title: Genetic disruption of Abl nuclear import reduces renal apoptosis in a mouse model of cisplatin-induced nephrotoxicity.
abstract: DNA damage activates nuclear Abl tyrosine kinase to stimulate intrinsic apoptosis in cancer cell lines and mouse embryonic stem cells. To examine the in vivo function of nuclear Abl in apoptosis, we generated Abl-μNLS (μ, mutated in nuclear localization signals) mice. We show here that cisplatin-induced apoptosis is defective in the renal proximal tubule cells (RPTC) from the Abl(μ/μ) mice. When injected with cisplatin, we found similar levels of platinum in the Abl(+/+) and the Abl(μ/μ) kidneys, as well as similar initial inductions of p53 and PUMAα expression. However, the accumulation of p53 and PUMAα could not be sustained in the Abl(μ/μ) kidneys, leading to reductions in renal apoptosis and tubule damage. Co-treatment of cisplatin with the Abl kinase inhibitor, imatinib, reduced the accumulation of p53 and PUMAα in the Abl(+/+) but not in the Abl(μ/μ) kidneys. The residual apoptosis in the Abl(μ/μ) mice was not further reduced in the Abl(μ/μ); p53(-/-) double-mutant mice, suggesting that nuclear Abl and p53 are epistatic to each other in this apoptosis response. Although apoptosis and tubule damage were reduced, cisplatin-induced increases in phospho-Stat-1 and blood urea nitrogen were similar between the Abl(+/+) and the Abl(μ/μ) kidneys, indicating that RPTC apoptosis is not the only factor in cisplatin-induced nephrotoxicity. These results provide in vivo evidence for the pro-apoptotic function of Abl, and show that its nuclear localization and tyrosine kinase activity are both required for the sustained expression of p53 and PUMAα in cisplatin-induced renal apoptosis.
authors: Division of Hematology-Oncology, Department of Medicine, Moores UCSD Cancer Center, UCSD School of Medicine, University of California, San Diego, La Jolla, CA 92093-0820, USA.
authors: P
authors: P
authors: Sridevi
authors: M K
authors: MK
authors: Nhiayi
authors: J Y J
authors: JY
authors: Wang
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology; D002945:Cisplatin / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D000068877:Imatinib Mesylate; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D019913:Nuclear Localization Signals / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D001549:Benzamides; D019913:Nuclear Localization Signals; C488588:PUMA protein, mouse; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D002945:Cisplatin
references: Nature. 1999 Jun 24;399(6738):814-7
references: 10391251
references: Mol Cell. 2001 Mar;7(3):673-82
references: 11463391
references: Am J Physiol Renal Physiol. 2007 Oct;293(4):F1282-91
references: 17670903
references: Nature. 1997 May 29;387(6632):516-9
references: 9168116
references: Toxins (Basel). 2010 Nov;2(11):2490-518
references: 22069563
references: J Clin Invest. 2011 Jul;121(7):2709-22
references: 21633170
references: Cell Death Differ. 2007 Jun;14(6):1139-48
references: 17363963
references: Science. 2004 Feb 13;303(5660):1010-4
references: 14963330
references: Curr Biol. 1994 Jan 1;4(1):1-7
references: 7922305
references: Cell. 1991 Jun 28;65(7):1153-63
references: 2065352
references: J Cell Sci. 2003 Jul 1;116(Pt 13):2613-26
references: 12775773
references: Mol Cell. 2003 Mar;11(3):577-90
references: 12667443
references: Am J Physiol Renal Physiol. 2007 Aug;293(2):F476-85
references: 17475898
references: Cell. 2012 Jun 22;149(7):1536-48
references: 22726440
references: J Biol Chem. 2013 Feb 15;288(7):5198-209
references: 23243310
references: Cell Death Dis. 2011 Jul 21;2:e180
references: 21776018
references: Cell. 1992 Jun 26;69(7):1237-45
references: 1535557
references: Cell Death Differ. 2012 Jan;19(1):107-20
references: 21760595
references: Nucleic Acids Res. 2011 Dec;39(22):9498-507
references: 21835778
references: Cancer Ther. 2003;1:47-61
references: 18185852
references: Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7457-62
references: 9636171
references: Annu Rev Pharmacol Toxicol. 2008;48:463-93
references: 17937594
references: Oncogene. 2000 Nov 20;19(49):5643-50
references: 11114745
references: Nephrol Dial Transplant. 1997 Dec;12(12):2478-80
references: 9430835
references: Nat Med. 2001 Feb;7(2):228-34
references: 11175855
references: J Biol Chem. 2006 Jun 9;281(23):16034-42
references: 16608847
references: Oncogene. 2007 May 31;26(26):3868-77
references: 17173068
references: Nature. 1999 Jun 24;399(6738):806-9
references: 10391249
references: Mol Cell Biol. 2007 Dec;27(24):8480-91
references: 17938203
references: EMBO J. 2011 Aug 23;30(18):3667-83
references: 21863020
references: Oncogene. 2008 Dec;27 Suppl 1:S71-83
references: 19641508
references: Nature. 1999 Jun 24;399(6738):809-13
references: 10391250
references: EMBO J. 2002 Jul 15;21(14):3715-27
references: 12110584
references: Kidney Int. 1998 Feb;53(2):358-66
references: 9461095
references: Neuron. 1998 Dec;21(6):1259-72
references: 9883720
references: J Biol Chem. 1998 Feb 13;273(7):4135-42
references: 9461608
references: Nat Med. 2009 Oct;15(10):1179-85
references: 19783996
references: J Vet Med Sci. 2001 Dec;63(12):1339-42
references: 11789615
references: N Engl J Med. 1996 May 30;334(22):1448-60
references: 8618585
references: Science. 2005 Sep 9;309(5741):1685-6
references: 16151000
references: Cell Cycle. 2009 Sep 1;8(17):2692-6
references: 19652530
references: Nature. 2002 Apr 4;416(6880):560-4
references: 11932750
references: Kidney Int. 2008 May;73(9):994-1007
references: 18272962
references: J Biol Chem. 1999 Mar 26;274(13):8371-4
references: 10085066
references: Genes Dev. 2004 Aug 1;18(15):1824-37
references: 15289456
references: Cell Death Dis. 2011 Dec 01;2:e235
references: 22130069
references: Cell Death Differ. 2009 Sep;16(9):1192-202
references: 19444283
references: EMBO J. 1996 Apr 1;15(7):1583-95
references: 8612582
references: Fed Proc. 1983 Oct;42(13):2974-8
references: 6684595
references: J Biol Chem. 2001 May 18;276(20):17281-5
references: 11350980
references: EMBO J. 1993 Feb;12(2):461-8
references: 8440237
references: Recent Pat Anticancer Drug Discov. 2006 Jun;1(2):285-95
references: 18221042
references: Chembiochem. 2012 Mar 19;13(5):665-73
references: 22334513
references: Cancer Cell. 2003 Oct;4(4):248-9
references: 14585351
references: Cell Res. 2005 Jan;15(1):43-8
references: 15686626
references: Mol Cell Biol. 2000 May;20(9):3224-33
references: 10757806
references: Am J Physiol Renal Physiol. 2009 Mar;296(3):F505-11
references: 19144690
references: Clin Cancer Res. 2004 May 15;10(10):3528-34
references: 15161712