Rescue from granzyme B-induced apoptosis by Wee1 kinase.
Granzymes are a family of granule-associated serine esterases that mediate apoptosis by cytotoxic T lymphocytes and natural killer cells. We have previously shown that cdc2, the mitosis-regulating cyclin-dependent kinase, is required for granzyme B-induced apoptosis in target cells. In addition, granzyme B induces premature activation and tyrosine dephosphorylation of cdc2 during apoptosis. Throughout most of the cell cycle and until the cell is prepared to enter mitosis, cdc2 kinase activity is negatively regulated by phosphorylation of a residue within its adenosine triphosphate-binding domain by Wee1, a nuclear kinase that maintains mitotic timing in eukaryotic cells. We have transiently expressed c-myc epitope-tagged Wee1 cDNA in BHK cells. Cells that expressed Wee1 in the nucleus became resistant to apoptosis induced by granzyme B and perforin. Wee1-transfected cells also exhibited markedly increased cdc2 tyrosine phosphorylation. Thus, Wee1 can rescue cells from granzyme-induced apoptosis by preventing cdc2 dephosphorylation.
Chen
G
G
Manitoba Institute of Cell Biology, Manitoba Cancer Treatment and Research Foundation, University of Manitoba, Winnipeg, Canada.
Shi
L
L
Litchfield
D W
DW
Greenberg
A H
AH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D006224:Cricetinae; D016259:Genes, myc; D053804:Granzymes; D006706:Homeostasis; D006801:Humans; D007668:Kidney; D008938:Mitosis; D009687:Nuclear Proteins; D010766:Phosphorylation; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D011994:Recombinant Proteins / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism; D012697:Serine Endopeptidases / Q000494:pharmacology*; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D019000:Phosphotyrosine; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D016203:CDC2 Protein Kinase; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases