Guardians of cell death: the Bcl-2 family proteins.
Apoptosis is mediated through at least three major pathways that are regulated by (i) the death receptors, (ii) the mitochondria and (iii) the ER (endoplasmic reticulum). In most cells, these pathways are controlled by the Bcl-2 family of proteins that can be divided into anti-apoptotic and pro-apoptotic members. Although the overall amino acid sequence homology between the family members is relatively low, they contain highly conserved domains, referred to as BH (Bcl-2 homology) domains (BH1-4), that are essential for homo- and hetero-complex formation, as well as for their cell-death-inducing capacity. Structural and functional analyses revealed that the pro-apoptotic homologues can be subdivided into the Bax subfamily and the growing BH3-only subfamily. Recent data indicate that BH3-only proteins act as mediators that link various upstream signals, including death receptors and DNA damage signalling, to the mitochondrial and the ER pathway. This review discusses recent structural and functional insights into how these subfamilies promote or inhibit cell-death signals, and how these properties may be utilized for development of apoptosis-promoting small molecules, e.g. in cancer therapy.
Daniel
Peter T
PT
Molecular Hematology and Oncology, Charité - Campus Berlin-Buch, Humboldt University, Lindenberger Weg 80, 13125 Berlin-Buch, Germany. pdaniel@mdc-berlin.de
Schulze-Osthoff
Klaus
K
Belka
Claus
C
Güner
Dilek
D
D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000378:metabolism; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D008322:Mammals; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
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