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Oxygen sensing in neuroendocrine cells and other cell types: Pheochromocytoma (PC12) cells as an experimental model

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Abstract

A steady supply of oxygen is an absolute requirement for mammalian cells to maintain normal cellular functions. To answer the challenge that oxygen deprivation represents, mammals have evolved specialized cell types that can sense changes in oxygen tension and alter gene expression to enhance oxygen delivery to hypoxic areas. These oxygen-sensing cells are rare and difficult to study in vivo. As a result, pheochromocytoma (PC12) cells have become a vital in vitro model system for deciphering the molecular events that confer the hypoxia-resistant and oxygen-sensing phenotypes. Research over the last few years has revealed that the hypoxia response in PC12 cells involves the interactions of several signal transduction pathways (Ca2+/calmodulin-dependent kinases, Akt, SAPKs, and MAPKs) and transcription factors (HIFs, CREB, and c-fos/junB). This review summarizes the current understanding of the role these signal transduction pathways and transcription factors play in determining the hypoxic response.

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References

  1. Brundin T. Studies on the preaortal paraganglia of newborn rabbits. Acta Physiol Scand Suppl 290:1–54, 1966.

    PubMed  CAS  Google Scholar 

  2. Hervonen A, Korkala O. The effect of hypoxia on the catecholamine content of human fetal abdominal paraganglia and adrenal medulla. Acta Obstet Gynecol Scand 51:17–24, 1972.

    Article  PubMed  CAS  Google Scholar 

  3. Conforti L, Millhorn DE. Selective inhibition of a slow-inactivating voltage-dependent K+ channel in rat PC12 cells by hypoxia. J Physiol 502:293–305, 1997.

    Article  PubMed  CAS  Google Scholar 

  4. Zhu WH, Conforti L, Czyzyk-Krzeska MF, Millhorn DE. Membrane depolarization in PC12 cells during hypoxia is regulated by an O2-sensitive K+ current. Am J Physiol 40:C658-C665, 1996.

    Google Scholar 

  5. Evinger MJ, Cikos S, Nwafor-Anene V, Powers JF, Tischler AS. Hypoxia activates multiple transcriptional pathways in mouse pheochromocytoma cells. Ann NY Acad Sci 971:61–65, 2002.

    Article  PubMed  CAS  Google Scholar 

  6. Lopez-Barneo J. Oxygen-sensing ion channels and the regulation of cellular functions. Trends Neurosci 19:435–440, 1996.

    PubMed  CAS  Google Scholar 

  7. Lopez-Barneo J, Lopez-Lopez JR, Urens J, Gonzalez C. Chemotransduction in the carotid body: K+ current modulated by pO2 in the type 1 chemoreceptor cells. Science 241:580–582, 1988.

    Article  PubMed  CAS  Google Scholar 

  8. Weir EK, Archer SL. The mechanism of acute hypoxic pulmonary vasoconstriction, the tale of two channels. FASEB J 9:183–189, 1995.

    PubMed  CAS  Google Scholar 

  9. Delpiano MA, Hescheler J. Evidence for a PO2 sensitive K+ channel in the type-I cell of the rabbit carotid body. FEBS Lett 249:195–198, 1989.

    Article  PubMed  CAS  Google Scholar 

  10. Gonzales CY, Kwok Y, Gibb J, Fidone S. Effects of hypoxia on tyrosine hydroxylase activity in rat carotid body. J Neurochem 33:713–719, 1979.

    Article  Google Scholar 

  11. Czyzyk-Krzeska MF, Bayliss DA, Lawson EE, Millhorn DE. Regulation of tyrosine hydroxylase gene expression in the rat carotid body by hypoxia. J Neurochem 58:1538–1546, 1992.

    Article  PubMed  CAS  Google Scholar 

  12. Shaw K, Montague W, Yoshizaki K. Biochemical studies on the release of dopamine from the rat carotid body in vitro. Biochem Biophys Acta 1013:42–46, 1989.

    Article  PubMed  CAS  Google Scholar 

  13. Fishman M, Greene WL, Platika D. Oxygen chemoreception by carotid body cells in culture. Proc Natl Acad Sci USA 82:1448–1450, 1985.

