PUBLICATION

A novel chemical screening strategy in zebrafish identifies common pathways in embryogenesis and rhabdomyosarcoma development

Authors
Le, X., Pugach, E.K., Hettmer, S., Storer, N.Y., Liu, J., Wills, A.A., Dibiase, A., Chen, E.Y., Ignatius, M.S., Poss, K.D., Wagers, A.J., Langenau, D.M., and Zon, L.I.
ID
ZDB-PUB-130502-13
Date
2013
Source
Development (Cambridge, England)   140(11): 2354-64 (Journal)
Registered Authors
Ignatius, Myron, Langenau, David, Le, Xiuning, Poss, Kenneth D., Storer, Narie, Wills, Airon, Zon, Leonard I.
Keywords
none
Datasets
GEO:GSE44364
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Cell Line, Tumor
  • Eukaryotic Initiation Factors/metabolism
  • Flavonoids/pharmacology
  • Gene Expression Regulation, Developmental*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • MAP Kinase Kinase 1/metabolism
  • Oligonucleotide Array Sequence Analysis
  • Protein Biosynthesis
  • Rhabdomyosarcoma/genetics
  • Rhabdomyosarcoma/metabolism
  • Rhabdomyosarcoma/pathology*
  • Ribosomal Protein S6 Kinases/metabolism
  • Signal Transduction*
  • Tosylphenylalanyl Chloromethyl Ketone/pharmacology
  • Transgenes
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish Proteins/metabolism
  • ras Proteins/metabolism*
PubMed
23615277 Full text @ Development
Abstract

The zebrafish is a powerful genetic model that has only recently been used to dissect developmental pathways involved in oncogenesis. We hypothesized that operative pathways during embryogenesis would also be used for oncogenesis. In an effort to define RAS target genes during embryogenesis, gene expression was evaluated in Tg(hsp70-HRASG12V) zebrafish embryos subjected to heat shock. dusp6 was activated by RAS, and this was used as the basis for a chemical genetic screen to identify small molecules that interfere with RAS signaling during embryogenesis. A KRASG12D-induced zebrafish embryonal rhabdomyosarcoma was then used to assess the therapeutic effects of the small molecules. Two of these inhibitors, PD98059 and TPCK, had anti-tumor activity as single agents in both zebrafish embryonal rhabdomyosarcoma and a human cell line of rhabdomyosarcoma that harbored activated mutations in NRAS. PD98059 inhibited MEK1 whereas TPCK suppressed S6K1 activity; however, the combined treatment completely suppressed eIF4B phosphorylation and decreased translation initiation. Our work demonstrates that the activated pathways in RAS induction during embryogenesis are also important in oncogenesis and that inhibition of these pathways suppresses tumor growth.

Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes