Gene Symbol: sima
Description: similar
Alias: 7951, CG31031, CG45051, CG7951, DMU43090, Dmel\CG45051, Dmel_CG31031, Dmel_CG7951, HIF alpha, HIF-1, HIF-1alpha, HIF-alpha/sima, HIF1alpha, Hif-1A, Hif1alpha, SIMA, Sima, bHLHe56, dHIF-1alpha, dHIF-alpha, l(3)j11B7, CG45051-PA, CG45051-PB, CG45051-PC, CG45051-PD, HIF alpha, HIF-alpha, hypoxia inducible factor, hypoxia inducible factor ortholog, hypoxia-inducible factor-1, sima-PA, sima-PB, sima-PC, sima-PD
Species: fruit fly

Top Publications

  1. Nambu J, Chen W, Hu S, Crews S. The Drosophila melanogaster similar bHLH-PAS gene encodes a protein related to human hypoxia-inducible factor 1 alpha and Drosophila single-minded. Gene. 1996;172:249-54 pubmed
    The Drosophila melanogaster (Dm) similar (sima) gene was isolated using a low-stringency hybridization screen employing a Dm single-minded gene basic helix-loop-helix (bHLH) DNA probe...
  2. Acevedo J, Centanin L, Dekanty A, Wappner P. Oxygen sensing in Drosophila: multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFalpha/Sima. PLoS ONE. 2010;5:e12390 pubmed publisher
    The Hypoxia Inducible Factor (HIF) mediates cellular adaptations to low oxygen. Prolyl-4-hydroxylases are oxygen sensors that hydroxylate the HIF alpha-subunit, promoting its proteasomal degradation in normoxia...
  3. Centanin L, Dekanty A, Romero N, Irisarri M, Gorr T, Wappner P. Cell autonomy of HIF effects in Drosophila: tracheal cells sense hypoxia and induce terminal branch sprouting. Dev Cell. 2008;14:547-58 pubmed publisher
    ..Here, we show that extra sprouting depends on the Hypoxia-Inducible Factor (HIF)-alpha homolog Sima and on the HIF-prolyl hydroxylase Fatiga that operates as an oxygen sensor...
  4. Reiling J, Hafen E. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev. 2004;18:2879-92 pubmed
  5. Gorr T, Tomita T, Wappner P, Bunn H. Regulation of Drosophila hypoxia-inducible factor (HIF) activity in SL2 cells: identification of a hypoxia-induced variant isoform of the HIFalpha homolog gene similar. J Biol Chem. 2004;279:36048-58 pubmed
    ..Here, we report that the Drosophila HIFalpha homolog, the basic helix-loop-helix/PAS protein Sima (Similar), in hypoxic cultures of SL2 cells is expressed in full-length (fl) and splice variant (sv) isoforms...
  6. Bacon N, Wappner P, O Rourke J, Bartlett S, Shilo B, Pugh C, et al. Regulation of the Drosophila bHLH-PAS protein Sima by hypoxia: functional evidence for homology with mammalian HIF-1 alpha. Biochem Biophys Res Commun. 1998;249:811-6 pubmed
    b>Hypoxia inducible factor-1 (HIF-1) is a heterodimeric complex of two basic-helix-loop-helix proteins of the PAS family which is critical for oxygen-dependent expression of many mammalian genes...
  7. Lavista Llanos S, Centanin L, Irisarri M, Russo D, Gleadle J, Bocca S, et al. Control of the hypoxic response in Drosophila melanogaster by the basic helix-loop-helix PAS protein similar. Mol Cell Biol. 2002;22:6842-53 pubmed
    ..We show that the bHLH-PAS proteins Similar (Sima) and Tango (Tgo) function as HIF-alpha and HIF-beta homologues, respectively, and demonstrate a conserved mode of ..
  8. Kim J, Jang W, Lee H, Park E, Kim C. Neurodegeneration of Drosophila drop-dead mutants is associated with hypoxia in the brain. Genes Brain Behav. 2012;11:177-84 pubmed publisher
    ..Feeding of anti-reactive oxygen species agents partially rescue the drd from sudden death. We propose that drd flies can provide a non-invasive animal model for hypoxia-induced cell death. ..
  9. Arquier N, Vigne P, Duplan E, Hsu T, Therond P, Frelin C, et al. Analysis of the hypoxia-sensing pathway in Drosophila melanogaster. Biochem J. 2006;393:471-80 pubmed
    ..Hypoxic stabilization of ODD-GFP in the ectoderm was restored by inducing VHL expression in these cells. These results show that Drosophila tissues exhibit different sensitivities to hypoxia. ..