    Article  PubMed  CAS  Google Scholar 

  14. Czyzyk-Krzeska MF, Furnari BA, Lawson EE, Millhorn DE. Hypoxia increases rate of transcription and stability of tyrosine hydroxylase mRNA in pheochromocytoma (PC12) cells. J Biol Chem 269:760–764, 1994.

    PubMed  CAS  Google Scholar 

  15. Norris ML, Millhorn DE. Hypoxia-induced protein binding of O2-responsive sequences on the tyrosine hydroxylase gene. J Biol Chem 270:23774–23779, 1995.

    Article  PubMed  CAS  Google Scholar 

  16. Zhu W, Conforti L, Millhorn DE. Expression of dopamine D2 receptor in PC-12 cells and regulation of membrane conductances by dopamine. Am J Physiol 273:C1143-C1150, 1997.

    PubMed  CAS  Google Scholar 

  17. Conforti L, Millhorn DE. Regulation of Shakcr-type potassium channels by hypoxia. Oxygen-sensitive K+ channels in PC12 cells. Adv Exp Med Biol 475:265–274, 2000.

    PubMed  CAS  Google Scholar 

  18. Sheng M, McFadden G, Greenberg ME. Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB. Neuron 4:571–582, 1990.

    Article  PubMed  CAS  Google Scholar 

  19. Sheng M, Thompson M, Greenberg ME. CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252:1427–1430, 1991.

    Article  PubMed  CAS  Google Scholar 

  20. West A, Chen W, Dalva M, et al. Calcium regulation of neuronal gene expression. Proc Natl Acad Sci USA 98:11024–11031, 2001.

    Article  PubMed  CAS  Google Scholar 

  21. Conrad PW, Freeman TL, Beitner-Johnson D, Millhorn DE. EPAS1 trans-activation during hypoxia requires p42/p44 MAPK. J Biol Chem 274:33709–33713, 1999.

    Article  PubMed  CAS  Google Scholar 

  22. Premkumar DR, Mishra RR. L-type Ca(2+) channel activation regulates induction of c-fos transcription by hypoxia. 88:1898–1906, 2000.

  23. Kobayashi S, Millhorn, DE. Stimulation of expression for the adenosine A2A receptor gene by hypoxia in PC12 cells. A potential role in cell protection. J Biol Chem 274:20358–20365, 1999.

    Article  PubMed  CAS  Google Scholar 

  24. Lev S, Moreno H, Martinez R, et al. Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions. Nature 376:737–745, 1995.

    Article  PubMed  CAS  Google Scholar 

  25. Sasaki H, Nagura K, Ishino M, Tobioka H, Kotani K, Sasaki T. Cloning and characterization of cell adhesion kinase beta, a novel protein-tyrosine kinase of the focal adhesion kinase subfamily. J Biol Chem 270:21206–21219, 1995.

    Article  PubMed  CAS  Google Scholar 

  26. Yu H, Li X, Marchetto G, et al. Activation of a novel calcium-dependent protein-tyrosine kinase. Correlation with c-Jun N-terminal kinase but not mitogen-activated protein kinase activation. J Biol Chem 271:29993–29998, 1996.

    Article  PubMed  CAS  Google Scholar 

  27. Li J, Avraham H, Rogers R, Raja S, Avraham S. Characterization of RAFTK, a novel focal adhesion kinase, and its integrin-dependent phosphorylation and activation in megakaryocytes. Blood 88:417–428, 1996.

    PubMed  CAS  Google Scholar 

  28. Dikic I, Tokiwa G, Lev S, Courtneidge S, Schlessinger J. A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation. Nature 383:547–550, 1996.

    Article  PubMed  CAS  Google Scholar 

  29. Beitner-Johnson D, Ferguson T, Rust R, Kobayashi S, Millhorn DE. Calcium-dependent activation of PYK2 by hypoxia. Cellular Signalling 14:133–137, 2002.

    Article  PubMed  CAS  Google Scholar 

  30. Conforti L, Bodi I, Nisbet JW, Millhorn DE. O2-sensitive K+ channels: role of the Kv1.2-subunit in mediating the hypoxic response. J Physiol 524:783–793, 2000.

