The role of CaMKII in calcium-activated death pathways in bone marrow B cells.
Calcium is an essential signaling molecule in developing B cells, thus altering calcium dynamics represents a potential target for toxicant effects. GW7845, a tyrosine analog and potent peroxisome proliferator-activated receptor γ agonist, induces rapid mitogen-activated protein kinase (MAPK)-dependent apoptosis in bone marrow B cells. Changes in calcium dynamics are capable of mediating rapid initiation of cell death; therefore, we investigated the contribution of calcium to GW7845-induced apoptosis. Treatment of a nontransformed murine pro/pre-B cell line (BU-11) with GW7845 (40 μM) resulted in intracellular calcium release. Multiple features of GW7845-induced cell death were suppressed by the calcium chelator BAPTA, including MAPK activation, loss of mitochondrial membrane potential, cytochrome c release, caspase-3 activation, and DNA fragmentation. A likely mechanism for the calcium-mediated effects is activation of CaMKII, a calcium-dependent MAP4K. We observed that three CaMKII isoforms (β, γ, and δ) are expressed in lymphoid tissues and bone marrow B cells. Treatment with GW7845 increased CaMKII activity. All features of GW7845-induced cell death, except loss of mitochondrial membrane potential, were suppressed by CaMKII inhibitors (KN93 and AIP-II), suggesting the activation of multiple calcium-driven pathways. To determine if CaMKII activation is a common feature of early B cell death following perturbation of Ca(2+) flux, we dissected tributyltin (TBT)-induced death signaling. High-dose TBT (1 μM) is known to activate calcium-dependent death. TBT induced rapid apoptosis that was associated with intracellular calcium release, CaMKII activation and MAPK activation, and was inhibited by AIP-II. Thus, we show that early B cells are susceptible to calcium-triggered cell death through a CaMKII/MAPK-dependent pathway.
Bissonnette
Stephanie L
SL
Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
Haas
Amelia
A
Mann
Koren K
KK
Schlezinger
Jennifer J
JJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes; D008024:Ligands; D048670:MAP Kinase Kinase 4 / Q000096:biosynthesis; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D010080:Oxazoles / Q000494:pharmacology; D014220:Trialkyltin Compounds / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008024:Ligands; D010080:Oxazoles; D014220:Trialkyltin Compounds; C401311:GW 7845; D014443:Tyrosine; C011559:tributyltin; D004533:Egtazic Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048670:MAP Kinase Kinase 4; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium
J Biol Chem. 2009 Feb 6;284(6):3804-13
19074436
Int J Cell Biol. 2010;2010:546163
20300548
Toxicol Appl Pharmacol. 1984 Sep 30;75(3):387-408
6474470
BMC Chem Biol. 2008 Aug 01;8:2
18673549
Biochem Biophys Res Commun. 1991 Dec 31;181(3):968-75
1662507
J Cell Biol. 2008 Dec 1;183(5):849-63
19047462
Toxicol Appl Pharmacol. 2000 Dec 1;169(2):185-90
11097871
Toxicol Sci. 2007 Jul;98(1):125-36
17400580
Toxicol Appl Pharmacol. 1997 Dec;147(2):190-203
9439715
J Biol Chem. 2007 Apr 6;282(14):10833-9
17296607
J Exp Med. 1995 Dec 1;182(6):1943-9
7500040
Cell Death Differ. 2004 Apr;11(4):372-80
14765132
J Biol Chem. 2005 Mar 18;280(11):10109-18
15649892
Nat Rev Immunol. 2007 Oct;7(10):778-89
17853903
Cardiovasc Res. 2007 Mar 1;73(4):641-7
17137569
Eur J Immunol. 1988 Jun;18(6):863-72
3260182
Mol Cancer Ther. 2004 Oct;3(10):1249-62
15486192
J Immunol. 2000 Dec 15;165(12):6796-802
11120801
J Biol Chem. 1989 Oct 25;264(30):17907-12
2553697
J Clin Invest. 2009 Oct;119(10):2925-41
19741297
Blood. 2005 Feb 15;105(4):1750-8
15498850
Biochem Biophys Res Commun. 1999 Dec 20;266(2):460-5
10600525
EMBO J. 1999 Sep 15;18(18):4988-98
10487751
Toxicol Sci. 2006 Aug;92(2):433-44
16672323
Arch Toxicol. 1993;67(4):231-6
8517778
J Biol Chem. 2001 Aug 24;276(34):32257-63
11413128
Clin Immunol. 2004 Nov;113(2):203-13
15451478
Biochem Biophys Res Commun. 2006 Jul 14;345(4):1606-10
16730662
Biochem J. 2002 Jun 15;364(Pt 3):593-611
11931644
J Biol Chem. 2002 Jan 25;277(4):2804-11
11713251
EMBO Rep. 2004 Feb;5(2):161-6
14749717
FEBS Lett. 2004 Jun 1;567(1):111-5
15165902
Am J Physiol Cell Physiol. 2002 Nov;283(5):C1399-413
12372801
J Immunol. 2005 May 1;174(9):5583-92
15843557
Biochim Biophys Acta. 2009 Nov;1787(11):1395-401
19576166
Mol Pharmacol. 2005 Jul;68(1):169-78
15821150
Biochem Biophys Res Commun. 1995 Jul 26;212(3):806-12
7626114
Cancer Res. 2005 Apr 1;65(7):2890-8
15805291
Nat Rev Mol Cell Biol. 2003 Jul;4(7):552-65
12838338
J Immunol. 2002 Dec 15;169(12):6831-41
12471115
Cancer Res. 2010 Jun 15;70(12):4949-60
20501850
Cytometry. 2001 May 1;44(1):45-56
11309808
J Biol Chem. 2002 Jun 7;277(23):20301-8
11909872
Cardiovasc Res. 2007 Mar 1;73(4):689-98
17217936
Hum Exp Toxicol. 1999 Oct;18(10):619-24
10557013
Toxicol Appl Pharmacol. 2000 Nov 1;168(3):200-7
11042092
Toxicol Sci. 2007 Jun;97(2):438-47
17341481
J Immunol. 2004 Sep 1;173(5):3165-77
15322177
J Immunol. 2000 Dec 15;165(12):6941-8
11120820
Mol Pharmacol. 2005 Jul;68(1):119-28
15798084