More Information


  1. Centanin L, Ratcliffe P, Wappner P. Reversion of lethality and growth defects in Fatiga oxygen-sensor mutant flies by loss of hypoxia-inducible factor-alpha/Sima. EMBO Rep. 2005;6:1070-5 pubmed
    ..We also report a null mutation in dHIF-alpha/sima, which is unable to adapt to hypoxia but is fully viable in normoxic conditions...
  2. Mortimer N, Moberg K. Regulation of Drosophila embryonic tracheogenesis by dVHL and hypoxia. Dev Biol. 2009;329:294-305 pubmed publisher
    ..Larval tracheal cells respond to hypoxia by activating a program of branching and growth driven by HIF-1alpha/sima-dependent expression of the breathless (btl) FGF receptor...
  3. Vigne P, Frelin C. The role of polyamines in protein-dependent hypoxic tolerance of Drosophila. BMC Physiol. 2008;8:22 pubmed publisher
    ..Pharmacological evidence suggests that the synthesis of polyamines and the hypusination of eIF5A contributed to the life-shortening effect of dietary amino acids. ..
  4. van Uden P, Kenneth N, Webster R, Müller H, Mudie S, Rocha S. Evolutionary conserved regulation of HIF-1β by NF-κB. PLoS Genet. 2011;7:e1001285 pubmed publisher
    b>Hypoxia Inducible Factor-1 (HIF-1) is essential for mammalian development and is the principal transcription factor activated by low oxygen tensions...
  5. Bruick R, McKnight S. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294:1337-40 pubmed
    ..These findings indicate that HPH is an essential component of the pathway through which cells sense oxygen. ..
  6. Sonnenfeld M, Ward M, Nystrom G, Mosher J, Stahl S, Crews S. The Drosophila tango gene encodes a bHLH-PAS protein that is orthologous to mammalian Arnt and controls CNS midline and tracheal development. Development. 1997;124:4571-82 pubmed
    ..These experiments support the existence of an evolutionarily conserved, functionally diverse bHLH-PAS protein regulatory system. ..
  7. Li Y, Padmanabha D, Gentile L, Dumur C, Beckstead R, Baker K. HIF- and non-HIF-regulated hypoxic responses require the estrogen-related receptor in Drosophila melanogaster. PLoS Genet. 2013;9:e1003230 pubmed publisher
    ..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...
  8. Irisarri M, Lavista Llanos S, Romero N, Centanin L, Dekanty A, Wappner P. Central role of the oxygen-dependent degradation domain of Drosophila HIFalpha/Sima in oxygen-dependent nuclear export. Mol Biol Cell. 2009;20:3878-87 pubmed publisher
    The Drosophila HIFalpha homologue, Sima, is localized mainly in the cytoplasm in normoxia and accumulates in the nucleus upon hypoxic exposure...
  9. Dekanty A, Lavista Llanos S, Irisarri M, Oldham S, Wappner P. The insulin-PI3K/TOR pathway induces a HIF-dependent transcriptional response in Drosophila by promoting nuclear localization of HIF-alpha/Sima. J Cell Sci. 2005;118:5431-41 pubmed
    ..In Drosophila, the bHLH-PAS proteins Similar (Sima) and Tango (Tgo) are the functional homologues of the mammalian HIF-alpha and HIF-beta subunits, respectively...
  10. Jiang L, Crews S. The Drosophila dysfusion basic helix-loop-helix (bHLH)-PAS gene controls tracheal fusion and levels of the trachealess bHLH-PAS protein. Mol Cell Biol. 2003;23:5625-37 pubmed
    ..These results suggest the possibility that competitive interactions between basic helix-loop-helix-PAS proteins (Dysfusion, Trachealess, and possibly Similar) may be important for the proper development of the trachea. ..
  11. Shmueli M, Schnaider L, Herzog G, Gazit E, Segal D. Computational and experimental characterization of dVHL establish a Drosophila model of VHL syndrome. PLoS ONE. 2014;9:e109864 pubmed publisher
    ..This novel transgenic Drosophila model is thus useful for studying the VHL syndrome, and for testing drug candidates to treat it. ..
