Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins.
BH3-only proteins are structurally distant members of the Bcl-2 protein family that trigger apoptosis. Genetic experiments have shown that these proteins are essential initiators of programmed cell death in species as distantly related as mice and C. elegans. BH3-only proteins share with each other and with the remainder of the Bcl-2 family only a nine amino acid BH3 (Bcl-2 Homology) region. Mutational analyses have demonstrated that this domain is required for their ability to bind to Bcl-2-like pro-survival proteins and to initiate apoptosis. So far only one BH3-only protein, EGL-1, has been identified in C. elegans and it is required for all developmentally programmed death of somatic cells in this species. In contrast, mammals have at least 10 BH3-only proteins that differ in their expression pattern and mode of activation. Studies in gene targeted mice have indicated that different BH3-only proteins are required for the initiation of distinct apoptotic stimuli. The pro-apoptotic activities of BH3-only proteins are stringently controlled by a variety of mechanisms. C. elegans egl-1 as well as mammalian hrk/dp5, noxa, puma/bbc3 and bim/bod are regulated by a diverse range of transcription factors. Certain BH3-only proteins, including Bad, Bik/Nbk, Bid, Bim/Bod and Bmf, are restrained by post-translational modifications that cause their sequestration from pro-survival Bcl-2 family members. In this review we describe current knowledge of the functions and transcriptional as well as post-translational control mechanisms of BH3-only proteins.
Puthalakath
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The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Strasser
A
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
C494772:BAK1 protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein