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J Biol Chem. 2010 Oct 08;285(41):31217-32. doi: 10.1074/jbc.M110.149161. Epub 2010 Jun 17.

Selective translational control of the Alzheimer amyloid precursor protein transcript by iron regulatory protein-1.

The Journal of biological chemistry

Hyun-Hee Cho, Catherine M Cahill, Charles R Vanderburg, Clemens R Scherzer, Bin Wang, Xudong Huang, Jack T Rogers

Affiliations

  1. Neurochemistry Laboratory, Department of Psychiatry-Neuroscience, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

PMID: 20558735 PMCID: PMC2951196 DOI: 10.1074/jbc.M110.149161

Abstract

Iron influx increases the translation of the Alzheimer amyloid precursor protein (APP) via an iron-responsive element (IRE) RNA stem loop in its 5'-untranslated region. Equal modulated interaction of the iron regulatory proteins (IRP1 and IRP2) with canonical IREs controls iron-dependent translation of the ferritin subunits. However, our immunoprecipitation RT-PCR and RNA binding experiments demonstrated that IRP1, but not IRP2, selectively bound the APP IRE in human neural cells. This selective IRP1 interaction pattern was evident in human brain and blood tissue from normal and Alzheimer disease patients. We computer-predicted an optimal novel RNA stem loop structure for the human, rhesus monkey, and mouse APP IREs with reference to the canonical ferritin IREs but also the IREs encoded by erythroid heme biosynthetic aminolevulinate synthase and Hif-2α mRNAs, which preferentially bind IRP1. Selective 2'-hydroxyl acylation analyzed by primer extension analysis was consistent with a 13-base single-stranded terminal loop and a conserved GC-rich stem. Biotinylated RNA probes deleted of the conserved CAGA motif in the terminal loop did not bind to IRP1 relative to wild type probes and could no longer base pair to form a predicted AGA triloop. An AGU pseudo-triloop is key for IRP1 binding to the canonical ferritin IREs. RNA probes encoding the APP IRE stem loop exhibited the same high affinity binding to rhIRP1 as occurs for the H-ferritin IRE (35 pm). Intracellular iron chelation increased binding of IRP1 to the APP IRE, decreasing intracellular APP expression in SH-SY5Y cells. Functionally, shRNA knockdown of IRP1 caused increased expression of neural APP consistent with IRP1-APP IRE-driven translation.

