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Abstract:

Background: 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. Three HIFprolyl hydroxylases, encoded by independent genes, PHD1, PHD2, and PHD3, occur in mammals. PHD2, the longest PHD isoform includes a MYND domain, whose biochemical function is unclear. PHD2 and PHD3 genes are induced in hypoxia to shut down HIF dependent transcription upon reoxygenation, while expression of PHD1 is oxygen-independent. The physiologic significance of the diversity of the PHD oxygen sensors is intriguing. Methodology and Principal Findings: We have analyzed the Drosophila PHD locus, fatiga, which encodes 3 isoforms, FgaA, FgaB and FgaC that are originated through a combination of alternative initiation of transcription and alternative splicing. FgaA includes a MYND domain and is homologous to PHD2, while FgaB and FgaC are shorter isoforms most similar to PHD3. Through a combination of genetic experiments in vivo and molecular analyses in cell culture, we show that fgaB but not fgaA is induced in hypoxia, in a Sima-dependent manner, through a HIF-Responsive Element localized in the first intron of fgaA. The regulatory capacity of FgaB is stronger than that of FgaA, as complete reversion of fga loss-of-function phenotypes is observed upon transgenic expression of the former, and only partial rescue occurs after expression of the latter. Conclusions and Significance: Diversity of PHD isoforms is a conserved feature in evolution. As in mammals, there are hypoxia-inducible and non-inducible Drosophila PHDs, and a fly isoform including a MYND domain co-exists with isoforms lacking this domain. Our results suggest that the isoform devoid of a MYND domain has stronger regulatory capacity than that including this domain.

Registro:

Documento: Artículo
Título:Oxygen sensing in Drosophila: Multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFαSima
Autor:Acevedo, J.M.; Centanin, L.; Dekanty, A.; Wappner, P.
Filiación:Instituto Leloir, Buenos Aires, Argentina
Facultad de Ciencias Exactas y Naturales (FCEyN), Universidad de Buenos Aires, Buenos Aires, Argentina
Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
Palabras clave:hypoxia inducible factor; oxygenase; polyhistidine tag; procollagen proline 2 oxoglutarate 4 dioxygenase; prolyl 4 hydroxylase 1; prolyl 4 hydroxylase 2; prolyl 4 hydroxylase 3; unclassified drug; DNA binding protein; Drosophila protein; isoenzyme; messenger RNA; oxygen; procollagen proline 2 oxoglutarate 4 dioxygenase; Sima protein, Drosophila; alternative RNA splicing; animal cell; article; cell hypoxia; controlled study; Drosophila; embryo; gene expression regulation; gene locus; gene overexpression; imago; in vivo study; insect cell culture; intron; loss of function mutation; molecular dynamics; nonhuman; oxygen sensing; phenotypic variation; protein domain; protein localization; transcription initiation site; transgenics; animal; anoxia; chemistry; DNA responsive element; Drosophila melanogaster; enzymology; genetics; growth, development and aging; human; life cycle; metabolism; protein tertiary structure; upregulation; Mammalia; Alternative Splicing; Animals; Anoxia; DNA-Binding Proteins; Drosophila melanogaster; Drosophila Proteins; Gene Expression Regulation, Enzymologic; Genetic Loci; Humans; Isoenzymes; Life Cycle Stages; Oxygen; Procollagen-Proline Dioxygenase; Protein Structure, Tertiary; Response Elements; RNA, Messenger; Up-Regulation
Año:2010
Volumen:5
Número:8
DOI: http://dx.doi.org/10.1371/journal.pone.0012390
Título revista:PLoS ONE
Título revista abreviado:PLoS ONE
ISSN:19326203
CAS:oxygenase, 9037-29-0, 9046-59-7; procollagen proline 2 oxoglutarate 4 dioxygenase, 9028-06-2; oxygen, 7782-44-7; DNA-Binding Proteins; Drosophila Proteins; Isoenzymes; Oxygen, 7782-44-7; Procollagen-Proline Dioxygenase, 1.14.11.2; RNA, Messenger; Sima protein, Drosophila
PDF:https://bibliotecadigital.exactas.uba.ar/download/paper/paper_19326203_v5_n8_p_Acevedo.pdf
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19326203_v5_n8_p_Acevedo

