p27KIP1 is down-regulated by two different mechanisms in human lymphoid cells undergoing apoptosis.
The cyclin-dependent kinase inhibitor p27KIP1 is a crucial component of the mammalian restriction point, and as such is subject to multiple regulatory mechanisms. It has recently been shown that the abundance of p27KIP1 is also regulated during apoptosis; p27KIP1 is cleaved by a Z-VAD-fmk-sensitive caspase during apoptosis induced by growth factor deprivation in endothelial cells, and also following exposure of myeloid leukaemia cells to etoposide. Here, we investigate p27KIP1 regulation in B- and T-lymphoid cells undergoing apoptosis. We observe that p27KIP1 is down-regulated following exposure to a variety of apoptotic stimuli including an agonistic anti-Fas antibody, cycloheximide and etoposide. Further investigation revealed the existence of two different routes of p27KIP1 regulation in lymphoid cells undergoing apoptosis. The first pathway is utilized by lymphoid cells stimulated through Fas, is abrogated in a caspase-8-deficient T-cell line, and is blocked by the caspase inhibitors Z-VAD-fmk and Boc-D-fmk. In contrast, the loss of p27KIP1 in cells exposed to cycloheximide and etoposide occurs in the absence of caspase-8 or any Z-VAD-fmk- or Boc-D-fmk-sensitive caspase activities. Thus the down-regulation of p27KIP1 is a common occurrence in lymphoid cells undergoing apoptosis but, depending on the apoptotic trigger, this can be affected by two different mechanisms.
Frost
V
V
School of Biological Sciences, University of Sussex, Brighton, BN1 9QG, UK.
Sinclair
A J
AJ
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes / Q000502:physiology*; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation; D005047:Etoposide; D006801:Humans; D019169:Jurkat Cells; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*; D025521:Tumor Suppressor Proteins; D019014:fas Receptor / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D011506:Proteins; D025521:Tumor Suppressor Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005047:Etoposide; D003513:Cycloheximide; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases