Id1 regulates angiogenesis through transcriptional repression of thrombospondin-1.
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.
Volpert
Olga V
OV
Department of Urology and RH Lurie Cancer Center, Northwestern University Medical School, Chicago, IL 60611, USA.
Pili
Roberto
R
Sikder
Hashmat A
HA
Nelius
Thomas
T
Zaichuk
Tetiana
T
Morris
Chad
C
Shiflett
Clinton B
CB
Devlin
Meghann K
MK
Conant
Katherine
K
Alani
Rhoda M
RM
D000818:Animals; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D024721:E-Box Elements; D004622:Embryo, Mammalian; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D051798:Inhibitor of Differentiation Protein 1; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology*; D014158:Transcription, Genetic; D015854:Up-Regulation
C497453:ID1 protein, human; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D012097:Repressor Proteins; D019700:Thrombospondin 1; D014157:Transcription Factors