Abstract
Caspase-2 belongs to the caspase family of proteins responsible for essential cellular functions including apoptosis and inflammation. Uniquely, caspase-2 has been identified as a tumor suppressor, but how it regulates this function is still unknown. For many years, caspase-2 has been considered an “orphan” caspase because, although it is able to induce apoptosis, there is an abundance of conflicting evidence that questions its necessity for apoptosis. Recent evidence supports that caspase-2 has non-apoptotic functions in the cell cycle and protection from genomic instability. It is unclear how caspase-2 regulates these opposing functions, which has made the mechanism of tumor suppression by caspase-2 difficult to determine. As a protease, caspase-2 likely exerts its functions by proteolytic cleavage of cellular substrates. This review highlights the known substrates of caspase-2 with a special focus on their functional relevance to caspase-2’s role as a tumor suppressor.
Highlights
Members of the caspase family of proteases are essential for the initiation and execution of apoptosis
A cleavage defective mutant of PIDD1 that could not be processed to PIDD-CC failed to bind RAIDD and did not induce apoptosis after treatment with doxorubicin, demonstrating the necessity of PIDD-CC for PIDDosome assembly and caspase-2-mediated death (Tinel et al, 2007)
Using a model of MMTV/c-neu mammary tumor formation, we demonstrated that caspase-2 can act as a tumor suppressor in the context of an epithelial cancer (Parsons et al, 2013)
Summary
Members of the caspase family of proteases are essential for the initiation and execution of apoptosis. A cleavage defective mutant of PIDD1 that could not be processed to PIDD-CC failed to bind RAIDD and did not induce apoptosis after treatment with doxorubicin, demonstrating the necessity of PIDD-CC for PIDDosome assembly and caspase-2-mediated death (Tinel et al, 2007) Of this complex facilitates proximity-induced dimerization, and activation of caspase-2 (Bouchier-Hayes et al, 2009). Sub-cultured primary lymphoma cells from Eμ-Myc lymphomas lacking caspase-2 showed a decreased sensitivity to apoptosis induced by cytoskeletal disruption and irradiation as measured by Annexin V binding (Ho et al, 2009) Whether these results contradict due to the mechanism of action of their respective driver genes (Eμ-Myc vs Atm deficiency) or due to differences in the measurement of cell death (TUNEL staining vs Annexin V binding) is unclear. We contend that there exists a number of additional, as yet unidentified, caspase-2 substrates, the access
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