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)

The E6 and E7 proteins of the high risk human papillomaviruses (HPVs) are consistently expressed in HPV-positive cervical carcinomas. We investigated the ability of HPV-16 E6 and E7 to disrupt mitotic checkpoints in normal diploid human cells. Acute expression of HPV-16 E6, but not HPV-16 E7, decreased the fidelity of multiple checkpoints controlling entry into and exit from mitosis. After irradiation, nearly 50% of cells containing HPV-16 E6 readily entered mitosis as opposed to less than 10% of control cells. Consistent with this, asynchronous populations of cells expressing HPV-16 E6 had increased cdc2-associated histone H1 kinase activity relative to control populations. In addition, HPV-16 E6 increased sensitivity to chemically-induced S-phase premature mitosis and decreased mitotic spindle assembly checkpoint function relative to control populations. HPV-16 E6 mutants with a reduced ability to target p53 for degradation were unable to abrogate mitotic checkpoints, suggesting a possible mechanism by which HPV-16 E6 disrupts mitotic checkpoints. Expression of a mutant p53 gene yielded an intermediate phenotype relative to HPV-16 E6, generating moderate increases in sensitivity to chemically-induced S-phase PCC and mitotic spindle disruption and a heightened propensity to enter mitosis after irradiation.
 ...
PMID:The human papillomavirus-16 E6 oncoprotein decreases the vigilance of mitotic checkpoints. 944 51

Rad9 is required for the activity of the genotoxin-induced checkpoint signaling pathway to control cell cycle progress and maintain genomic stability. In the fission yeast S. Pombe and chicken cells, the Rad9 gene is essential for prevention of premature chromosomal condensation (PCC:S/M checkpoint control). However, precise features in the S/M checkpoint controlled by Rad9 in mammalian cells are still not clear. In this study, mouse embryonic stem (ES) cells with a targeted deletion of Mrad9, the counterpart of S. pombe rad9, were used to evaluate the detailed function of Mrad9 in S/M checkpoint control. We found that Mrad9 deletion from ES cells led to failure of S/M checkpoint control across the entire S phase, and was alleviated by introducing mouse or human Rad9 into the Mrad9-deleted cells. We also found that the phosphorylation sites on Tyr28 and the C-terminus of Rad9 are required for this checkpoint control. Moreover, the DNA replication inhibitor hydroxyurea (HU) induced cdc2 Tyr15 phosphorylation and increased 14-3-3sigma protein levels in Mrad9(+)/(+) ES cells, but failed to do so in Mrad9(-)/(-) ES cells. Taken together, these results suggest that phosphorylation of Rad9 plays a critical role in the activation of the S/M checkpoint, and that downstream proteins cdc2 and 14-3-3sigma mediate this function.
 ...
PMID:Phosphorylation sites on Tyr28 and the C-terminus of Rad9 are required for inhibition of premature chromosomal condensation across the entire S phase. 1876 57

The activity of the dual specificity phosphatase cdc25C is required for mitotic progression though the mechanisms by which cdc25C is activated prior to mitosis in human cells remain unclear. The data presented herein show that the actin binding protein Filamin A forms a complex with cdc25C in vivo and binds preferentially to the mitotic form of cdc25C. Co-expression of Filamin A with cdc25C results in an increase in PCC induced by cdc25C, while knocking down Filamin A expression reduces the levels of PCC induced by cdc25C overexpression. Further, only a Filamin A fragment that forms a complex with both cdc25C and cyclin B1 and retains the dimerization domain can stimulate the ability of cdc25C to induce PCC. These results suggest that Filamin A provides a platform for the assembly of the cyclin B1-cdk1- cdc25C complex resulting in cdk1 activation and mitotic progression.
 ...
PMID:Filamin A stimulates cdc25C function and promotes entry into mitosis. 2132 83