. FASEB J 18, 300-310.
Lapi, E., Iovino, A., Fontemaggi, G., Soliera, A.R., Iacovelli, S., Sacchi, A., Rechavi, G., Givol, D., Blandino, G., and Strano, S. (2006). S100A2 gene is a direct transcriptional target of p53 homologues during keratinocyte differentiation. Oncogene 25, 3628-3637.
Lawrence, T. (2009). The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 1, a001651.
Li, Y., Gudjonsson, J.E., Woods, T.L., Zhang, T., Johnston, A., Stoll, S.W., and Elder, J.T. (2009). Transgenic expression of S100A2 in hairless mouse skin enhances Cxcl13 mRNA in response to solar-simulated radiation. Arch Dermatol Res 301, 205-217.
Martin, P. (1997). Wound healing--aiming for perfect skin regeneration. Science 276, 75-81.
Matsubara, D., Niki, T., Ishikawa, S., Goto, A., Ohara, E., Yokomizo, T., Heizmann, C.W., Aburatani, H., Moriyama, S., Moriyama, H., et al. (2005). Differential expression of S100A2 and S100A4 in lung adenocarcinomas: clinicopathological significance, relationship to p53 and identification of their target genes. Cancer Sci 96, 844-857.
Mauch, C., Zamek, J., Abety, A.N., Grimberg, G., Fox, J.W., and Zigrino, P. (2010). Accelerated wound repair in ADAM-9 knockout animals. J Invest Dermatol 130, 2120-2130.
Minghetti, L. (2004). Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J Neuropathol Exp Neurol 63, 901-910.
Mueller, A., Bachi, T., Hochli, M., Schafer, B.W., and Heizmann, C.W. (1999). Subcellular distribution of S100 proteins in tumor cells and their relocation in response to calcium activation. Histochem Cell Biol 111, 453-459.
Mueller, A., Schafer, B.W., Ferrari, S., Weibel, M., Makek, M., Hochli, M., and Heizmann, C.W. (2005). The calcium-binding protein S100A2 interacts with p53 and modulates its transcriptional activity. J Biol Chem 280, 29186-29193.
Mutsaers, S.E., Bishop, J.E., McGrouther, G., and Laurent, G.J. (1997). Mechanisms of tissue repair: from wound healing to fibrosis. Int J Biochem Cell Biol 29, 5-17.
Naz, S., Bashir, M., Ranganathan, P., Bodapati, P., Santosh, V., and Kondaiah, P. (2014). Protumorigenic actions of S100A2 involve regulation of PI3/Akt signaling and functional interaction with Smad3. Carcinogenesis 35, 14-23.
Nissen, N.N., Polverini, P.J., Koch, A.E., Volin, M.V., Gamelli, R.L., and DiPietro, L.A. (1998). Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing. Am J Pathol 152, 1445-1452.
Nunan, R., Campbell, J., Mori, R., Pitulescu, M.E., Jiang, W.G., Harding, K.G., Adams, R.H., Nobes, C.D., and Martin, P. (2015). Ephrin-Bs Drive Junctional Downregulation and Actin Stress Fiber Disassembly to Enable Wound Re-epithelialization. Cell Rep 13, 1380-1395.
Nunan, R., Harding, K.G., and Martin, P. (2014). Clinical challenges of chronic wounds: searching for an optimal animal model to recapitulate their complexity. Dis Model Mech 7, 1205-1213.
Page-McCaw, A., Ewald, A.J., and Werb, Z. (2007). Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8, 221-233.
Pastar, I., Stojadinovic, O., Yin, N.C., Ramirez, H., Nusbaum, A.G., Sawaya, A., Patel, S.B., Khalid, L., Isseroff, R.R., and Tomic-Canic, M. (2014). Epithelialization in Wound Healing: A Comprehensive Review. Adv Wound Care (New Rochelle) 3, 445-464.
Redd, M.J., Cooper, L., Wood, W., Stramer, B., and Martin, P. (2004). Wound healing and inflammation: embryos reveal the way to perfect repair. Philos Trans R Soc Lond B Biol Sci 359, 777-784.
Rieger, S., Zhao, H., Martin, P., Abe, K., and Lisse, T.S. (2015). The role of nuclear hormone receptors in cutaneous wound repair. Cell Biochem Funct 33, 1-13.