Referencias:

  • Wang, G.L., Jiang, B.H., Rue, E.A., Semenza, G.L., Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension (1995) Proc Natl Acad Sci U S A, 92, pp. 5510-5514
  • Bruick, R.K., Oxygen sensing in the hypoxic response pathway: Regulation of the hypoxia-inducible transcription factor (2003) Genes Dev, 17, pp. 2614-2623
  • Schofield, C.J., Ratcliffe, P.J., Oxygen sensing by HIF hydroxylases (2004) Nat Rev Mol Cell Biol, 5, pp. 343-354
  • Semenza, G.L., HIF-1, O(2), and the 3 PHDs: How animal cells signal hypoxia to the nucleus (2001) Cell, 107, pp. 1-3
  • Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing (2001) Science, 292, pp. 464-468
  • Jaakkola, P., Mole, D.R., Tian, Y.M., Wilson, M.I., Gielbert, J., Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation (2001) Science, 292, pp. 468-472
  • Bruick, R.K., McKnight, S.L., A conserved family of prolyl-4-hydroxylases that modify HIF (2001) Science, 294, pp. 1337-1340
  • Epstein, A.C., Gleadle, J.M., McNeill, L.A., Hewitson, K.S., O'Rourke, J., C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation (2001) Cell, 107, pp. 43-54
  • Kallio, P.J., Okamoto, K., O'Brien, S., Carrero, P., Makino, Y., Signal transduction in hypoxic cells: Inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha (1998) EMBO J, 17, pp. 6573-6586
  • Maxwell, P.H., Pugh, C.W., Ratcliffe, P.J., Inducible operation of the erythropoietin 39 enhancer in multiple cell lines: Evidence for a widespread oxygen-sensing mechanism (1993) Proc Natl Acad Sci U S A, 90, pp. 2423-2427
  • Wang, G.L., Semenza, G.L., General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia (1993) Proc Natl Acad Sci U S A, 90, pp. 4304-4308
  • Wenger, R.H., Stiehl, D.P., Camenisch, G., Integration of oxygen signaling at the consensus HRE (2005) Sci STKE 2005, , re12
  • Appelhoff, R.J., Tian, Y.M., Raval, R.R., Turley, H., Harris, A.L., Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor (2004) J Biol Chem, 279, pp. 38458-38465
  • Metzen, E., Berchner-Pfannschmidt, U., Stengel, P., Marxsen, J.H., Stolze, I., Intracellular localisation of human HIF-1 alpha hydroxylases: Implications for oxygen sensing (2003) J Cell Sci, 116, pp. 1319-1326
  • Berra, E., Benizri, E., Ginouves, A., Volmat, V., Roux, D., HIF prolylhydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia (2003) EMBO J, 22, pp. 4082-4090
  • Fong, G.H., Takeda, K., Role and regulation of prolyl hydroxylase domain proteins (2008) Cell Death Differ, 15, pp. 635-641
  • Takeda, K., Aguila, H.L., Parikh, N.S., Li, X., Lamothe, K., Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins (2008) Blood, 111, pp. 3229-3235
  • Aragones, J., Schneider, M., van Geyte, K., Fraisl, P., Dresselaers, T., Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism (2008) Nat Genet, 40, pp. 170-180
  • Lavista-Llanos, S., Centanin, L., Irisarri, M., Russo, D.M., Gleadle, J.M., Control of the hypoxic response in Drosophila melanogaster by the basic helixloop-helix PAS protein similar (2002) Mol Cell Biol, 22, pp. 6842-6853
  • Centanin, L., Ratcliffe, P.J., Wappner, P., Reversion of lethality and growth defects in Fatiga oxygen-sensor mutant flies by loss of hypoxia-inducible factoralpha/Sima (2005) EMBO Rep, 6, pp. 1070-1075
