Proteins of the bcl-2 family in apoptosis signalling: from mechanistic insights to therapeutic opportunities.
1. Proteins of the Bcl-2 family are central regulators of apoptosis and are thought to act primarily on the mitochondria. 2. Members of the Bcl-2 family possess either anti-apoptotic or pro-apoptotic function. They are characterized by the presence of conserved sequence motifs, known as Bcl-2 homology (BH) domains. Anti-apoptotic members share all four BH domains, designated as BH1-4; the multidomain pro-apoptotic members contain BH1-3 domains, whereas another subgroup of pro-apoptotic members only have a BH3 domain. 3. The BH3-only proteins act as sensors for distinct apoptosis pathways, whereas multidomain pro-apoptotic Bax and Bak are executioners of death orders relayed by the BH3-only proteins. 4. Anti-apoptotic Bcl-2 family members appear to function, at least in part, by interacting with and antagonizing pro-apoptotic family members. The BH1-3 domains of BclXL form an elongated hydrophobic groove, which is the docking site for the BH3 domains of pro-apoptotic binding partners. 5. The deregulation of the various Bcl-2 proteins has been implicated in many pathological conditions. 6. Knowledge derived from the understanding of the function and regulation of the Bcl-2 family of proteins has allowed us to contemplate new therapeutic strategies for diseases where apoptosis signalling mechanisms can potentially be manipulated. 7. The anti-apoptotic Bcl-2 members have been targeted successfully using an antisense approach, BH3-peptides and small molecular weight chemicals that are inhibitors of their anti-apoptotic function.
Chan
Shing-Leng
SL
Institute of Molecular and Cell Biology and Department of Pharmacology, National University of Singapore, Singapore.
Yu
Victor C
VC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002986:Clinical Trials as Topic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2