Bcl-2-regulated apoptosis: mechanism and therapeutic potential.
Apoptosis is essential for tissue homeostasis, particularly in the hematopoietic compartment, where its impairment can elicit neoplastic or autoimmune diseases. Whether stressed cells live or die is largely determined by interplay between opposing members of the Bcl-2 protein family. Bcl-2 and its closest homologs promote cell survival, but two other factions promote apoptosis. The BH3-only proteins sense and relay stress signals, but commitment to apoptosis requires Bax or Bak. The BH3-only proteins appear to activate Bax and Bak indirectly, by engaging and neutralizing their pro-survival relatives, which otherwise constrain Bax and Bak from permeabilizing mitochondria. The Bcl-2 family may also regulate autophagy and mitochondrial fission/fusion. Its pro-survival members are attractive therapeutic targets in cancer and perhaps autoimmunity and viral infections.
Adams
Jerry M
JM
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne 3050 Australia. adams@wehi.edu.au
Cory
Suzanne
S
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D051023:BH3 Interacting Domain Death Agonist Protein / Q000737:chemistry / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D053858:Metabolic Networks and Pathways; D008928:Mitochondria / Q000502:physiology / Q000648:ultrastructure; D018716:Molecular Mimicry; D009369:Neoplasms / Q000188:drug therapy; D009596:Nitrophenols / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
C501332:ABT-737; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides