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Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma.
Mol Cell Biol. 2005 Jul; 25(13):5675-86.MC

Abstract

Defective function of the von Hippel-Lindau (VHL) tumor suppressor ablates proteolytic regulation of hypoxia-inducible factor alpha subunits (HIF-1alpha and HIF-2alpha), leading to constitutive activation of hypoxia pathways in renal cell carcinoma (RCC). Here we report a comparative analysis of the functions of HIF-1alpha and HIF-2alpha in RCC and non-RCC cells. We demonstrate common patterns of HIF-alpha isoform transcriptional selectivity in VHL-defective RCC that show consistent and striking differences from patterns in other cell types. We also show that HIF-alpha isoforms display unexpected suppressive interactions in RCC cells, with enhanced expression of HIF-2alpha suppressing HIF-1alpha and vice-versa. In VHL-defective RCC cells, we demonstrate that the protumorigenic genes encoding cyclin D1, transforming growth factor alpha, and vascular endothelial growth factor respond specifically to HIF-2alpha and that the proapoptotic gene encoding BNip3 responds positively to HIF-1alpha and negatively to HIF-2alpha, indicating that HIF-1alpha and HIF-2alpha have contrasting properties in the biology of RCC. In keeping with this, HIF-alpha isoform-specific transcriptional selectivity was matched by differential effects on the growth of RCC as tumor xenografts, with HIF-1alpha retarding and HIF-2alpha enhancing tumor growth. These findings indicate that therapeutic approaches to targeting of the HIF system, at least in this setting, will need to take account of HIF isoform-specific functions.

Authors+Show Affiliations

The Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

15964822

Citation

Raval, Raju R., et al. "Contrasting Properties of Hypoxia-inducible Factor 1 (HIF-1) and HIF-2 in Von Hippel-Lindau-associated Renal Cell Carcinoma." Molecular and Cellular Biology, vol. 25, no. 13, 2005, pp. 5675-86.
Raval RR, Lau KW, Tran MG, et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol. 2005;25(13):5675-86.
Raval, R. R., Lau, K. W., Tran, M. G., Sowter, H. M., Mandriota, S. J., Li, J. L., Pugh, C. W., Maxwell, P. H., Harris, A. L., & Ratcliffe, P. J. (2005). Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Molecular and Cellular Biology, 25(13), 5675-86.
Raval RR, et al. Contrasting Properties of Hypoxia-inducible Factor 1 (HIF-1) and HIF-2 in Von Hippel-Lindau-associated Renal Cell Carcinoma. Mol Cell Biol. 2005;25(13):5675-86. PubMed PMID: 15964822.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. AU - Raval,Raju R, AU - Lau,Kah Weng, AU - Tran,Maxine G B, AU - Sowter,Heidi M, AU - Mandriota,Stefano J, AU - Li,Ji-Liang, AU - Pugh,Christopher W, AU - Maxwell,Patrick H, AU - Harris,Adrian L, AU - Ratcliffe,Peter J, PY - 2005/6/21/pubmed PY - 2005/8/3/medline PY - 2005/6/21/entrez SP - 5675 EP - 86 JF - Molecular and cellular biology JO - Mol Cell Biol VL - 25 IS - 13 N2 - Defective function of the von Hippel-Lindau (VHL) tumor suppressor ablates proteolytic regulation of hypoxia-inducible factor alpha subunits (HIF-1alpha and HIF-2alpha), leading to constitutive activation of hypoxia pathways in renal cell carcinoma (RCC). Here we report a comparative analysis of the functions of HIF-1alpha and HIF-2alpha in RCC and non-RCC cells. We demonstrate common patterns of HIF-alpha isoform transcriptional selectivity in VHL-defective RCC that show consistent and striking differences from patterns in other cell types. We also show that HIF-alpha isoforms display unexpected suppressive interactions in RCC cells, with enhanced expression of HIF-2alpha suppressing HIF-1alpha and vice-versa. In VHL-defective RCC cells, we demonstrate that the protumorigenic genes encoding cyclin D1, transforming growth factor alpha, and vascular endothelial growth factor respond specifically to HIF-2alpha and that the proapoptotic gene encoding BNip3 responds positively to HIF-1alpha and negatively to HIF-2alpha, indicating that HIF-1alpha and HIF-2alpha have contrasting properties in the biology of RCC. In keeping with this, HIF-alpha isoform-specific transcriptional selectivity was matched by differential effects on the growth of RCC as tumor xenografts, with HIF-1alpha retarding and HIF-2alpha enhancing tumor growth. These findings indicate that therapeutic approaches to targeting of the HIF system, at least in this setting, will need to take account of HIF isoform-specific functions. SN - 0270-7306 UR - https://www.unboundmedicine.com/medline/citation/15964822/Contrasting_properties_of_hypoxia_inducible_factor_1__HIF_1__and_HIF_2_in_von_Hippel_Lindau_associated_renal_cell_carcinoma_ L2 - https://journals.asm.org/doi/10.1128/MCB.25.13.5675-5686.2005?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -