Id1 regulates angiogenesis through transcriptional repression of thrombospondin-1

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.

Id1 cooperates with oncogenic Ras to induce metastatic mammary carcinoma by subversion of the cellular senescence response

“…Id1 regulates angiogenesis under certain circumstances (26,27) and an alternative explanation for our observations is that Id1 permits Ras-dependent tumorigenesis by driving tumor angiogenesis. However, several lines of evidence refute this proposal.…”

ID1 Facilitates the Growth and Metastasis of Non-Small Cell Lung Cancer in Response to Nicotinic Acetylcholine Receptor and Epidermal Growth Factor Receptor Signaling

“…Given that ID1 has been shown to promote angiogenesis by repressing the antiangiogenic protein thrombospondin-1 (66) and the observations that nicotine can induce angiogenesis significantly (6,19), attempts were made to assess whether ID1 contributes to nicotine-and VEGF-induced angiogenic tubule formation in Matrigel. Primary human microvascular endothelial cells from the lung (HMEC-Ls) were transiently transfected with a control siRNA or ID1 siRNA and serum starved for 24 h as in the previous experiments.…”

Inhibitor of DNA binding-4 promotes angiogenesis and growth of glioblastoma multiforme by elevating matrix GLA levels

“…Histological examination of these xenografts revealed stunted, occluded vessels in the tumors of the Id1 þ /À /Id3 À/À animals followed by complete regression at 2 weeks, and continued good health for well over a year (Lyden et al, 1999). Subsequent studies have confirmed the central function of ID1 and ID3 in tumor angiogenesis (Volpert et al, 2002;Sakurai et al, 2004;Ling et al, 2005) and their elevation in tumor endothelium, although the molecular mechanisms mediating these events are unknown.…”