    Article  PubMed  CAS  Google Scholar 

  31. Felsch J, Cachero T, Peralta E. Activation of protein tyrosine kinase PYK2 by the m1 muscarinic acetylcholine receptor. Proc Natl Acad Sci USA 95:5051–5056, 1998.

    Article  PubMed  CAS  Google Scholar 

  32. Conrad PW, Rust RT, Han J, Millhorn DE, Beitner-Johnson D. Selective activation of p38α and p38γ by hypoxia. Role in regulation of cyclin D1 by hypoxia in PC12 cells. J Biol Chem 274:23570–23576, 1999.

    Article  PubMed  CAS  Google Scholar 

  33. Beitner-Johnson D, Rust RT, Hsieh TC, Millhorn DE. Hypoxia activates Akt and induces phosphorylation of GSK-3 in PC12 cells. Cellular Signalling 13:23–27, 2001.

    Article  PubMed  CAS  Google Scholar 

  34. Conrad PW, Millhorn DE, Beitner-Johnson D. Novel regulation of p38γ by dopamine D2 receptors during hypoxia. Cellular Signalling 12:463–467, 2000.

    Article  PubMed  CAS  Google Scholar 

  35. Nair VD, Olanow CW, Sealfon SC. Activation of phosphoinositide 3-kinase by D2 receptor prevents apoptosis in dopaminergic cell lines. Biochem J 373:25–32, 2003.

    Article  PubMed  CAS  Google Scholar 

  36. Datta S, Brunet A, Greenberg M. Cellular survival: a play in three Akts. Genes Dev 13:2905–2927, 1999.

    Article  PubMed  CAS  Google Scholar 

  37. Vanhaesebroeck B, Alessi D. The P13K-PDK1 connection: more than just a road to PKB. Biochem J 346:561–576, 2000.

    Article  PubMed  CAS  Google Scholar 

  38. Dudek H, Datta S, Franke T, et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275:661–665, 1997.

    Article  PubMed  CAS  Google Scholar 

  39. Meier R, Alessi D, Cron P, Andjelkovic M, Hemmings B. Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta. J Biol Chem 272:30491–30497, 1997.

    Article  PubMed  CAS  Google Scholar 

  40. Alvarez-Tejado M, Naranjo-Suarez S, Jimenez C, Carrera AC, Landazuri MO, del Peso L. Hypoxia induces the activation of the phosphatidylinositol 3-kinase/Akt cell survival pathway in PC12 cells: protective role in apoptosis. J Biol Chem 276:22368–22374, 2001.

    Article  PubMed  CAS  Google Scholar 

  41. Cross D, Alessi D, Cohen P, Andjelkovich M, Hemmings B. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995:785–789, 1995.

    Article  Google Scholar 

  42. Pap M, Cooper G. Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem 273:19929–19932, 1998.

    Article  PubMed  CAS  Google Scholar 

  43. Widmann C, Gibson S, Jarpe M, Johnson G. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 79:143–180, 1999.

    PubMed  CAS  Google Scholar 

  44. Su B, Karin M. Mitogen-activated protein kinase cascades and regulation of gene expression. Curr Opin Immunol 8:402–411, 1996.

    Article  PubMed  CAS  Google Scholar 

  45. Hibi M, Lin A, Smeal T, Minden A, Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev 7:2135–2148, 1993.

    PubMed  CAS  Google Scholar 

  46. Derijard B, Hibi M, Wu I, et al. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76:1025–1037, 1994.

    Article  PubMed  CAS  Google Scholar 

  47. Kyriakis J, Banerjee P, Nikolakaki E, et al. The stress-activated protein kinase subfamily of c-Jun kinases. Nature 369:156–160, 1994.

    Article  PubMed  CAS  Google Scholar 

  48. Han J, Lee J, Bibbs L, Ulevitch R. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265:808–811, 1994.

    Article  PubMed  CAS  Google Scholar 

  49. Kyriakis J, Avruch J. Sounding the alarm: protein kinase cascades activated by stress and inflammation. J Biol Chem 271:24313–24316, 1996.