  12. Choo A, O Keefe L, Lee C, Gregory S, Shaukat Z, Colella A, et al. Tumor suppressor WWOX moderates the mitochondrial respiratory complex. Genes Chromosomes Cancer. 2015;54:745-61 pubmed publisher
    ..Thus, the ability of WWOX to facilitate escape from mitochondrial damage-induced glycolysis (Warburg effect) is, therefore, a plausible mechanism for its tumor suppressor activity. ..
  13. Hahn M, Karchner S, Shapiro M, Perera S. Molecular evolution of two vertebrate aryl hydrocarbon (dioxin) receptors (AHR1 and AHR2) and the PAS family. Proc Natl Acad Sci U S A. 1997;94:13743-8 pubmed
  14. Crews S, Brenman J. Spineless provides a little backbone for dendritic morphogenesis. Genes Dev. 2006;20:2773-8 pubmed
  15. Vigne P, Tauc M, Frelin C. Strong dietary restrictions protect Drosophila against anoxia/reoxygenation injuries. PLoS ONE. 2009;4:e5422 pubmed publisher
    ..AMP kinase and the insulin signalling pathway are possible mediators of diet dependent anoxic tolerance in Drosophila. ..
  16. Mortimer N, Moberg K. The archipelago ubiquitin ligase subunit acts in target tissue to restrict tracheal terminal cell branching and hypoxic-induced gene expression. PLoS Genet. 2013;9:e1003314 pubmed publisher
    ..This tracheogenic phenotype shows a genetic dependence on sima, which encodes the HIF-1? subunit of the hypoxia-inducible transcription factor dHIF and its target the FGF ligand ..
  17. Crews S. Control of cell lineage-specific development and transcription by bHLH-PAS proteins. Genes Dev. 1998;12:607-20 pubmed
  18. Gorr T, Cahn J, Yamagata H, Bunn H. Hypoxia-induced synthesis of hemoglobin in the crustacean Daphnia magna is hypoxia-inducible factor-dependent. J Biol Chem. 2004;279:36038-47 pubmed
    ..In human cells, this -146 complex interferes with HIF occupancy at the adjacent -107 HRE and thus controls the extent of HIF-mediated hypoxic activation of the downstream target. ..
  19. Grifoni D, Sollazzo M, Fontana E, Froldi F, Pession A. Multiple strategies of oxygen supply in Drosophila malignancies identify tracheogenesis as a novel cancer hallmark. Sci Rep. 2015;5:9061 pubmed publisher
    ..In summary, our findings identify tracheogenesis as a novel cancer hallmark in Drosophila, further expanding the power of the fly model in cancer research. ..
  20. Mukherjee T, Kim W, Mandal L, Banerjee U. Interaction between Notch and Hif-alpha in development and survival of Drosophila blood cells. Science. 2011;332:1210-3 pubmed publisher
    ..We report that crystal cells express elevated levels of Sima protein orthologous to mammalian hypoxia-inducible factor-? (Hif-?) even under conditions of normal oxygen ..
  21. Zelzer E, Shilo B. Interaction between the bHLH-PAS protein Trachealess and the POU-domain protein Drifter, specifies tracheal cell fates. Mech Dev. 2000;91:163-73 pubmed
    ..A direct interaction between Drifter and Trh proteins, mediated by the PAS domain of Trh and the POU domain of Drifter, was demonstrated. ..
  22. Sansone C, Blumenthal E. Neurodegeneration in drop-dead mutant drosophila melanogaster is associated with the respiratory system but not with Hypoxia. PLoS ONE. 2013;8:e68032 pubmed publisher
  23. Rytkönen K, Williams T, Renshaw G, Primmer C, Nikinmaa M. Molecular evolution of the metazoan PHD-HIF oxygen-sensing system. Mol Biol Evol. 2011;28:1913-26 pubmed publisher
    ..b>HIF alpha proteins are commonly posttranslationally regulated by prolyl-4-hydroxylase (PHD) enzymes, which are direct &..
  24. Ivanov D, Escott Price V, Ziehm M, Magwire M, Mackay T, Partridge L, et al. Longevity GWAS Using the Drosophila Genetic Reference Panel. J Gerontol A Biol Sci Med Sci. 2015;70:1470-8 pubmed publisher
    ..This analysis suggests that our understanding of the genetic basis of natural variation in lifespan from induced mutations is incomplete. ..
