Dissection of angiogenic signaling in zebrafish using a chemical genetic approach

Cancer Cell. 2002 Apr;1(3):257-67. doi: 10.1016/s1535-6108(02)00042-9.

Abstract

Striking homology between signaling molecules in zebrafish and humans suggests that compounds known to inhibit human kinases may enable a chemical genetic approach to dissect signaling pathways in the zebrafish embryo. We tested this hypothesis using a vascular endothelial growth factor receptor inhibitor, PTK787/ZK222584. Zebrafish embryos treated with this compound lacked all major blood vessels. Overexpression of AKT/PKB, a putative effector of vascular endothelial growth factor signaling, allowed blood vessels to form in the presence of drug. Endothelial cell apoptosis induced by the drug is prevented by increasing AKT/PKB activity, thus establishing the physiological relevance of AKT/PKB in the angiogenic process. This approach allowed us to examine the effects of blood flow and the role of endothelial signals in organogenesis.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • DNA, Complementary
  • Embryo, Nonmammalian / blood supply*
  • Endothelium, Vascular / cytology
  • Enzyme Inhibitors / pharmacology
  • In Situ Hybridization
  • In Situ Nick-End Labeling
  • Molecular Sequence Data
  • Neovascularization, Physiologic / physiology*
  • Phthalazines / pharmacology
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Pyridines*
  • RNA / metabolism
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Growth Factor / antagonists & inhibitors
  • Receptors, Growth Factor / metabolism
  • Receptors, Vascular Endothelial Growth Factor
  • Sequence Homology, Amino Acid
  • Signal Transduction / physiology*
  • Up-Regulation
  • Zebrafish / embryology*

Substances

  • Angiogenesis Inhibitors
  • DNA, Complementary
  • Enzyme Inhibitors
  • Phthalazines
  • Proto-Oncogene Proteins
  • Pyridines
  • Receptors, Growth Factor
  • vatalanib
  • RNA
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt

Associated data

  • GENBANK/AY056465
  • GENBANK/AY056466