    Article  PubMed  CAS  Google Scholar 

  50. Garrington T, Johnson G. Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol 11:211–218, 1999.

    Article  PubMed  CAS  Google Scholar 

  51. Whitmarsh A, Davis R. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med 74:589–607, 1996.

    Article  PubMed  CAS  Google Scholar 

  52. Raingeaud J, Gupta S, Rogers J, et al. Proinflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem 270:7420–7426, 1995.

    Article  PubMed  CAS  Google Scholar 

  53. Logan S, Falasca M, Hu P, Schlessinger J. Phosphatidylinositol 3-kinase mediates epidermal growth factor-induced activation of the c-Jun N-terminal kinase signaling pathway. Mol Cell Biol 17:5784–5790, 1997.

    PubMed  CAS  Google Scholar 

  54. Xing J, Kornhauser J, Xia Z, Thiele E, Greenberg M. Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation. Mol Cell Biol 18:1946–1955, 1998.

    PubMed  CAS  Google Scholar 

  55. Lavoie JN, L’Alleman G, Brunet A, Muller R, Pouyssegur J. Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem 271:20608–20616, 1996.

    Article  PubMed  CAS  Google Scholar 

  56. Baldin V, Lukas J, Marcote M, Pagano M, Draetta G. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev 7:812–821, 1993.

    PubMed  CAS  Google Scholar 

  57. Quelle D, Ashmun R, Shurtleff S, et al. Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev. 7:1559–1571, 1993.

    PubMed  CAS  Google Scholar 

  58. Conrad PW, Millhorn DE, Beitner-Johnson D. Hypoxia differentially regulates the mitogen- and stress-activated protein kinases. Role of Ca2+/CaM in the activation of MAPK and p38γ. In: Lahiri Sea, ed. Oxygen Sensing: Molecule to Man. New York, NY: Kluwer Academic/Plenum Publishers, 2000; pp. 293–302.

    Google Scholar 

  59. Liu YZ, Thomas NS, Latchman DS. CBP associates with the p42/p44 MAPK enzymes and is phosphorylated following NGF treatment. Neuroreport 10:1239–1243, 1999.

    Article  PubMed  CAS  Google Scholar 

  60. Janknecht R, Nordheim A. MAP kinase-dependent transcriptional coactivation by Elk-1 and its cofactor CBP. Biochem Biophys Res Commun 228:831–837, 1996.

    Article  PubMed  CAS  Google Scholar 

  61. Sang N, Stiehl DP, Bohensky J, Leshchinsky I, Srinivas V, Caro J. MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. J Biol Chem 278:14013–14019, 2003.

    Article  PubMed  CAS  Google Scholar 

  62. Ema M, Hirota K, Mimura J, et al. Molecular mechanisms of transcription activation by HLF and HIF1 alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300. EMBO J 18:1905–1914, 1999.

    Article  PubMed  CAS  Google Scholar 

  63. Semenza GL. HIF-1 and human disease: one highly involved factor. Genes Dev 14:1983–1981, 2000.

    PubMed  CAS  Google Scholar 

  64. Semenza G. HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell 107:1–3, 2001.

    Article  PubMed  CAS  Google Scholar 

  65. Gu Y, Moran S, Hogenesch J, Wartman L, Bradfield C. Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha. Gene Exp 7:205–213, 1998.

    CAS  Google Scholar 

  66. Srinivas V, Zhang L, Zhu X, Caro J. Characterization of an oxygen/redox-dependent degradation domain of hypoxia-inducible factor alpha (HIF-alpha) proteins. Biochem Biophys Res Commun 260:557–561, 1999.

    Article  PubMed  CAS  Google Scholar 

  67. Hara S, Hamada J, Kobayashi C, Kondo Y, Imura N. Expression and characterization of hypoxia-inducible factor (HIF)-3alpha in human kidney: suppression of HIF-mediated gene expression by HIF-3alpha. Biochem Biophys Res Commun 287:808–813, 2001.

    Article  PubMed  CAS  Google Scholar 

  68. Huang LE, Gu J, Schau M, Bunn HF. Regulation of hypoxia-inducible factor 1 is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 95:7987–7992, 1998.