  25. Ali Y, McCormack R, Darr A, Zhai R. Nicotinamide mononucleotide adenylyltransferase is a stress response protein regulated by the heat shock factor/hypoxia-inducible factor 1alpha pathway. J Biol Chem. 2011;286:19089-99 pubmed publisher
    ..Our studies provide an in vivo mechanism for transcriptional regulation of NMNAT under stress and establish an essential role for this neuroprotective factor in cellular stress response. ..
  26. Dong W, Zhang X, Liu W, Chen Y, Huang J, Austin E, et al. A conserved polybasic domain mediates plasma membrane targeting of Lgl and its regulation by hypoxia. J Cell Biol. 2015;211:273-86 pubmed publisher
  27. Freije W, Mandal S, Banerjee U. Expression profiling of attenuated mitochondrial function identifies retrograde signals in Drosophila. G3 (Bethesda). 2012;2:843-51 pubmed publisher
    ..This rich dataset provides many novel targets for further understanding the mechanism whereby the mitochondrion manages energy substrate disposition and directs cellular fate decisions. ..
  28. Wong D, Shen Z, Owyang K, Martinez Agosto J. Insulin- and warts-dependent regulation of tracheal plasticity modulates systemic larval growth during hypoxia in Drosophila melanogaster. PLoS ONE. 2014;9:e115297 pubmed publisher
  29. Stolze I, Tian Y, Appelhoff R, Turley H, Wykoff C, Gleadle J, et al. Genetic analysis of the role of the asparaginyl hydroxylase factor inhibiting hypoxia-inducible factor (FIH) in regulating hypoxia-inducible factor (HIF) transcriptional target genes [corrected]. J Biol Chem. 2004;279:42719-25 pubmed
  30. Bandarra D, Biddlestone J, Mudie S, Müller H, Rocha S. HIF-1α restricts NF-κB-dependent gene expression to control innate immunity signals. Dis Model Mech. 2015;8:169-81 pubmed publisher
    ..These results indicate that HIF-1α is required to restrain the NF-κB response, and thus prevents excessive and damaging pro-inflammatory responses. ..
  31. Zarndt R, Piloto S, Powell F, Haddad G, Bodmer R, Ocorr K. Cardiac responses to hypoxia and reoxygenation in Drosophila. Am J Physiol Regul Integr Comp Physiol. 2015;309:R1347-57 pubmed publisher
    ..Hearts from flies with mutations in sima, the Drosophila homolog of the hypoxia-inducible factor alpha subunit (HIF-α), exhibited exaggerated reductions in ..
  32. Harvey K, Mattila J, Sofer A, Bennett F, Ramsey M, Ellisen L, et al. FOXO-regulated transcription restricts overgrowth of Tsc mutant organs. J Cell Biol. 2008;180:691-6 pubmed publisher
    ..Analogous transcriptional changes are observed in mammalian cells, which implies that FOXO attenuates TOR-driven growth in diverse species. ..
  33. Gersten M, Zhou D, Azad P, Haddad G, Subramaniam S. Wnt pathway activation increases hypoxia tolerance during development. PLoS ONE. 2014;9:e103292 pubmed publisher
    ..with short-term hypoxia include increased ATP production via anaerobic respiration and stabilization of Hypoxia Inducible Factor 1? (HIF-1?)...
  34. Bandarra D, Biddlestone J, Mudie S, Müller H, Rocha S. Hypoxia activates IKK-NF-κB and the immune response in Drosophila melanogaster. Biosci Rep. 2014;34: pubmed publisher
    ..The results indicate that hypoxia activation of the IKK-NF-κB pathway and the immune response is an important and evolutionary conserved response. ..
  35. Bertolin A, Katz M, Yano M, Pozzi B, Acevedo J, Blanco Obregón D, et al. Musashi mediates translational repression of the Drosophila hypoxia inducible factor. Nucleic Acids Res. 2016;44:7555-67 pubmed publisher
    Adaptation to hypoxia depends on a conserved ?/? heterodimeric transcription factor called Hypoxia Inducible Factor (HIF), whose ?-subunit is regulated by oxygen through different concurrent mechanisms...
  36. Smulders Srinivasan T, Lin H. Screens for piwi suppressors in Drosophila identify dosage-dependent regulators of germline stem cell division. Genetics. 2003;165:1971-91 pubmed
    ..The other two types are deficiencies that cause lethality and female-specific lethality in a piwi2 mutant background, revealing the zygotic function of piwi in somatic development. ..
