Caspase-3 (CASP3)
Caspase-3 is the main executioner caspase: the protease that carries out the dismantling of the cell once a death pathway has been triggered.
Function
Caspase-3 circulates as an inactive zymogen. Initiator caspases — caspase-9 from the APAF1 apoptosome, caspase-8 from death receptors such as FAS — cleave caspase-3 at conserved aspartates, and the mature enzyme cuts hundreds of cellular substrates: structural proteins, repair enzymes, cell-cycle machinery, and other caspases. Two of its cuts are amplification loops, one cleaving caspase-6 and one inactivating the inhibitor XIAP, which is why caspase-3 activity, once begun, runs to completion. Its substrates also include the enzymes that fragment DNA and the flippases that mark membrane for phagocytosis, so the dying cell disassembles in the ordered way that lets its neighbors clear it without inflammation.
In cancer
Tumors rarely mutate caspase-3 directly because the BCL-2-family proteins guard the pathways upstream of it. Loss of caspase-3 expression occurs in some breast cancers and hormone-resistant tumors and correlates with poorer prognosis. The enzyme has a second role outside cell death: transient caspase-3 activity drives the terminal differentiation of platelet-producing megakaryocytes and the enucleation of erythrocytes.
Notes
- Human gene symbol: CASP3; UniProt P42574; 277 amino acids; cysteine-aspartic acid protease, cleaving after aspartic acid residues.