    Article  PubMed  CAS  Google Scholar 

  69. Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275, 1999.

    Article  PubMed  CAS  Google Scholar 

  70. Yu F, White SB, Zhao Q, Lee FS. Dynamic, site-specific interaction of hypoxia-inducible factor-1alpha with the von Hippel-Lindau tumor suppressor protein. Cancer Res 61:4136–4142, 2001.

    PubMed  CAS  Google Scholar 

  71. Levy AP, Levy NS, Iliopoulos O, Jiang C, Kaplin WGJ, Goldberg MA. Regulation of vascular endothelial growth factor by hypoxia and its modulation by the von Hippel-Lindau tumor suppressor gene. Kidney Internatl 51:575–578, 1997.

    Article  CAS  Google Scholar 

  72. Iwai K, Yamanaka K, Kamura T, et al. Identification of the von Hippel-Lindau tumorsuppressor protein as part of an active E3 ubiquitin ligase complex. Proc Natl Acad Sci USA 96:12436–12441, 1999.

    Article  PubMed  CAS  Google Scholar 

  73. Yuan Y, Beitner-Johnson D, Millhorn DE. Hypoxia-inducible factor 2α binds cobalt in vitro. Biochem Biophys Res Commun 288:849–854, 2001.

    Article  PubMed  CAS  Google Scholar 

  74. Ohh M, Park C, Ivan M, et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2:423–427, 2000.

    Article  PubMed  CAS  Google Scholar 

  75. Ivan M, Kondo K, Yang H, et al. HIF alpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468, 2001.

    PubMed  CAS  Google Scholar 

  76. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472, 2001.

    PubMed  CAS  Google Scholar 

  77. Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J 20:5197–5206, 2001.

    Article  PubMed  CAS  Google Scholar 

  78. Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43–54, 2001.

    Article  PubMed  CAS  Google Scholar 

  79. Darby C, Cosma CL, Thomas JH, Manoil C. Lethal paralysis of Caenorhabditis elegans by Pseudomonas aeruginosa. Proc Natl Acad Sci USA 97:958–959, 1999.

    Google Scholar 

  80. Wax SD, Rosenfeld CL, Taubman MB. Identification of a novel growth factor-responsive gene in vascular smooth muscle cells. J Biol Chem 269:13041–13047, 1994.

    PubMed  CAS  Google Scholar 

  81. Moschella MC, Menzies K, Tsao L, et al. SM-20 is a novel growth factor-responsive gene regulated during skeletal muscle development and differentiation. Gene Exp 8:59–66, 1999.

    CAS  Google Scholar 

  82. Plisov SY, Ivanov SV, Yoshino K, et al. Mesenchymal-epithelial transition in the developing metanephric kidney: gene expression study by differential display. Genesis 27:22–31, 2000.

    Article  PubMed  CAS  Google Scholar 

  83. Lipscomb EA, Sarmiere PD, Freeman RS. SM-20 is a novel mitochondrial protein that causes caspase-dependent cell death in nerve growth factor-dependent neurons. J Biol Chem 276:5085–5092, 2001.

    Article  PubMed  CAS  Google Scholar 

  84. Wolf G, Harendza S, Schroeder R, et al. Angiotensin II’s antiproliferative effects mediated through AT2-receptors depend on down-regulation of SM-20. Lab Invest 82:1305–1317, 2002.

    PubMed  CAS  Google Scholar 

  85. Semenza G, Wang G. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12:5447–5454, 1992.

    PubMed  CAS  Google Scholar 

  86. Semenza GL, Jiang B-H, Leung SW, et al. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271:32529–32537, 1996.

    Article  PubMed  CAS  Google Scholar 

  87. Ginty D, Bonni A, Greenberg M. Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB. Cell 77:713–725, 1994.

    Article  PubMed  Google Scholar 

  88. Deisseroth K, Bito H, Tsien R. Signaling from synapse to nucleus: postsynaptic CREB phosphorylation during multiple forms of hippocampal synaptic plasticity. Neuron 16:89–101, 1996.

