title: Regulation of apoptosis by C. elegans CED-9 in the absence of the C-terminal transmembrane domain.
abstract: Bcl-2 proteins regulate apoptosis in organisms as diverse as mammals and nematodes. These proteins are often localized at mitochondria by a C-terminal transmembrane domain. Although the transmembrane domain and mitochondrial localization are centrally involved in specific cases of vertebrate Bcl-2 activity, the significance of this localization is not clear for all species. Studying the Caenorhabditis elegans Bcl-2 homolog CED-9, we found that the transmembrane domain was both necessary and sufficient for localization at mitochondrial outer membranes. Furthermore, we found that in our assays, ced-9 transgenes lacking the transmembrane domain, although somewhat less active than equivalent transgenes derived from wild-type ced-9, rescued embryonic lethality of ced-9(lf) animals and responded properly to upstream signals in controlling the fate of Pn.aap neurons. Both of these apoptotic activities were retained in a construct where CED-9 lacking the transmembrane domain was targeted to the cytosolic surface of the endoplasmic reticulum and derived organelles, suggesting that in wild-type animals, accumulation at mitochondria is not essential for CED-9 to either inhibit or promote apoptosis in C. elegans. Taken together, these data are consistent with a multimodal character of CED-9 action, with an ability to regulate apoptosis through interactions in the cytosol coexisting with additional evolutionarily conserved role(s) at the membrane.
authors: Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
authors: F J
authors: FJ
authors: Tan
authors: A Z
authors: AZ
authors: Fire
authors: R B
authors: RB
authors: Hill
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D047108:Embryonic Development; D051336:Mitochondrial Membranes / Q000378:metabolism* / Q000648:ultrastructure; D009132:Muscles / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D015388:Organelles / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; C087233:Ced-9 protein, C elegans; D019253:Proto-Oncogene Proteins c-bcl-2
references: Science. 2000 Feb 25;287(5457):1485-9
references: 10688797
references: Nature. 2005 Oct 6;437(7060):831-7
references: 16208361
references: Oncogene. 2000 Nov 16;19(48):5453-63
references: 11114722
references: EMBO J. 2001 Mar 15;20(6):1363-72
references: 11250902
references: Nature. 2001 Jul 12;412(6843):198-202
references: 11449278
references: J Cell Biol. 2003 Jan 6;160(1):53-64
references: 12515824
references: Cell. 2004 Jan 23;116(2):205-19
references: 14744432
references: Gene. 2004 May 26;333:71-9
references: 15177682
references: Genetics. 1979 Jun;92(2):419-35
references: 573721
references: EMBO J. 1991 Dec;10(12):3959-70
references: 1935914
references: Development. 1991 Oct;113(2):399-408
references: 1782857
references: Nature. 1992 Apr 9;356(6369):494-9
references: 1560823
references: J Biol Chem. 1993 May 25;268(15):10920-6
references: 8496157
references: Cell. 1994 Feb 25;76(4):665-76
references: 7907274
references: Nature. 1994 May 26;369(6478):318-20
references: 7910376
references: J Cell Biol. 1994 Aug;126(4):1059-68
references: 8051205
references: J Immunol. 1994 Nov 15;153(10):4388-98
references: 7963517
references: J Cell Biol. 1995 May;129(4):1127-41
references: 7744961
references: Development. 1995 Aug;121(8):2525-35
references: 7671816
references: Methods Cell Biol. 1995;48:451-82
references: 8531738
references: Mol Cell. 2006 Mar 17;21(6):761-73
references: 16543146
references: EMBO J. 2006 Jun 7;25(11):2287-96
references: 16642033
references: J Mol Biol. 2006 Jun 16;359(4):1045-58
references: 16650855
references: Nature. 2006 Oct 12;443(7112):658-62
references: 17035996
references: J Biol Chem. 2006 Nov 24;281(47):35802-11
references: 17005564
references: Biochemistry. 2006 Dec 5;45(48):14533-42
references: 17128992
references: Apoptosis. 2007 May;12(5):897-911
references: 17453159
references: Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11649-54
references: 17606912
references: Genes Dev. 1999 Nov 15;13(22):2958-70
references: 10580003
references: Genetics. 1999 Dec;153(4):1655-71
references: 10581274
references: Mol Cell. 1999 Nov;4(5):815-26
references: 10619028
references: Genes Dev. 1996 Mar 1;10(5):578-91
references: 8598288
references: Nature. 1996 May 23;381(6580):335-41
references: 8692274
references: Science. 1997 Feb 21;275(5303):1126-9
references: 9027313
references: Science. 1997 Jul 18;277(5324):370-2
references: 9219694
references: J Cell Biol. 1997 Dec 1;139(5):1281-92
references: 9382873
references: EMBO J. 1999 Feb 1;18(3):632-43
references: 9927423
references: Nature. 2005 Feb 17;433(7027):754-60
references: 15716954
references: Nat Rev Mol Cell Biol. 2005 Aug;6(8):657-63
references: 16025099
references: Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):11916-21
references: 11027303