  37. Kamps Hughes N, Preston J, Randel M, Johnson E. Genome-wide identification of hypoxia-induced enhancer regions. Peerj. 2015;3:e1527 pubmed publisher
    ..This work provides a novel method for high-throughput assay of enhancer activity and the genome-scale identification of 31 hypoxia-activated enhancers in Drosophila. ..
  38. Cagin U, Duncan O, Gatt A, Dionne M, Sweeney S, Bateman J. Mitochondrial retrograde signaling regulates neuronal function. Proc Natl Acad Sci U S A. 2015;112:E6000-9 pubmed publisher
    ..We show that the Drosophila hypoxia inducible factor alpha (HIFα) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, ..
  39. Hsouna A, Nallamothu G, Kose N, Guinea M, Dammai V, Hsu T. Drosophila von Hippel-Lindau tumor suppressor gene function in epithelial tubule morphogenesis. Mol Cell Biol. 2010;30:3779-94 pubmed publisher
    ..Importantly, the regulatory function in tubular morphogenesis is conserved in the mammalian system, as conditional knockout of Vhl in mouse kidney also resulted in similar cell motility and lumen phenotypes. ..
  40. Bailey A, Koster G, Guillermier C, Hirst E, Macrae J, Lechene C, et al. Antioxidant Role for Lipid Droplets in a Stem Cell Niche of Drosophila. Cell. 2015;163:340-53 pubmed publisher
    ..This study reveals an antioxidant role for lipid droplets that could be relevant in many different biological contexts. ..
  41. Doronkin S, Djagaeva I, Nagle M, Reiter L, Seagroves T. Dose-dependent modulation of HIF-1alpha/sima controls the rate of cell migration and invasion in Drosophila ovary border cells. Oncogene. 2010;29:1123-34 pubmed publisher
    ..Similarly, manipulating the expression levels of sima, the Drosophila hypoxia-inducible factor (HIF)-1alpha ortholog, revealed that Sima can either block or restore BCM ..
  42. Romero N, Irisarri M, Roth P, Cauerhff A, Samakovlis C, Wappner P. Regulation of the Drosophila hypoxia-inducible factor alpha Sima by CRM1-dependent nuclear export. Mol Cell Biol. 2008;28:3410-23 pubmed publisher
    ..We show here that the Drosophila melanogaster HIF-alpha protein Sima shuttles continuously between the nucleus and the cytoplasm...
  43. Baird N, Turnbull D, Johnson E. Induction of the heat shock pathway during hypoxia requires regulation of heat shock factor by hypoxia-inducible factor-1. J Biol Chem. 2006;281:38675-81 pubmed publisher
    ..This cross-regulation represents a mechanism by which the low oxygen response pathway has assimilated complex new functions by regulating the key transcriptional activator of the heat shock pathway...
  44. Ikeshima Kataoka H, Skeath J, Nabeshima Y, Doe C, Matsuzaki F. Miranda directs Prospero to a daughter cell during Drosophila asymmetric divisions. Nature. 1997;390:625-9 pubmed
    ..miranda thus creates intrinsic differences between sibling cells by mediating the asymmetric segregation of a transcription factor into only one daughter cell during neural stem-cell division. ..
  45. Cruz L, Ecker A, Dias R, Seeger R, Braga M, Boligon A, et al. Brazilian Pampa Biome Honey Protects Against Mortality, Locomotor Deficits and Oxidative Stress Induced by Hypoxia/Reperfusion in Adult Drosophila melanogaster. Neurochem Res. 2016;41:116-29 pubmed publisher
    ..Hypoxia also induced an up-regulation in mRNA expression of Sima (HIF-1), NFκβ, NRF2, HOX, AKT-1, InR, dILP2, dILP5 and HSP27...
  46. De Lella Ezcurra A, Bertolin A, Kim K, Katz M, Gandara L, Misra T, et al. miR-190 Enhances HIF-Dependent Responses to Hypoxia in Drosophila by Inhibiting the Prolyl-4-hydroxylase Fatiga. PLoS Genet. 2016;12:e1006073 pubmed publisher
    ..Thus, miR-190 is a novel regulator of the hypoxia response that represses the oxygen sensor Fatiga, leading to HIF? stabilization and enhancement of hypoxic responses. ..
  47. Perez Perri J, Dengler V, Audetat K, Pandey A, Bonner E, Urh M, et al. The TIP60 Complex Is a Conserved Coactivator of HIF1A. Cell Rep. 2016;16:37-47 pubmed publisher
    ..Thus, HIF1A employs functionally diverse cofactors to regulate different subsets of genes within its transcriptional program. ..