Functional Analysis of Stat3 Signaling on Zebrafish Skin Development

• Main Authors: Chiun-Feng Chiou, 邱群鳳
• Other Authors: Chung-Der Hsiao
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/7e8n9m

碩士 === 中原大學 === 生物科技研究所 === 98 === Stat3 (Signal transducer and activator of transcription 3) is a member of the STAT protein family. STAT family proteins response to cytokines and growth factors and they are phosphorylated by the receptor associated kinases. They are activated on two residues, tyrosine 705 and serine 727 and trigger the homo- or heterodimers formation then translocate to nucleus to activate downstream target genes. Stat3 is a multiple-face protein to play many biological roles, including cell proliferation, survival and cell migration. Stat3 participates in these processes through regulated of genes such as cyclin D1, Bcl-xL and others. Deregulated expression of Stat3 is frequently detected in many different kinds of human cancers. In the mouse studies, transgenic mice (K5.Stat3C) over-expressed constitutively active/dimerized form of Stat3 (Stat3C) under the control of bovine keratin K5 promoter will develop psoriasis either spontaneously or in response to wounding. K5.Stat3C mice will not develop skin cancer until treat them with physical (UVB) or chemical (DMBA/TPA carcinogens) stresses. The Stat3C transformed epidermis in K5.Stat3C mice was more resistant to UVB- and DMBA-induced apoptosis. Compared to mammals, few studies are addressed on the biological function of Stat3 in zebrafish skin development. We addressed this question by generating stable transgenic zebrafish of Tg(krt4：Stat3C) to over-express Stat3C specifically in zebrafish skin. However, in Tg(krt4：Stat3C) embryos, we detect Stat3C enhanced cell proliferation but can’t induce cancer formation. Next, we challenged Tg(krt4：Stat3C) with either UVB irradiation or oxidative stress which generated by double stranded DNA crosslink. We found low dose UVB stress can trigger skin lesion formation in Tg(krt4：Stat3C) but not in non-transgenic siblings. In addition, the Stat3C transformed skin is more resistant to cell death stress which generated by double stranded DNA crosslink. In cell line studies, Stat3 can regulate cell proliferation through C-myc. We crossing Tg(krt4：Stat3C) with Tg(krt4：C-myc) to generate Tg(krt4：Stat3C);Tg(krt4：C-myc). In double transgenics, we detected skin cancer formation and support the idea that Stat3 and C-myc signaling are synergistically working in vivo. In conclusion, we provided direct evidence to demonstrate Stat3 play a role on skin development to maintain skin homeostasis and attenuate stress damage. The combined deregulation of Stat3 and C-myc in skin that can oncogenic transform zebrafish skin into tumor formation.