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Differential effects of HIF-α isoforms on apoptosis in renal carcinoma cell lines
BACKGROUND: Germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene predispose individuals to clear cell renal carcinomas, hemangioblastomas, and pheochromocytomas. The VHL gene product forms an ubiquitin E3 ligase complex, with regulation of hypoxia-inducible factor alpha (HIF-α) as...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342814/ https://www.ncbi.nlm.nih.gov/pubmed/25729330 http://dx.doi.org/10.1186/s12935-015-0175-3 |
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author | Doonachar, Alana Gallo, Michael D Doukas, Donald Pasricha, Rajiv Lantsberg, Igor Schoenfeld, Alan R |
author_facet | Doonachar, Alana Gallo, Michael D Doukas, Donald Pasricha, Rajiv Lantsberg, Igor Schoenfeld, Alan R |
author_sort | Doonachar, Alana |
collection | PubMed |
description | BACKGROUND: Germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene predispose individuals to clear cell renal carcinomas, hemangioblastomas, and pheochromocytomas. The VHL gene product forms an ubiquitin E3 ligase complex, with regulation of hypoxia-inducible factor alpha (HIF-α) as its best known function. Lack of VHL expression has been shown previously to sensitize renal cells to apoptosis caused by certain cellular stresses. In this report, the role of HIF-α in apoptosis was investigated using two parent VHL-null renal carcinoma cell lines. METHODS: 786-O and RCC10 renal carcinoma cell lines with manipulated levels of VHL, HIF-1α, or HIF-2α were subjected to cellular stresses and analyzed by western blotting for the abundance of apoptotic markers. RESULTS: Cell lines expressing mutant VHL proteins that were unable to regulate HIF-α had increased levels of apoptosis when irradiated with ultraviolet (UV) light. The influences of the two major isoforms of HIF-α, HIF-1α and HIF-2α, on apoptosis, were compared by creating cell lines in which levels of each isoform were modulated via short hairpin RNA interference. In UV-irradiated cells, HIF-2α expression was determined to promote apoptosis, whereas HIF-1α was anti-apoptotic. In cells deprived of either glucose or serum, HIF-1α expression was generally anti-apoptotic, while HIF-2α expression was observed to either promote apoptosis or have less of an influence on apoptosis, depending on the cell line used. CONCLUSIONS: HIF-1α and HIF-2α exerted distinct effects in each of the conditions tested, with expression of HIF-1α largely blocking apoptosis and HIF-2α generally promoting apoptosis. These results reinforce that HIF-1α and HIF-2α have distinct biological roles and that their relative expression levels may influence some therapeutic interventions that are dependent on apoptosis. |
format | Online Article Text |
id | pubmed-4342814 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-43428142015-02-28 Differential effects of HIF-α isoforms on apoptosis in renal carcinoma cell lines Doonachar, Alana Gallo, Michael D Doukas, Donald Pasricha, Rajiv Lantsberg, Igor Schoenfeld, Alan R Cancer Cell Int Primary Research BACKGROUND: Germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene predispose individuals to clear cell renal carcinomas, hemangioblastomas, and pheochromocytomas. The VHL gene product forms an ubiquitin E3 ligase complex, with regulation of hypoxia-inducible factor alpha (HIF-α) as its best known function. Lack of VHL expression has been shown previously to sensitize renal cells to apoptosis caused by certain cellular stresses. In this report, the role of HIF-α in apoptosis was investigated using two parent VHL-null renal carcinoma cell lines. METHODS: 786-O and RCC10 renal carcinoma cell lines with manipulated levels of VHL, HIF-1α, or HIF-2α were subjected to cellular stresses and analyzed by western blotting for the abundance of apoptotic markers. RESULTS: Cell lines expressing mutant VHL proteins that were unable to regulate HIF-α had increased levels of apoptosis when irradiated with ultraviolet (UV) light. The influences of the two major isoforms of HIF-α, HIF-1α and HIF-2α, on apoptosis, were compared by creating cell lines in which levels of each isoform were modulated via short hairpin RNA interference. In UV-irradiated cells, HIF-2α expression was determined to promote apoptosis, whereas HIF-1α was anti-apoptotic. In cells deprived of either glucose or serum, HIF-1α expression was generally anti-apoptotic, while HIF-2α expression was observed to either promote apoptosis or have less of an influence on apoptosis, depending on the cell line used. CONCLUSIONS: HIF-1α and HIF-2α exerted distinct effects in each of the conditions tested, with expression of HIF-1α largely blocking apoptosis and HIF-2α generally promoting apoptosis. These results reinforce that HIF-1α and HIF-2α have distinct biological roles and that their relative expression levels may influence some therapeutic interventions that are dependent on apoptosis. BioMed Central 2015-02-22 /pmc/articles/PMC4342814/ /pubmed/25729330 http://dx.doi.org/10.1186/s12935-015-0175-3 Text en © Doonachar et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Primary Research Doonachar, Alana Gallo, Michael D Doukas, Donald Pasricha, Rajiv Lantsberg, Igor Schoenfeld, Alan R Differential effects of HIF-α isoforms on apoptosis in renal carcinoma cell lines |
title | Differential effects of HIF-α isoforms on apoptosis in renal carcinoma cell lines |
title_full | Differential effects of HIF-α isoforms on apoptosis in renal carcinoma cell lines |
title_fullStr | Differential effects of HIF-α isoforms on apoptosis in renal carcinoma cell lines |
title_full_unstemmed | Differential effects of HIF-α isoforms on apoptosis in renal carcinoma cell lines |
title_short | Differential effects of HIF-α isoforms on apoptosis in renal carcinoma cell lines |
title_sort | differential effects of hif-α isoforms on apoptosis in renal carcinoma cell lines |
topic | Primary Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342814/ https://www.ncbi.nlm.nih.gov/pubmed/25729330 http://dx.doi.org/10.1186/s12935-015-0175-3 |
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