title: Activation of MEK2 is sufficient to induce skin papilloma formation in transgenic zebrafish.
abstract: BACKGROUND
  Mutations in mitogen-activated protein kinase (MAPK) kinase 1 (MEK1) that occur during cell proliferation and tumor formation are well described. Information on the roles of MEK2 in these effects is still limited. We established a constitutive MEK2 transgenic zebrafish, Tg(krt14:MEK2S219D-GFP), to elucidate the role of MEK2 in skin tumor formation.
  
  
  RESULTS
  We found that both constitutive MEK2 and MEK1 are able to phosphorylate the extracellular signal-regulated kinase 1 (ERK1) protein. Transient expression of constitutive MEK2 and MEK1 in the zebrafish epidermis induced papillary formation at 48 h post-fertilization, but no effects were observed due to the expression of MEK1, MEK2, or the dominant negative form of MEK2. The transgenic zebrafish, Tg(krt14:MEK2S219D-GFP), developed skin papillomas in the epidermis within 6 days post-fertilization (dpf). The phospho-ERK signal was detected in section of skin papillomas in an immunohistochemical experiment. Treatment with 50 μM of the MEK inhibitor, U0126, had significantly decreased the skin papilloma formation in Tg(krt14:MEK2S219D-GFP) zebrafish by 6 dpf. In vitro and in vivo proliferation assay in COS-1 cells and in Tg(krt14:MEK2S219D-GFP) transgenic fish show significantly increased cell number and Ki-67 signaling.
  
  
  CONCLUSIONS
  Our data indicate that MEK2 is sufficient to induce epidermal papilloma formation through MAPK signaling in zebrafish, and this transgenic model can be used as a new platform for drug screening.
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan. cmchou@tmu.edu.tw.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan. cmchou@tmu.edu.tw.
authors.forename: Chih-Ming
authors.initials: CM
authors.lastname: Chou
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, 128 Academia Rd., Sec 2, Taipei, 115, Taiwan. 893020260@ndmctsgh.edu.tw.
authors.forename: Yi-Chung
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, 128 Academia Rd., Sec 2, Taipei, 115, Taiwan. susan0702@hotmail.com.
authors.forename: San
authors.initials: S
authors.lastname: Su
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, 128 Academia Rd., Sec 2, Taipei, 115, Taiwan. veranica.g@gmail.com.
authors.forename: Gen-Der
authors.initials: GD
authors.lastname: Chen
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, 128 Academia Rd., Sec 2, Taipei, 115, Taiwan. kai0007tw@gmail.com.
authors.forename: Kai-Yun
authors.initials: KY
authors.lastname: Huang
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, 128 Academia Rd., Sec 2, Taipei, 115, Taiwan. brian2940@hotmail.com.
authors.forename: Huang-Wei
authors.initials: HW
authors.lastname: Lien
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, 128 Academia Rd., Sec 2, Taipei, 115, Taiwan. cjibc@gate.sinica.edu.tw.
authors.forename: Chang-Jen
authors.initials: CJ
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan. chcheng@tmu.edu.tw.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan. chcheng@tmu.edu.tw.|Department of Biochemistry, School of Medicine, College of Medicine, Taipei Medical University, 250, Wuxing Street, Taipei, 11013, Taiwan. chcheng@tmu.edu.tw.
authors.forename: Chia-Hsiung
authors.initials: CH
authors.lastname: Cheng
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism*; D010212:Papilloma / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029961:Zebrafish Proteins; D048370:MAP Kinase Kinase 2