Id1 regulates angiogenesis through transcriptional repression of thrombospondin-1

Cancer Cell. 2002 Dec;2(6):473-83. doi: 10.1016/s1535-6108(02)00209-x.

Abstract

Id proteins are helix-loop-helix transcription factors that regulate tumor angiogenesis. In order to identify downstream effectors of Id1 involved in the regulation of angiogenesis, we performed PCR-select subtractive hybridization on wild-type and Id1 knockout mouse embryo fibroblasts (MEFs). Here we demonstrate that thrombospondin-1 (TSP-1), a potent inhibitor of angiogenesis, is a target of transcriptional repression by Id1. We also show that Id1-null MEFs secrete an inhibitor of endothelial cell migration, which is completely inactivated by depletion of TSP-1. Furthermore, in vivo studies revealed decreased neovascularization in matrigel assays in Id1-null mice compared to their wild-type littermates. This decrease was completely reversed by a TSP-1 neutralizing antibody. We conclude that TSP-1 is a major target for Id1 effects on angiogenesis.

Publication types

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

MeSH terms

  • Animals
  • Cattle
  • Cell Movement / drug effects
  • Cells, Cultured
  • E-Box Elements
  • Embryo, Mammalian
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Fibroblasts / physiology
  • Gene Expression Regulation*
  • Humans
  • Immunohistochemistry
  • Inhibitor of Differentiation Protein 1
  • Mice
  • Mice, Knockout
  • Neovascularization, Pathologic / genetics*
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic
  • Repressor Proteins*
  • Thrombospondin 1 / antagonists & inhibitors
  • Thrombospondin 1 / biosynthesis
  • Thrombospondin 1 / genetics*
  • Thrombospondin 1 / pharmacology
  • Transcription Factors / deficiency
  • Transcription Factors / physiology*
  • Transcription, Genetic
  • Up-Regulation

Substances

  • ID1 protein, human
  • Idb1 protein, mouse
  • Inhibitor of Differentiation Protein 1
  • Repressor Proteins
  • Thrombospondin 1
  • Transcription Factors