BH3-only proteins in apoptosis and beyond: an overview.
BH3-only BCL-2 family proteins are effectors of canonical mitochondrial apoptosis. They discharge their pro-apoptotic functions through BH1-3 pro-apoptotic proteins such as BAX and BAK, while their activity is suppressed by BH1-4 anti-apoptotic BCL-2 family members. The precise mechanism by which BH3-only proteins mediate apoptosis remains unresolved. The existing data are consistent with three mutually non-exclusive models (1) displacement of BH1-3 proteins from complexes with BH1-4 proteins; (2) direct interaction with and conformational activation of BH1-3 proteins; and (3) membrane insertion and membrane remodeling. The BH3-only proteins appear to play critical roles in restraining cancer and inflammatory diseases such as rheumatoid arthritis. Molecules that mimic the effect of BH3-only proteins are being used in treatments against these diseases. The cell death activity of a subclass of BH3-only members (BNIP3 and BNIP3L) is linked to cardiomyocyte loss during heart failure. In addition to their established role in apoptosis, several BH3-only members also regulate diverse cellular functions in cell-cycle regulation, DNA repair and metabolism. Several members are implicated in the induction of autophagy and autophagic cell death, possibly through unleashing of the BH3-only autophagic effector Beclin 1 from complexes with BCL-2/BCL-xL. The Chapters included in the current Oncogene Review issues provide in-depth discussions on various aspects of major BH3-only proteins.
Lomonosova
E
E
Institute for Molecular Virology, Saint Louis University School of Medicine, Doisy Research Center, St Louis, MO 63104, USA.
Chinnadurai
G
G
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D001343:Autophagy / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D016384:Consensus Sequence / Q000502:physiology*; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008322:Mammals / Q000378:metabolism; D051379:Mice; D051336:Mitochondrial Membranes / Q000378:metabolism; D008969:Molecular Sequence Data; D005810:Multigene Family; D010446:Peptide Fragments / Q000737:chemistry / Q000502:physiology*; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000502:physiology*
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C474007:Bax protein (53-86); D029742:Caenorhabditis elegans Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2