References

  1. Nature. 2005 Aug 18;436(7053):1035-39 - PubMed
  2. Nature. 1991 Apr 18;350(6319):564 - PubMed
  3. J Mol Biol. 1997 Nov 21;274(1):72-83 - PubMed
  4. Histochem Cell Biol. 2001 Mar;115(3):195-203 - PubMed
  5. Free Radic Biol Med. 2001 Feb 15;30(4):447-50 - PubMed
  6. Nat Rev Neurosci. 2004 Nov;5(11):863-73 - PubMed
  7. Biochim Biophys Acta. 2006 Jul;1763(7):668-89 - PubMed
  8. J Biol Chem. 2009 Oct 30;284(44):30122-8 - PubMed
  9. J Biol Chem. 2002 Nov 22;277(47):45518-28 - PubMed
  10. J Mol Biol. 2009 Jan 16;385(2):642-52 - PubMed
  11. J Alzheimers Dis. 2001 Jun;3(3):339-344 - PubMed
  12. J Neurosci. 1997 Apr 15;17(8):2653-7 - PubMed
  13. Mol Cell Biol. 2003 Oct;23(19):6973-81 - PubMed
  14. RNA. 2007 Jul;13(7):952-66 - PubMed
  15. Bioinformatics. 2010 Mar 1;26(5):632-9 - PubMed
  16. Nat Protoc. 2006;1(3):1610-6 - PubMed
  17. Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):12028-33 - PubMed
  18. J Neural Transm Suppl. 2006;(71):237-47 - PubMed
  19. J Neurochem. 1995 Aug;65(2):717-24 - PubMed
  20. Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2987-92 - PubMed
  21. Science. 2001 Mar 2;291(5509):1755-9 - PubMed
  22. J Biol Chem. 2007 Aug 24;282(34):24650-9 - PubMed
  23. J Neural Transm Park Dis Dement Sect. 1990;2(4):327-40 - PubMed
  24. Annu Rev Nutr. 2008;28:197-213 - PubMed
  25. Biochem Biophys Res Commun. 1995 Nov 13;216(2):702-7 - PubMed
  26. Blood. 2005 Oct 1;106(7):2580-9 - PubMed
  27. EMBO J. 2006 Feb 8;25(3):544-53 - PubMed
  28. J Biol Chem. 1998 Sep 11;273(37):23637-40 - PubMed
  29. EMBO J. 2004 Jan 28;23(2):386-95 - PubMed
  30. J Biol Chem. 2007 Feb 16;282(7):4318-4325 - PubMed
  31. Nature. 2002 Apr 4;416(6880):535-9 - PubMed
  32. Trends Neurosci. 2004 Mar;27(3):129-34 - PubMed
  33. FEBS Lett. 2001 Dec 7;509(2):309-16 - PubMed
  34. Structure. 2006 Jan;14(1):129-39 - PubMed
  35. J Struct Biol. 2006 Jul;155(1):45-51 - PubMed
  36. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10540-3 - PubMed
  37. Arch Neurol. 2003 Dec;60(12):1685-91 - PubMed
  38. J Neurol Sci. 1998 Jun 11;158(1):47-52 - PubMed
  39. FASEB J. 2004 Aug;18(11):1288-90 - PubMed
  40. Biochem J. 2005 May 15;388(Pt 1):143-50 - PubMed
  41. Ann N Y Acad Sci. 2004 Mar;1012:65-83 - PubMed
  42. J Biol Chem. 1995 Mar 10;270(10):4983-6 - PubMed
  43. J Biol Chem. 1996 Mar 22;271(12):7168-76 - PubMed
  44. Neuron. 2008 Jul 10;59(1):43-55 - PubMed
  45. Nucleic Acids Res. 2008 Dec;36(21):6835-47 - PubMed
  46. J Biol Chem. 2005 Jun 3;280(22):20978-86 - PubMed
  47. J Biol Chem. 2005 Dec 23;280(51):41987-96 - PubMed
  48. RNA. 2010 Jan;16(1):154-69 - PubMed
  49. Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):10907-12 - PubMed
  50. J Neuropathol Exp Neurol. 2005 Dec;64(12):1037-45 - PubMed
  51. Biometals. 2003 Mar;16(1):63-75 - PubMed
  52. Biochemistry. 1999 Jun 15;38(24):7609-16 - PubMed
  53. Nat Genet. 2006 Sep;38(9):967-9; discussion 969-70 - PubMed
  54. J Biol Chem. 1999 Sep 10;274(37):26439-47 - PubMed
  55. Biochim Biophys Acta. 2009 Jul;1790(7):615-28 - PubMed
  56. Science. 2006 Dec 22;314(5807):1903-8 - PubMed
  57. Carcinogenesis. 2007 Apr;28(4):785-91 - PubMed
  58. Neuropsychopharmacology. 2001 Jul;25(1):84-90 - PubMed
  59. J Neurochem. 2007 Jan;100(2):490-502 - PubMed
  60. J Biol Chem. 2005 Aug 26;280(34):30032-45 - PubMed
  61. Sci Am. 2006 May;294(5):72-9 - PubMed
  62. Nat Genet. 2001 Feb;27(2):209-14 - PubMed
  63. Lancet. 1991 Jun 1;337(8753):1304-8 - PubMed
  64. Cell Mol Life Sci. 2007 Nov;64(22):2945-55 - PubMed
  65. Science. 1996 Mar 8;271(5254):1406-9 - PubMed
  66. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10681-6 - PubMed
  67. Structure. 2009 Mar 11;17(3):326-34 - PubMed
  68. J Biol Chem. 2008 Oct 3;283(40):26956-64 - PubMed
  69. J Biol Chem. 2005 Feb 11;280(6):4207-12 - PubMed
  70. EMBO J. 1991 Jul;10(7):1891-902 - PubMed
  71. Mol Cell Biol. 2009 Apr;29(8):2219-29 - PubMed
  72. J Biol Chem. 2004 May 7;279(19):20378-86 - PubMed
  73. Nat Chem Biol. 2006 Aug;2(8):406-14 - PubMed
  74. J Neurochem. 2006 Apr;97(2):527-36 - PubMed
  75. Mol Cell. 2008 Dec 26;32(6):838-48 - PubMed
  76. J Biol Chem. 1993 Dec 25;268(36):27363-70 - PubMed
  77. J Mol Neurosci. 2004;24(1):129-36 - PubMed
  78. J Neurosci Res. 1992 Jan;31(1):75-83 - PubMed
  79. Ann N Y Acad Sci. 2004 Mar;1012:224-36 - PubMed
  80. Mol Cell. 1998 Sep;2(3):383-8 - PubMed
  81. Cell Mol Biol (Noisy-le-grand). 2000 Jun;46(4):761-76 - PubMed
  82. Nature. 1999 Apr 8;398(6727):513-7 - PubMed
  83. Biochemistry. 2000 May 23;39(20):6235-42 - PubMed
  84. Neurology. 2003 Jun 24;60(12):2013-4 - PubMed
  85. Blood. 2005 Aug 1;106(3):1084-91 - PubMed
  86. J Biol Chem. 2000 Oct 13;275(41):31609-15 - PubMed
  87. J Biol Chem. 2001 Jul 20;276(29):27685-92 - PubMed
  88. Science. 2004 Dec 17;306(5704):2087-90 - PubMed
  89. Biochem Soc Trans. 2008 Dec;36(Pt 6):1282-7 - PubMed
  90. Life Sci. 1997;60(25):2273-8 - PubMed
  91. Eur J Biochem. 1993 Dec 1;218(2):657-67 - PubMed

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