title: HIF1α and HIF2α exert distinct nutrient preferences in renal cells.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Genetics Department, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Arreola
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Now at Baylor Sammons Cancer Center, Dallas, Texas, United States of America.
authors.forename: C Lance
authors.initials: CL
authors.lastname: Cowey
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America; Now at Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Coloff
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Rathmell
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Genetics Department, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Medicine, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: W Kimryn
authors.initials: WK
authors.lastname: Rathmell
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism*; D002244:Carbon / Q000378:metabolism; D002460:Cell Line; D003470:Culture Media / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005502:Food; D015870:Gene Expression / Q000235:genetics; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D055442:Metabolome / Q000235:genetics; D051379:Mice; D010085:Oxidative Phosphorylation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002244:Carbon; D003470:Culture Media; D005947:Glucose; D018698:Glutamic Acid; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse