HIF1α and HIF2α exert distinct nutrient preferences in renal cells.
<h4>Background</h4>Hypoxia Inducible Factors (HIF1α and HIF2α) are commonly stabilized and play key roles related to cell growth and metabolic programming in clear cell renal cell carcinoma. The relationship of these factors to discretely alter cell metabolic activities has largely been...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24879016/pdf/?tool=EBI |
| _version_ | 1819240688691183616 |
|---|---|
| author | Alexandra Arreola C Lance Cowey Jonathan L Coloff Jeffrey C Rathmell W Kimryn Rathmell |
| author_facet | Alexandra Arreola C Lance Cowey Jonathan L Coloff Jeffrey C Rathmell W Kimryn Rathmell |
| author_sort | Alexandra Arreola |
| collection | DOAJ |
| description | <h4>Background</h4>Hypoxia Inducible Factors (HIF1α and HIF2α) are commonly stabilized and play key roles related to cell growth and metabolic programming in clear cell renal cell carcinoma. The relationship of these factors to discretely alter cell metabolic activities has largely been described in cancer cells, or in hypoxic conditions, where other confounding factors undoubtedly compete. These transcription factors and their specific roles in promoting cancer metabolic phenotypes from the earliest stages are poorly understood in pre-malignant cells.<h4>Methods</h4>We undertook an analysis of SV40-transformed primary kidney epithelial cells derived from newborn mice genetically engineered to express a stabilized HIF1α or HIF2α transgene. We examined the metabolic profile in relation to each gene.<h4>Results</h4>Although the cells proliferated similarly, the metabolic profile of each genotype of cell was markedly different and correlated with altered gene expression of factors influencing components of metabolic signaling. HIF1α promoted high levels of glycolysis as well as increased oxidative phosphorylation in complete media, but oxidative phosphorylation was suppressed when supplied with single carbon source media. HIF2α, in contrast, supported oxidative phosphorylation in complete media or single glucose carbon source, but these cells were not responsive to glutamine nutrient sources. This finding correlates to HIF2α-specific induction of Glul, effectively reducing glutamine utilization by limiting the glutamate pool, and knockdown of Glul allows these cells to perform oxidative phosphorylation in glutamine media.<h4>Conclusion</h4>HIF1α and HIF2α support highly divergent patterns of kidney epithelial cell metabolic phenotype. Expression of these factors ultimately alters the nutrient resource utilization and energy generation strategy in the setting of complete or limiting nutrients. |
| first_indexed | 2024-12-23T14:12:00Z |
| format | Article |
| id | doaj.art-66c8728aa04a4df58283485dded54e1c |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T14:12:00Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-66c8728aa04a4df58283485dded54e1c2022-12-21T17:44:01ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0195e9870510.1371/journal.pone.0098705HIF1α and HIF2α exert distinct nutrient preferences in renal cells.Alexandra ArreolaC Lance CoweyJonathan L ColoffJeffrey C RathmellW Kimryn Rathmell<h4>Background</h4>Hypoxia Inducible Factors (HIF1α and HIF2α) are commonly stabilized and play key roles related to cell growth and metabolic programming in clear cell renal cell carcinoma. The relationship of these factors to discretely alter cell metabolic activities has largely been described in cancer cells, or in hypoxic conditions, where other confounding factors undoubtedly compete. These transcription factors and their specific roles in promoting cancer metabolic phenotypes from the earliest stages are poorly understood in pre-malignant cells.<h4>Methods</h4>We undertook an analysis of SV40-transformed primary kidney epithelial cells derived from newborn mice genetically engineered to express a stabilized HIF1α or HIF2α transgene. We examined the metabolic profile in relation to each gene.<h4>Results</h4>Although the cells proliferated similarly, the metabolic profile of each genotype of cell was markedly different and correlated with altered gene expression of factors influencing components of metabolic signaling. HIF1α promoted high levels of glycolysis as well as increased oxidative phosphorylation in complete media, but oxidative phosphorylation was suppressed when supplied with single carbon source media. HIF2α, in contrast, supported oxidative phosphorylation in complete media or single glucose carbon source, but these cells were not responsive to glutamine nutrient sources. This finding correlates to HIF2α-specific induction of Glul, effectively reducing glutamine utilization by limiting the glutamate pool, and knockdown of Glul allows these cells to perform oxidative phosphorylation in glutamine media.<h4>Conclusion</h4>HIF1α and HIF2α support highly divergent patterns of kidney epithelial cell metabolic phenotype. Expression of these factors ultimately alters the nutrient resource utilization and energy generation strategy in the setting of complete or limiting nutrients.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24879016/pdf/?tool=EBI |
| spellingShingle | Alexandra Arreola C Lance Cowey Jonathan L Coloff Jeffrey C Rathmell W Kimryn Rathmell HIF1α and HIF2α exert distinct nutrient preferences in renal cells. PLoS ONE |
| title | HIF1α and HIF2α exert distinct nutrient preferences in renal cells. |
| title_full | HIF1α and HIF2α exert distinct nutrient preferences in renal cells. |
| title_fullStr | HIF1α and HIF2α exert distinct nutrient preferences in renal cells. |
| title_full_unstemmed | HIF1α and HIF2α exert distinct nutrient preferences in renal cells. |
| title_short | HIF1α and HIF2α exert distinct nutrient preferences in renal cells. |
| title_sort | hif1α and hif2α exert distinct nutrient preferences in renal cells |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24879016/pdf/?tool=EBI |
| work_keys_str_mv | AT alexandraarreola hif1aandhif2aexertdistinctnutrientpreferencesinrenalcells AT clancecowey hif1aandhif2aexertdistinctnutrientpreferencesinrenalcells AT jonathanlcoloff hif1aandhif2aexertdistinctnutrientpreferencesinrenalcells AT jeffreycrathmell hif1aandhif2aexertdistinctnutrientpreferencesinrenalcells AT wkimrynrathmell hif1aandhif2aexertdistinctnutrientpreferencesinrenalcells |