Saxena, A., Rorie, C.J., Dimitrova, D., Daniely, Y., and Borowiec, J.A. (2006). Nucleolin inhibits Hdm2 by multiple pathways leading to p53 stabilization. Oncogene 25, 7274-7288.
Schiller, M., Javelaud, D., and Mauviel, A. (2004). TGF-beta-induced SMAD signaling and gene regulation: consequences for extracellular matrix remodeling and wound healing. J Dermatol Sci 35, 83-92.
Schneider-Poetsch, T., Ju, J., Eyler, D.E., Dang, Y., Bhat, S., Merrick, W.C., Green, R., Shen, B., and Liu, J.O. (2010). Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin. Nat Chem Biol 6, 209-217.
Scholzen, T., and Gerdes, J. (2000). The Ki-67 protein: from the known and the unknown. J Cell Physiol 182, 311-322.
Shaw, T.J., and Martin, P. (2009). Wound repair at a glance. J Cell Sci 122, 3209-3213.
Shih, R.H., Wang, C.Y., and Yang, C.M. (2015). NF-kappaB Signaling Pathways in Neurological Inflammation: A Mini Review. Front Mol Neurosci 8, 77.
Shrestha, P., Muramatsu, Y., Kudeken, W., Mori, M., Takai, Y., Ilg, E.C., Schafer, B.W., and Heizmann, C.W. (1998). Localization of Ca(2+)-binding S100 proteins in epithelial tumours of the skin. Virchows Arch 432, 53-59.
Subbaramaiah, K., Altorki, N., Chung, W.J., Mestre, J.R., Sampat, A., and Dannenberg, A.J. (1999). Inhibition of cyclooxygenase-2 gene expression by p53. J Biol Chem 274, 10911-10915.
Suzuma, K., Takagi, H., Otani, A., and Honda, Y. (1998). Hypoxia and vascular endothelial growth factor stimulate angiogenic integrin expression in bovine retinal microvascular endothelial cells. Invest Ophthalmol Vis Sci 39, 1028-1035.
Szymonowicz, M., Kucharska, M., Wisniewska-Wrona, M., Dobrzynski, M., Kolodziejczyk, K., and Rybak, Z. (2017). The evaluation of resorbable haemostatic wound dressings in contact with blood in vitro. Acta Bioeng Biomech 19, 151-165.
Tsai, W.C., Tsai, S.T., Jin, Y.T., and Wu, L.W. (2006). Cyclooxygenase-2 is involved in S100A2-mediated tumor suppression in squamous cell carcinoma. Mol Cancer Res 4, 539-547.
van Dieck, J., Fernandez-Fernandez, M.R., Veprintsev, D.B., and Fersht, A.R. (2009). Modulation of the oligomerization state of p53 by differential binding of proteins of the S100 family to p53 monomers and tetramers. J Biol Chem 284, 13804-13811.
van Dieck, J., Lum, J.K., Teufel, D.P., and Fersht, A.R. (2010). S100 proteins interact with the N-terminal domain of MDM2. FEBS Lett 584, 3269-3274.
Vatankhah, N., Jahangiri, Y., Landry, G.J., McLafferty, R.B., Alkayed, N.J., Moneta, G.L., and Azarbal, A.F. (2017). Predictive value of neutrophil-to-lymphocyte ratio in diabetic wound healing. J Vasc Surg 65, 478-483.
Vollmar, B., El-Gibaly, A.M., Scheuer, C., Strik, M.W., Bruch, H.P., and Menger, M.D. (2002). Acceleration of cutaneous wound healing by transient p53 inhibition. Lab Invest 82, 1063-1071.
Werner, S., Krieg, T., and Smola, H. (2007). Keratinocyte-fibroblast interactions in wound healing. J Invest Dermatol 127, 998-1008.
Wullaert, A., Bonnet, M.C., and Pasparakis, M. (2011). NF-kappaB in the regulation of epithelial homeostasis and inflammation. Cell Res 21, 146-158.
Zhang, T., Woods, T.L., and Elder, J.T. (2002). Differential responses of S100A2 to oxidative stress and increased intracellular calcium in normal, immortalized, and malignant human keratinocytes. J Invest Dermatol 119, 1196-1201.