CGC Bibliography Paper 5248

Keeping killers on a tight leash: transcriptional and posttranscriptional control of the pro-apoptotic activity of BH3-only proteins.

Puthalakath H, Strasser A

Medline:

11973609

Citation:

Cell Death and Differentiation 9: 505-512 2002

Type:

REVIEW

Genes:

ced-3 ced-4 ced-9 ces-1 ces-2 egl-1 tra-1

Abstract:

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 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 posttranslational 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.