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Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function.
Oncogene. 2000 Nov 16; 19(48):5435-43.O

Abstract

Hypoxia induces transcription of a range of physiologically important genes including erythropoietin and vascular endothelial growth factor. The transcriptional activation is mediated by the hypoxia-inducible factor-1 (HIF-1), a heterodimeric member of the basic helix-loop-helix PAS family, composed of alpha and beta subunits. HIF-1alpha shares 48 per cent identity with the recently identified HIF-2alpha protein that is also stimulated by hypoxia. In a previous study of hemangioblastomas, the most frequent manifestation of hereditary von Hippel-Lindau disease (VHL), we found elevated levels of vascular endothelial growth factor and HIF-2alpha mRNA in stromal cells of the tumors. Mutations of the VHL tumor suppressor gene are associated with a variety of tumors such as renal clear cell carcinomas (RCC). In this study, we analysed the expression of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in a range of VHL wildtype and VHL deficient RCC cell lines. In the presence of functional VHL protein, HIF-1alpha mRNA levels are elevated, whereas HIF-2alpha mRNA expression is increased only in cells lacking a functional VHL gene product. On the protein levels, however, in VHL deficient cell lines, both HIF-alpha subunits are constitutively expressed, whereas re-introduction of a functional VHL gene restores the instability of HIF-1alpha and HIF-2alpha proteins under normoxic conditions. Moreover, immunohistochemical analyses of RCCs and hemangioblastomas demonstrate up-regulation of HIF-1alpha and HIF-2alpha in the tumor cells. The data presented here provide evidence for a role of the VHL protein in regulation of angiogenesis and erythropoiesis mediated by the HIF-1alpha and HIF-2alpha proteins.

Authors+Show Affiliations

Neurocenter, Freiburg University Medical School, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11114720

Citation

Krieg, M, et al. "Up-regulation of Hypoxia-inducible Factors HIF-1alpha and HIF-2alpha Under Normoxic Conditions in Renal Carcinoma Cells By Von Hippel-Lindau Tumor Suppressor Gene Loss of Function." Oncogene, vol. 19, no. 48, 2000, pp. 5435-43.
Krieg M, Haas R, Brauch H, et al. Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene. 2000;19(48):5435-43.
Krieg, M., Haas, R., Brauch, H., Acker, T., Flamme, I., & Plate, K. H. (2000). Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene, 19(48), 5435-43.
Krieg M, et al. Up-regulation of Hypoxia-inducible Factors HIF-1alpha and HIF-2alpha Under Normoxic Conditions in Renal Carcinoma Cells By Von Hippel-Lindau Tumor Suppressor Gene Loss of Function. Oncogene. 2000 Nov 16;19(48):5435-43. PubMed PMID: 11114720.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. AU - Krieg,M, AU - Haas,R, AU - Brauch,H, AU - Acker,T, AU - Flamme,I, AU - Plate,K H, PY - 2000/12/15/pubmed PY - 2001/2/28/medline PY - 2000/12/15/entrez SP - 5435 EP - 43 JF - Oncogene JO - Oncogene VL - 19 IS - 48 N2 - Hypoxia induces transcription of a range of physiologically important genes including erythropoietin and vascular endothelial growth factor. The transcriptional activation is mediated by the hypoxia-inducible factor-1 (HIF-1), a heterodimeric member of the basic helix-loop-helix PAS family, composed of alpha and beta subunits. HIF-1alpha shares 48 per cent identity with the recently identified HIF-2alpha protein that is also stimulated by hypoxia. In a previous study of hemangioblastomas, the most frequent manifestation of hereditary von Hippel-Lindau disease (VHL), we found elevated levels of vascular endothelial growth factor and HIF-2alpha mRNA in stromal cells of the tumors. Mutations of the VHL tumor suppressor gene are associated with a variety of tumors such as renal clear cell carcinomas (RCC). In this study, we analysed the expression of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in a range of VHL wildtype and VHL deficient RCC cell lines. In the presence of functional VHL protein, HIF-1alpha mRNA levels are elevated, whereas HIF-2alpha mRNA expression is increased only in cells lacking a functional VHL gene product. On the protein levels, however, in VHL deficient cell lines, both HIF-alpha subunits are constitutively expressed, whereas re-introduction of a functional VHL gene restores the instability of HIF-1alpha and HIF-2alpha proteins under normoxic conditions. Moreover, immunohistochemical analyses of RCCs and hemangioblastomas demonstrate up-regulation of HIF-1alpha and HIF-2alpha in the tumor cells. The data presented here provide evidence for a role of the VHL protein in regulation of angiogenesis and erythropoiesis mediated by the HIF-1alpha and HIF-2alpha proteins. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/11114720/Up_regulation_of_hypoxia_inducible_factors_HIF_1alpha_and_HIF_2alpha_under_normoxic_conditions_in_renal_carcinoma_cells_by_von_Hippel_Lindau_tumor_suppressor_gene_loss_of_function_ L2 - https://doi.org/10.1038/sj.onc.1203938 DB - PRIME DP - Unbound Medicine ER -