Regulation of angiogenic factors by HDM2 in renal cell carcinoma.
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.
Carroll
Veronica A
VA
Cell Growth Regulation and Angiogenesis Laboratory, Cancer Research UK Centre for Cancer Therapeutics, Surrey, United Kingdom.
Ashcroft
Margaret
M
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
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