title: HIF- and non-HIF-regulated hypoxic responses require the estrogen-related receptor in Drosophila melanogaster.
abstract: Low-oxygen tolerance is supported by an adaptive response that includes a coordinate shift in metabolism and the activation of a transcriptional program that is driven by the hypoxia-inducible factor (HIF) pathway. The precise contribution of HIF-1a in the adaptive response, however, has not been determined. Here, we investigate how HIF influences hypoxic adaptation throughout Drosophila melanogaster development. We find that hypoxic-induced transcriptional changes are comprised of HIF-dependent and HIF-independent pathways that are distinct and separable. We show that normoxic set-points of carbohydrate metabolites are significantly altered in sima mutants and that these animals are unable to mobilize glycogen in hypoxia. Furthermore, we find that the estrogen-related receptor (dERR), which is a global regulator of aerobic glycolysis in larvae, is required for a competent hypoxic response. dERR binds to dHIFa and participates in the HIF-dependent transcriptional program in hypoxia. In addition, dERR acts in the absence of dHIFa in hypoxia and a significant portion of HIF-independent transcriptional responses can be attributed to dERR actions, including upregulation of glycolytic transcripts. These results indicate that competent hypoxic responses arise from complex interactions between HIF-dependent and -independent mechanisms, and that dERR plays a central role in both of these programs.
authors: Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America.
authors: Yan
authors: Y
authors: Li
authors: Divya
authors: D
authors: Padmanabha
authors: Luciana B
authors: LB
authors: Gentile
authors: Catherine I
authors: CI
authors: Dumur
authors: Robert B
authors: RB
authors: Beckstead
authors: Keith D
authors: KD
authors: Baker
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics; D004967:Estrogens / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D006019:Glycolysis; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D010100:Oxygen; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C475538:ERR protein, Drosophila; D004967:Estrogens; D051793:Hypoxia-Inducible Factor 1; D011960:Receptors, Estrogen; D010100:Oxygen
references: Dev Cell. 2008 Apr;14(4):547-58
references: 18410730
references: J Cell Physiol. 1984 Mar;118(3):287-90
references: 6699103
references: Cell. 1999 Jul 9;98(1):105-14
references: 10412985
references: Mol Cancer Res. 2007 Jan;5(1):71-85
references: 17259347
references: J Biol Chem. 2005 Sep 9;280(36):31557-63
references: 16014625
references: Genes Dev. 2007 Feb 15;21(4):450-64
references: 17322404
references: Cancer Res. 2003 Mar 1;63(5):1138-43
references: 12615733
references: Cancer Res. 2004 Jul 1;64(13):4670-6
references: 15231680
references: Nat Rev Cancer. 2003 Oct;3(10):721-32
references: 13130303
references: PLoS One. 2010 Aug 25;5(8):e12390
references: 20811646
references: EMBO Rep. 2005 Nov;6(11):1070-5
references: 16179946
references: J Biol Chem. 2006 Jun 2;281(22):15215-26
references: 16565084
references: Bioinformatics. 2004 Jun 12;20(9):1464-5
references: 14962934
references: Oncogene. 2013 Apr 18;32(16):2079-86
references: 22665055
references: J Steroid Biochem Mol Biol. 2009 Mar;114(1-2):106-12
references: 19429439
references: J Immunol. 2005 Nov 15;175(10):6257-63
references: 16272275
references: Kidney Int. 2008 Oct;74(7):867-72
references: 18633339
references: J Insect Physiol. 1997 Mar;43(3):203-210
references: 12769903
references: Endocr Relat Cancer. 2006 Dec;13 Suppl 1:S25-32
references: 17259555
references: Mol Cell Biol. 2001 May;21(10):3436-44
references: 11313469
references: Science. 1999 Jun 4;284(5420):1635-9
references: 10383344
references: PLoS Genet. 2008 Oct;4(10):e1000221
references: 18927626
references: EMBO J. 1998 Jun 1;17(11):3005-15
references: 9606183
references: J Biol Chem. 2008 Apr 18;283(16):10892-903
references: 18281291
references: Nucleic Acids Res. 2003 Feb 15;31(4):e15
references: 12582260
references: FEBS J. 2011 Aug;278(15):2613-24
references: 21624055
references: Anal Chem. 2009 Aug 15;81(16):6656-67
references: 19624122
references: Mol Syst Biol. 2007;3:99
references: 17437024
references: Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7821-6
references: 18509053
references: Genes Dev. 2006 Jun 1;20(11):1405-28
references: 16751179
references: Biochemistry. 2011 Feb 22;50(7):1194-202
references: 21207956
references: Cell Microbiol. 2008 Aug;10(8):1687-94
references: 18460012
references: J Biol Chem. 1998 Apr 3;273(14):8360-8
references: 9525945
references: J Neurobiol. 2006 Jan;66(1):19-32
references: 16187303
references: Science. 2001 Apr 20;292(5516):464-8
references: 11292862
references: Methods Enzymol. 2007;435:123-44
references: 17998052
references: Cell. 2001 Oct 5;107(1):43-54
references: 11595184
references: Biochem Biophys Res Commun. 1998 Aug 28;249(3):811-6
references: 9731218
references: Genes Dev. 1998 Jan 15;12(2):149-62
references: 9436976
references: BMC Biol. 2012 Jul 24;10:63
references: 22824239
references: Cell Death Differ. 2008 Apr;15(4):660-6
references: 18219320
references: J Cell Sci. 2005 Dec 1;118(Pt 23):5431-41
references: 16278294
references: N Engl J Med. 2011 Aug 11;365(6):537-47
references: 21830968
references: Cancer Res. 2004 Mar 1;64(5):1765-72
references: 14996738
references: J Biol Chem. 2006 Oct 27;281(43):32639-48
references: 16950777
references: Science. 2001 Nov 9;294(5545):1337-40
references: 11598268
references: J Biol Chem. 1995 Sep 8;270(36):21021-7
references: 7673128
references: J Clin Invest. 1999 Mar;103(5):691-6
references: 10074486
references: FEBS J. 2009 Mar;276(5):1370-82
references: 19187226
references: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10430-5
references: 10973499
references: Physiol Genomics. 2006 Mar 13;25(1):134-41
references: 16403841
references: Gene Expr. 2003;11(3-4):181-97
references: 14686790
references: J Cell Biol. 2007 Jun 18;177(6):1029-36
references: 17562787
references: J Biol Chem. 2005 May 27;280(21):20580-8
references: 15781453
references: Mol Cell Biol. 2002 Oct;22(19):6842-53
references: 12215541
references: Science. 2001 Apr 20;292(5516):468-72
references: 11292861
references: Science. 2002 May 10;296(5570):1118-20
references: 12004130
references: Cell Metab. 2009 Mar;9(3):228-39
references: 19254568
references: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
references: 11309499
references: Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9630-5
references: 11504942
references: Nature. 2012 May 06;486(7401):126-9
references: 22678294
references: Cell Metab. 2011 Feb 2;13(2):139-48
references: 21284981
references: J Cheminform. 2010 Oct 18;2(1):9
references: 20955607
references: Genet Res. 1966 Jun;7(3):383-407
references: 5940873
references: Nature. 1998 Jul 30;394(6692):485-90
references: 9697772
references: Dev Biol. 2009 May 15;329(2):294-305
references: 19285057
references: Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):3105-10
references: 15708981
references: Cancer Res. 2001 Sep 15;61(18):6755-61
references: 11559547