    Article  PubMed  CAS  Google Scholar 

  89. Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb M. FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J 15:4629–4642, 1996.

    PubMed  CAS  Google Scholar 

  90. Pende M, Fisher T, Simpson P, Russell J, Blenis J, Gallo V. Neurotransmitter- and growth factor-induced cAMP response element binding protein phosphorylation in glial cell progenitors: role of calcium ions, protein kinase C, and mitogen-activated protein kinase/ribosomal S6 kinase pathway. J Neurosci 17:1291–1301, 1997.

    PubMed  CAS  Google Scholar 

  91. Iordanov M, Bender K, Ade T, et al. CREB is activated by UVC through a p38/HOG-1-dependent protein kinase. EMBO J 16:1009–1022, 1997.

    Article  PubMed  CAS  Google Scholar 

  92. Frank D, Greenberg M. CREB: a mediator of long-term memory from mollusks to mammals. Cell 79:5–8, 1994.

    Article  PubMed  CAS  Google Scholar 

  93. Gonzalez G, Montminy M. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59:675–680, 1989.

    Article  PubMed  CAS  Google Scholar 

  94. Kwok R, Lundblad J, Chrivia J, et al. Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature 370:223–226, 1994.

    Article  PubMed  CAS  Google Scholar 

  95. Arias J, Alberts A, Brindle P, et al. Activation of cAMP and mitogen responsive genes relies on a common nuclear factor. Nature 370:226–228, 1994.

    Article  PubMed  CAS  Google Scholar 

  96. Brindle P, Nakajima T, Montminy M. Multiple protein kinase A-regulated events are required for transcriptional induction by cAMP. Proc Natl Sci USA 92:10521–10525, 1995.

    Article  CAS  Google Scholar 

  97. Du K, Asahara H, Jhala US, Wagner BL, Montminy M. Characterization of a CREB gain-of-function mutant with constitutive transcriptional activity in vivo. Mol Cell Biol 20:4320–4327, 2000.

    Article  PubMed  CAS  Google Scholar 

  98. Beitner-Johnson D, Millhorn DE. Hypoxia induces phosphorylation of the cyclic AMP response element-binding protein by a novel signaling mechanism. J Biol Chem 273:19834–19839, 1998.

    Article  PubMed  CAS  Google Scholar 

  99. Yamamoto K, Gonzalez G, Biggs WR, Montminy M. Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB. Nature 334:484–498, 1988.

    Article  Google Scholar 

  100. Xie H, Rothstein T. Protein kinase C mediates activation of nuclear cAMP response element-binding protein (CREB) in B lymphocytes stimulated through surface Ig. J Immunol 154:1717–1723, 1995.

    PubMed  CAS  Google Scholar 

  101. Xing J, Ginty D, Greenberg M. Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 273:959–963, 1996.

    Article  PubMed  CAS  Google Scholar 

  102. Kim K, Lee M, Carroll J, Joh T. Both the basal and inducible transcription of the tyrosine hydroxylase gene are dependent upon a cAMP response element. J Biol Chem 268:15689–15695, 1993.

    PubMed  CAS  Google Scholar 

  103. Freeland K, Boxer LM, Latchman DS. The cyclic AMP response element in the Bcl-2 promoter confers inducibility by hypoxia in neuronal cells. Brain Res Mol Brain Res 92:98–106, 2001.

    Article  PubMed  CAS  Google Scholar 

  104. Karin M. The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem 270:16483–16486, 1995.

    PubMed  CAS  Google Scholar 

  105. Angel P, Karin M. The role of jun, fos and AP-1 complex in cell proliferation and transformation. Biochem Biophys Acta 1072:129–157, 1991.

    PubMed  CAS  Google Scholar 

  106. Cherniack NS, Shenoy PC, Mishra R, Simonson M, Prabhakar NR. Induction of immediate early response genes by hypoxia. Possible molecular bases for systems adaptation to low pO2. Adv Exp Med Biol 410:127–134, 1996.

    PubMed  CAS  Google Scholar 

  107. Millhorn DE, Raymond R, Conforti L, et al. Regulation of gene expression for tyrosine hydroxylase in oxygen sensitive cells by hypoxia. Kidney Internatl 51:527–535, 1997.