  • Centanin, L., Dekanty, A., Romero, N., Irisarri, M., Gorr, T.A., Cell autonomy of HIF effects in Drosophila: Tracheal cells sense hypoxia and induce terminal branch sprouting (2008) Dev Cell, 14, pp. 547-558
  • Frei, C., Edgar, B.A., Drosophila cyclin D/Cdk4 requires Hif-1 prolyl hydroxylase to drive cell growth (2004) Dev Cell, 6, pp. 241-251
  • Pescador, N., Cuevas, Y., Naranjo, S., Alcaide, M., Villar, D., Identification of a functional hypoxia-responsive element that regulates the expression of the egl nine homologue 3 (egln3/phd3) gene (2005) Biochem J, 390, pp. 189-197
  • Choi, K.O., Lee, T., Lee, N., Kim, J.H., Yang, E.G., Inhibition of the catalytic activity of hypoxia-inducible factor-1alpha-prolyl-hydroxylase 2 by a MYND-type zinc finger (2005) Mol Pharmacol, 68, pp. 1803-1809
  • Barth, S., Edlich, F., Berchner-Pfannschmidt, U., Gneuss, S., Jahreis, G., Hypoxia-inducible factor prolyl-4-hydroxylase PHD2 protein abundance depends on integral membrane anchoring of FKBP38 (2009) J Biol Chem, 284, pp. 23046-23058
  • Barth, S., Nesper, J., Hasgall, P.A., Wirthner, R., Nytko, K.J., The peptidyl prolyl cis/trans isomerase FKBP38 determines hypoxia-inducible transcription factor prolyl-4-hydroxylase PHD2 protein stability (2007) Mol Cell Biol, 27, pp. 3758-3768
  • Ozer, A., Wu, L.C., Bruick, R.K., The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF) (2005) Proc Natl Acad Sci U S A, 102, pp. 7481-7486
  • To, K.K., Huang, L.E., Suppression of hypoxia-inducible factor 1alpha (HIF-1alpha) transcriptional activity by the HIF prolyl hydroxylase EGLN1 (2005) J Biol Chem, 280, pp. 38102-38107
  • Ansieau, S., Leutz, A., The conserved Mynd domain of BS69 binds cellular and oncoviral proteins through a common PXLXP motif (2002) J Biol Chem, 277, pp. 4906-4910
  • Ceriani, M.F., Darlington, T.K., Staknis, D., Mas, P., Petti, A.A., Lightdependent sequestration of TIMELESS by CRYPTOCHROME (1999) Science, 285, pp. 553-556
  • 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 (2005) J Cell Sci, 118, pp. 5431-5441

Citas:

---------- APA ----------
Acevedo, J.M., Centanin, L., Dekanty, A. & Wappner, P. (2010) . Oxygen sensing in Drosophila: Multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFαSima. PLoS ONE, 5(8).
http://dx.doi.org/10.1371/journal.pone.0012390
---------- CHICAGO ----------
Acevedo, J.M., Centanin, L., Dekanty, A., Wappner, P. "Oxygen sensing in Drosophila: Multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFαSima" . PLoS ONE 5, no. 8 (2010).
http://dx.doi.org/10.1371/journal.pone.0012390
---------- MLA ----------
Acevedo, J.M., Centanin, L., Dekanty, A., Wappner, P. "Oxygen sensing in Drosophila: Multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFαSima" . PLoS ONE, vol. 5, no. 8, 2010.
http://dx.doi.org/10.1371/journal.pone.0012390
---------- VANCOUVER ----------
Acevedo, J.M., Centanin, L., Dekanty, A., Wappner, P. Oxygen sensing in Drosophila: Multiple isoforms of the prolyl hydroxylase fatiga have different capacity to regulate HIFαSima. PLoS ONE. 2010;5(8).
http://dx.doi.org/10.1371/journal.pone.0012390