title: Glioma is formed by active Akt1 alone and promoted by active Rac1 in transgenic zebrafish.
abstract: BACKGROUND
  Ongoing characterization of glioma has revealed that Akt signaling plays a crucial role in gliomagenesis. In mouse models, however, Akt alone was not sufficient to induce glioma.
  
  
  METHODS
  We established transgenic zebrafish that overexpressed dominant-active (DA) human Akt1 or Rac1(G12V) (DARac1) at ptf1a domain and investigated transgenic phenotypes and mechanisms leading to gliomagenesis.
  
  
  RESULTS
  Transgene expressions were spatiotemporally restricted without any developmental abnormality of embryos and persisted at cerebellum and medulla in adult zebrafish. DAAkt1 alone induced glioma (with visible bumps at the head), with incidences of 36.6% and 49% at 6 and 9 months, respectively. Histologically, gliomas showed various histologic grades, increased proliferation, and frequent invasion into the fourth ventricle. Preferential location of small tumors at periventricular area and coexpression of Her4 suggested that tumors originated from Ptf1a- and Her4-positive progenitor cells at ventricular zone. Gliomagenesis was principally mediated by activation of survival pathway through upregulation of survivin genes. Although DARac1 alone was incapable of gliomagenesis, when coexpressed with DAAkt1, gliomagenesis was accelerated, showing higher tumor incidences (62.0% and 73.3% at 6 and 9 months, respectively), advanced histologic grade, invasiveness, and shortened survival. DARac1 upregulated survivin2, cyclin D1, β-catenin, and snail1a but downregulated E-cadherin, indicating that DARac1 promotes gliomagenesis by enhancing proliferation, survival, and epithelial-to-mesenchymal transition. On pharmacologic tests, only Akt1/2 inhibitor effectively suppressed gliomagenesis, inhibited cellular proliferation, and induced apoptosis in established gliomas.
  
  
  CONCLUSIONS
  The zebrafish model reinforces the pivotal role of Akt signaling in gliomagenesis and suggests Rac1 as an important protein involved in progression.
authors: Postgraduate School of National Core Research Center for Nanomedical Technology, Seoul, Korea.
authors: In Hye
authors: IH
authors: Jung
authors: Ga Lam
authors: GL
authors: Leem
authors: Dawoon E
authors: DE
authors: Jung
authors: Min Hee
authors: MH
authors: Kim
authors: Eun Young
authors: EY
authors: Kim
authors: Se Hoon
authors: SH
authors: Kim
authors: Hae-Chul
authors: HC
authors: Park
authors: Seung Woo
authors: SW
authors: Park
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004625:Embryo, Nonmammalian / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D014157:Transcription Factors; C062602:transcription factor PTF1; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein