title: Aberrant, differential and bidirectional regulation of the unfolded protein response towards cell survival by 3'-deoxyadenosine.
abstract: The unfolded protein response (UPR) is involved in a diverse range of pathologies triggered by endoplasmic reticulum (ER) stress. Endeavor to seek selective regulators of the UPR is a promising challenge towards therapeutic intervention in ER stress-related disorders. In the present report, we describe aberrant, differential and bidirectional regulation of the UPR by 3'-deoxyadenosine (cordycepin) towards cell survival. 3'-Deoxyadenosine blocked ER stress-induced apoptosis via inhibiting the IRE1-JNK pro-apoptotic pathway. 3'-Deoxyadenosine also inhibited apoptosis through reinforcement of the pro-survival eIF2α signaling without affecting PERK activity. It was associated with depression of GADD34 that dephosphorylates eIF2α, and dephosphorylation of eIF2α by salubrinal mimicked the anti-apoptotic effect of 3'-deoxyadenosine. Unexpectedly, although 3'-deoxyadenosine caused activation of eIF2α, it inhibited downstream pro-apoptotic events including induction of ATF4 and expression of CHOP. Cooperation of adenosine transporter and A3 adenosine receptor, but not A1/A2 receptors, mediated the pluripotent effects of 3'-deoxyadenosine. In mice, ER stress caused activation of JNK, expression of CHOP and induction of apoptosis in renal tubules. The apoptosis was significantly attenuated by administration with 3'-deoxyadenosine, and it was correlated with blunted induction of JNK and CHOP in the kidney. These results disclosed atypical pro-survival regulation of the UPR by 3'-deoxyadenosine, which may be advantageous for the treatment of intractable, ER stress-related disorders.
authors: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
authors: M
authors: M
authors: Kitamura
authors: H
authors: H
authors: Kato
authors: Y
authors: Y
authors: Saito
authors: S
authors: S
authors: Nakajima
authors: S
authors: S
authors: Takahashi
authors: H
authors: H
authors: Johno
authors: L
authors: L
authors: Gu
authors: R
authors: R
authors: Katoh
references: Science. 2005 Feb 11;307(5711):935-9
references: 15705855
references: Cancer Res. 1977 Oct;37(10):3824-33
references: 332340
references: Dev Cell. 2003 Feb;4(2):265-71
references: 12586069
references: Mol Cell Biol. 2003 Nov;23(21):7448-59
references: 14559994
references: Cancer Chemother Pharmacol. 2007 Jun;60(1):103-11
references: 17031645
references: Mol Cell. 2000 Nov;6(5):1099-108
references: 11106749
references: Cell Death Differ. 2007 Aug;14(8):1467-74
references: 17464326
references: Trends Mol Med. 2005 Aug;11(8):347-50
references: 16005683
references: J Biol Chem. 2002 May 24;277(21):19198-205
references: 11877448
references: Biochem Biophys Res Commun. 1964;14:456-7
references: 5836541
references: J Clin Invest. 1994 Aug;94(2):497-505
references: 8040302
references: Nat Med. 1999 Jul;5(7):745-51
references: 10395318
references: Anticancer Res. 2006 Jan-Feb;26(1A):43-7
references: 16475677
references: J Biol Chem. 2010 Jan 22;285(4):2610-21
references: 19940154
references: Free Radic Biol Med. 2008 Jul 1;45(1):50-9
references: 18394432
references: Apoptosis. 2006 Jan;11(1):5-13
references: 16374548
references: Methods Find Exp Clin Pharmacol. 2008 Jun;30(5):347-53
references: 18806893
references: Mol Cell Biol. 2004 Sep;24(17):7469-82
references: 15314157
references: Acta Biochim Pol. 2002;49(4):877-89
references: 12545194
references: Biochem Biophys Res Commun. 2006 Nov 24;350(3):709-15
references: 17026957
references: Trends Biochem Sci. 2001 Aug;26(8):504-10
references: 11504627
references: Trends Biochem Sci. 2007 Oct;32(10):469-76
references: 17920280
references: Gen Pharmacol. 1998 Jul;31(1):1-8
references: 9595270
references: Proc Natl Acad Sci U S A. 1970 Dec;67(4):1878-85
references: 5275385
references: Eur J Pharmacol. 2009 Aug 15;616(1-3):7-15
references: 19464286
references: J Mol Biol. 2002 May 17;318(5):1351-65
references: 12083523
references: Nature. 2006 Oct 5;443(7111):548-52
references: 17024087
references: Eur J Pharmacol. 2008 Nov 12;597(1-3):64-9
references: 18782572
references: Br J Haematol. 2008 Mar;140(6):682-391
references: 18205859
references: EMBO J. 2003 Mar 3;22(5):1180-7
references: 12606582
references: J Immunol. 1996 Apr 15;156(8):2964-71
references: 8609417
references: Nature. 2000 Jan 6;403(6765):98-103
references: 10638761
references: Cell Death Differ. 2006 Mar;13(3):374-84
references: 16397578
references: J Cell Biol. 2001 May 28;153(5):1011-22
references: 11381086
references: Nucleic Acids Res. 2006 Jul 28;34(13):e93
references: 16877567
references: J Biol Chem. 2010 Feb 26;285(9):6091-100
references: 20022965
references: Int J Biol Markers. 2004 Jan-Mar;19(1):58-66
references: 15077928
references: Mol Cell Biol. 2000 Oct;20(19):7192-204
references: 10982836
references: Nature. 1950 Dec 2;166(4231):949
references: 14796634