title: Regulation of angiogenic factors by HDM2 in renal cell carcinoma.
abstract: The oncogene HDM2 has been implicated in the regulation of the transcription factor, hypoxia inducible factor (HIF). We show in von Hippel-Lindau (VHL)-defective renal carcinoma cells that express constitutively high levels of HIF-1 alpha and HIF-2 alpha that down-regulation of HDM2 by siRNA leads to decreased levels of both HIF-1 alpha and HIF-2 alpha protein levels. However, we show a differential regulation of HDM2 on the HIF angiogenic targets, vascular endothelial growth factor (VEGF), plasminogen activator inhibitor-1 (PAI-1), and endothelin-1 (ET-1): siRNA to HDM2 leads to increased expression of VEGF and PAI-1 proteins but decreased levels of ET-1. We show that HDM2-mediated regulation of these proteins is independent of VHL and p53 but dependent on a novel action of HDM2. Ablation of HDM2 leads to phosphorylation of extracellular-regulated kinase (ERK)1/2 in renal carcinoma cells. We show that regulation of these angiogenic factors is dependent on ERK1/2 phosphorylation, which can be reversed by addition of the MAP/ERK1/2 kinase inhibitors PD98059 and PD184352. This study identifies a novel role for the HDM2 oncoprotein in the regulation of angiogenic factors in renal cell carcinoma.
authors.affiliation: Cell Growth Regulation and Angiogenesis Laboratory, Cancer Research UK Centre for Cancer Therapeutics, Surrey, United Kingdom.
authors.forename: Veronica A
authors.initials: VA
authors.lastname: Carroll
authors.forename: Margaret
authors.initials: M
authors.lastname: Ashcroft
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D006623:von Hippel-Lindau Disease / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D043925:Angiogenesis Inducing Agents; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051736:Proto-Oncogene Proteins c-mdm2; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C497206:MDM2 protein, human