Cycloheximide Can Induce Bax/Bak Dependent Myeloid Cell Death Independently of Multiple BH3-Only Proteins.
Apoptosis mediated by Bax or Bak is usually thought to be triggered by BH3-only members of the Bcl-2 protein family. BH3-only proteins can directly bind to and activate Bax or Bak, or indirectly activate them by binding to anti-apoptotic Bcl-2 family members, thereby relieving their inhibition of Bax and Bak. Here we describe a third way of activation of Bax/Bak dependent apoptosis that does not require triggering by multiple BH3-only proteins. In factor dependent myeloid (FDM) cell lines, cycloheximide induced apoptosis by a Bax/Bak dependent mechanism, because Bax-/-Bak-/- lines were profoundly resistant, whereas FDM lines lacking one or more genes for BH3-only proteins remained highly sensitive. Addition of cycloheximide led to the rapid loss of Mcl-1 but did not affect the expression of other Bcl-2 family proteins. In support of these findings, similar results were observed by treating FDM cells with the CDK inhibitor, roscovitine. Roscovitine reduced Mcl-1 abundance and caused Bax/Bak dependent cell death, yet FDM lines lacking one or more genes for BH3-only proteins remained highly sensitive. Therefore Bax/Bak dependent apoptosis can be regulated by the abundance of anti-apoptotic Bcl-2 family members such as Mcl-1, independently of several known BH3-only proteins.
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia.
Katharine J
KJ
Goodall
School of Chemistry and Biochemistry, University of Western Australia, Crawley, WA, Australia.
Megan L
ML
Finch-Edmondson
Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, the University of Western Australia, Crawley, WA, Australia.
Joanne
J
van Vuuren
School of Chemistry and Biochemistry, University of Western Australia, Crawley, WA, Australia.|Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, the University of Western Australia, Crawley, WA, Australia.
George C
GC
Yeoh
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia.|Institute for Medical Microbiology and Hygiene, Hermann-Herder-Str. 11 79104 Freiburg Germany.
Ian E
IE
Gentle
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia.|The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
James E
JE
Vince
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia.|The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC, Australia.
Paul G
PG
Ekert
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia.|The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
David L
DL
Vaux
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia.|School of Chemistry and Biochemistry, University of Western Australia, Crawley, WA, Australia.|School of Health Sciences, The University of Notre Dame Australia, Fremantle, WA, Australia.
Bernard A
BA
Callus
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D011500:Protein Synthesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D003513:Cycloheximide; D046988:Proteasome Endopeptidase Complex