Intracellular pro-apoptotic substrates

Intracellular pro-apoptotic substrates are a diverse collection of cellular proteins that serve as the downstream effectors of the apoptotic signaling cascade (PMID: 18446155). These proteins, which include structural components like lamins and functional enzymes such as Poly (ADP-ribose) polymerase (PARP), are targeted for proteolytic cleavage by executioner caspases, primarily Caspase-3, -6, and -7 (PMID: 8506190). The systematic cleavage of these substrates is the hallmark of the execution phase of apoptosis, resulting in the irreversible dismantling of the cell, DNA fragmentation, and the formation of apoptotic bodies (PMID: 9390559). In many diseases, particularly cancer, the pathways leading to the cleavage of these substrates are suppressed, allowing for uncontrolled cell survival and resistance to therapy (PMID: 21376230). Conversely, excessive cleavage of these substrates is associated with neurodegenerative conditions and tissue atrophy. While these substrates are not typically the direct binding targets of pharmacological agents, they are the functional endpoints for a wide range of pro-apoptotic drugs, including BCL-2 inhibitors like venetoclax and caspase activators like PAC-1 (PMID: 23291514, 16782871). Monitoring the presence of cleaved fragments of these substrates, such as cleaved PARP, is a critical biomarker used in clinical trials to confirm the induction of apoptosis by candidate anti-cancer therapies.

Other names

Caspase substratesDeath substratesApoptotic executioner substratesProteolytic substrates of caspases

Proteolytic cleavage by executioner caspases (Caspase-3, -6, -7) leading to irreversible cell death and cellular disassembly (PMID: 18446155).