Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Rescue from granzyme B-induced apoptosis by Wee1 kinase. 753 47

Granzyme B rapidly induces apoptosis in the presence of the pore-forming protein perforin. We have examined the cell cycle restriction of this apoptosis by separating Jurkat cells into fractions representing different stages of the cell cycle by centrifugal elutriation. Cells were susceptible to apoptosis from G1 through to G2/M, with no significant resistance detected at any stage. Similarly, cells arrested at G1/S or G2/M with either hydroxyurea or nocodazole were slightly more sensitive than asynchronously growing cells. Granzyme B induces Cdc2 kinase activity and requires its induction for apoptosis. Cyclin-dependent kinase (CDK) activity is regulated by phosphorylation and association with cyclins that also control subcellular localization of the CDK/cyclin complexes. Cdc2 associates with both cyclin A, which is synthesized at G1 and S, and cyclin B, which is produced later during S and G2 before G2/M transition. We find that the CDK activity induced by granzyme B is associated primarily with cyclin A in both asynchronous and G1/S-arrested cells, while cyclin B-associated kinase activity is minimal. Because cyclin A is also able to associate with Cdk2, a kinase that is important for G1/S transition, we examined the activation of this CDK during granzyme B-induced apoptosis and find that Cdk2 is induced as rapidly as Cdc2. In conclusion, we have identified a lack of cell cycle restriction of granzyme B-induced apoptosis and the rapid activation of both cyclin A/Cdc2 and cyclin A/Cdk2 kinase activity.
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PMID:Granzyme B induces apoptosis and cyclin A-associated cyclin-dependent kinase activity in all stages of the cell cycle. 880 36

Cytotoxic lymphocytes induce apoptosis of target cells by degranulating and releasing the serine protease granzyme B and the pore forming protein perforin. Granzyme B is an aspartic acid protease similar to members of the interleukin 1beta converting enzyme (ICE) family. We review the evidence for the participation members of the ICE family of proteases and cdc2 kinase in granzyme B-induced apoptosis.
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PMID:Activation of apoptosis pathways by granzyme B. 1718 95