title: Inhibitor of DNA binding 1 activates vascular endothelial growth factor through enhancing the stability and activity of hypoxia-inducible factor-1alpha.
abstract: Inhibitor of DNA binding 1 (Id-1) has been implicated in tumor angiogenesis by regulating the expression of vascular endothelial growth factor (VEGF), but its molecular mechanism has not been fully understood. Here, we show the cross talk between Id-1 and hypoxia-inducible factor-1alpha (HIF-1alpha), that Id-1 induces VEGF by enhancing the stability and activity of HIF-1alpha in human endothelial and breast cancer cells. Although both the transcript and proteins levels of VEGF were induced by Id-1, only the protein expression of HIF-1alpha was induced without transcriptional changes in both human umbilical endothelial cells and MCF7 breast cancer cells. Such induction of the HIF-1alpha protein did not require de novo protein synthesis but was dependent on the active extracellular response kinase (ERK) pathway. In addition, stability of the HIF-1alpha protein was enhanced in part by the reduced association of the HIF-1alpha protein with von Hippel-Lindau protein in the presence of Id-1. Furthermore, Id-1 enhanced nuclear translocation and the transcriptional activity of HIF-1alpha. Transcriptional activation of HIF-1-dependent promoters was dependent on the active ERK pathway, and the association of HIF-1alpha protein with cyclic AMP-responsive element binding protein was enhanced by Id-1. Finally, Id-1 induced tube formation in human umbilical endothelial cells, which also required active ERK signaling. In conclusion, we provide the molecular mechanism of the cross talk between HIF-1alpha and Id-1, which may play a critical role in tumor angiogenesis.
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Hyun-Jun
authors.initials: HJ
authors.lastname: Kim
authors.forename: Heekyoung
authors.initials: H
authors.lastname: Chung
authors.forename: Young-Gun
authors.initials: YG
authors.lastname: Yoo
authors.forename: Hwan
authors.initials: H
authors.lastname: Kim
authors.forename: Jeong-Yeon
authors.initials: JY
authors.lastname: Lee
authors.forename: Mi-Ock
authors.initials: MO
authors.lastname: Lee
authors.forename: Gu
authors.initials: G
authors.lastname: Kong
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D014158:Transcription, Genetic; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051798:Inhibitor of Differentiation Protein 1; D042461:Vascular Endothelial Growth Factor A