Premium
PROTEINS OF THE BCL‐2 FAMILY IN APOPTOSIS SIGNALLING: FROM MECHANISTIC INSIGHTS TO THERAPEUTIC OPPORTUNITIES
Author(s) -
Chan ShingLeng,
Yu Victor C
Publication year - 2004
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2004.03975.x
Subject(s) - apoptosis , bcl 2 family , microbiology and biotechnology , function (biology) , mitochondrion , biology , puma , protein family , inhibitor of apoptosis domain , homology (biology) , chemistry , programmed cell death , genetics , caspase , gene
SUMMARY 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.