    Article  CAS  Google Scholar 

  108. Prabhakar NR, Shenoy BC, Simonson MS, Cherniack NS. Cell selective induction and transcriptional activation of immediate early genes by hypoxia. Brain Res 697:266–270, 1995.

    Article  PubMed  CAS  Google Scholar 

  109. Premkumar DR, Adhikary G, Overholt JL, Simonson MS, Cherniack NS, Prabhakar NR. Intracellular pathways linking hypoxia to activation of c-fos and AP-1. Adv Exp Med Biol 475:101–109, 2000.

    Article  PubMed  CAS  Google Scholar 

  110. Mishra RR, Adhikary G, Simonson MS, Cherniack NS, Prabhakar NR. Role of c-fos in hypoxia-induced AP-1 cis-element activity and tyrosine hydroxylase gene expression. Brain Res Mol Brain Res 59:74–83, 1998.

    Article  PubMed  CAS  Google Scholar 

  111. Beitner-Johnson D, Seta K, Yuan Y, et al. Identification of hypoxia-responsive genes in a dopaminergic cell line by subtractive cDNA libraries and microarray analysis. Parkinsonism Rel Disord 7:273–281, 2001.

    Article  Google Scholar 

  112. Seta KA, Kim R, Kim H-W, Millhorn DE, Beitner-Johnson D. Hypoxia-induced regulation of MAPK phosphatase-1 as identified by subtractive suppression hybridization and cDNA microarray analysis. J Biol Chem 276:44405–44412, 2001.

    Article  PubMed  CAS  Google Scholar 

  113. Diatchenko L, Lau Y-FC, Campbell AP, et al. Suppression subtractive hybridization: A method for generating differentially regulated or tissue-specific cDNA probes and libraries. Proc Natl Acad Sci USA 93:6025–6030, 1996.

    Article  PubMed  CAS  Google Scholar 

  114. Diatchenko L, Chenchik A, Siebert P. Suppression subtractive hybridization: A method for generating subtracted cDNA libraries starting from poly (A+) or total RNA. In: Siebert P, Larrick J, eds. RT-PCR methods for gene cloning and analysis. MA: BioTechniques Books, 1998; pp. 213–239.

    Google Scholar 

  115. Niitsu Y, Hori O, Yamaguchi A, et al. Exposure of cultured primary rat astrocytes to hypoxia results in intracellular glucose depletion and induction of glycolytic enzymes. Brain Res Mol Brain Res 74:26–34, 1999.

    Article  PubMed  CAS  Google Scholar 

  116. Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxiainducible factor 1. J Biol Chem 269:23757–23763, 1994.

    PubMed  CAS  Google Scholar 

  117. Scharte M, Han X, Bertges DL, Fink MP, Delude RL. Cytokines induce HIF-1 DNA binding and the expression of HIF-1-dependent genes in cultured rat enterocytes. Am J Physiol Gastrointest Liver Physiol 284:G373-G384, 2003.

    PubMed  CAS  Google Scholar 

  118. Vinores SA, Marangos PJ, Parma AM, Guroff G. Increased levels of neuron-specific enolase in PC12 pheochromocytoma cells as a result of nerve growth factor treatment. J Neurochem 37:597–600, 1981.

    Article  PubMed  CAS  Google Scholar 

  119. Zhang HM, Cheung P, Yanagawa B, McManus BM, Yang DC. BNips: a group of proapoptotic proteins in the Bcl-2 family. Apoptosis 8:229–236, 2003.

    Article  PubMed  CAS  Google Scholar 

  120. Xia H, Mao Q, Paulson H, Davidson B. siRNA-mediated gene silencing in vitro and in vivo. Nat Biotechnol 20:1006–1010, 2002.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to David E. Millhorn PhD.

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Spicer, Z., Millhorn, D.E. Oxygen sensing in neuroendocrine cells and other cell types: Pheochromocytoma (PC12) cells as an experimental model. Endocr Pathol 14, 277–291 (2003). https://doi.org/10.1385/EP:14:4:277

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