Editors' ChoiceApoptosis

Caspases Open the Door

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Science's STKE  05 Dec 2000:
Vol. 2000, Issue 61, pp. tw1
DOI: 10.1126/stke.2000.61.tw1

During apoptosis, many cellular structures are dismantled through the activities of caspases; however, the nuclear membrane is not degraded. Despite having an intact nuclear membrane, some of the substrates of caspases are nuclear proteins, such as the inhibitor of the DNase CAD (ICAD), which is cleaved by caspase-3, leading to activation of CAD and DNA fragmentation and condensation. Faleiro and Lazebnik studied the breast cancer cell line MCF-7, which does not express caspase-3 and does not undergo DNA condensation during apoptosis. Expression of a green fluorescent protein-tagged version of caspase-3 (GFP-c3) restored chromatin condensation after treatment with cisplatin and resulted in the equilibration of GFP-c3 between the nuclear and cytosolic compartments. The ability of GFP-c3 to enter the nucleus during apoptosis was dependent on the activity of caspase-9, but not the catalytic activity of caspase-3. Studies with oligomers of GFP, GFP with a nuclear localization signal (GFP-NLS), and Ran suggested that caspase-9 increases the permeability of the nuclear pore, because a 140-kD GFP pentamer, the GFP-NLS, and Ran all became evenly distributed between the nucleus and cytosol in response to cisplatin treatment by a mechanism that depended on active caspase-9. However, a GFP-β-galactosidase construct was excluded from the nucleus in normal and apoptotic cells, indicating that the nuclear membrane was still intact. Although the nuclear pore target of caspase-9 was not identified, two different antibodies against the nuclear pore complex fail to recognize the pores in apoptotic cells, suggesting that the pore structure may change during apoptosis, masking the antigenic sites. The data suggest that during apoptosis, caspase-9 acts to disrupt the nuclear-cytoplasmic barrier by altering the size exclusion limits of the nuclear pore.

Faleiro, L., and Lazebnik, Y. (2000) Caspases disrupt the nuclear-cytoplasmic barrier. J. Cell Biol. 151: 951-959. [Abstract] [Full Text]

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