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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.

Original publication

DOI

10.1371/journal.pone.0164003

Type

Journal article

Journal

PLoS One

Publication Date

2016

Volume

11

Keywords

Animals, Apoptosis, Apoptosis Regulatory Proteins, Cell Death, Cell Line, Cycloheximide, Dose-Response Relationship, Drug, Gene Knockout Techniques, Humans, Mice, Myeloid Cells, Proteasome Endopeptidase Complex, Protein Synthesis Inhibitors, Proto-Oncogene Proteins c-bcl-2, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein