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)

PC-SPES is an herbal mixture, with evidence of clinical efficacy against prostate cancer (CaP), recently attracting tremendous attention. Using immunoblot and cell cycle specific cDNA array analyses, we investigated effects of PC-SPES on LNCaP, a hormone-dependent prostate cancer cell line. PC-SPES inhibited expression of cyclins D and E, inhibited Rb phosphorylation, switching it to a G1-to-S inhibitory state. Moreover, cDNA array analysis showed that PC-SPES caused up-regulation of p21(WAF1/CIP1) and decreased expression of cyclin B, Nedd8, cdc2, skp1, PCNA, MAD2L1, cyclin H, CKS2, E2F, Rbx1, MCM2, MCM5, Mpp2, Cullin-Cul4A, Cks1p9 and McM7, which are involved in cell cycle progression. Taken together, our results provide a mechanistic explanation for antiproliferative and antitumor effects of PC-SPES, suggesting that induction of CDK inhibitors and downregulation of cyclins leads to dephosphorylation of Rb and growth arrest.
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PMID:PC-SPES inhibits cell proliferation by modulating p21, cyclins D, E and B and multiple cell cycle-related genes in prostate cancer cells. 1269 90

Centrosomes are the primary microtubule-organizing centers in animal cells and are required for bipolar spindle assembly during mitosis. Amplification of centrosome number is commonly observed in human cancer cells and might contribute to genomic instability. Cyclin E-Cdk2 has been implicated in regulating centrosome duplication both in Xenopus embryos and extracts and in mammalian cells. Localization of cyclin E on centrosomes is mediated by a 20-amino acid domain termed the centrosomal localization sequence (CLS). In this paper, cyclin E is shown to directly interact with and colocalize on centrosomes with the DNA replication factor MCM5 in a CLS-dependent but Cdk2-independent manner. The domain in MCM5 that is responsible for interaction with cyclin E is distinct from any previously described for MCM5 function and is highly conserved in MCM5 proteins from yeast to mammals. Expression of MCM5 or its cyclin E-interacting domain, but not MCM2, significantly inhibits over-duplication of centrosomes in CHO cells arrested in S-phase. These results indicate that proteins involved in DNA replication might also regulate centrosome duplication.
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PMID:Cyclin E-dependent localization of MCM5 regulates centrosome duplication. 1879 89

Centrosomes are the major microtubule-organizing centers in animal cells and regulate formation of a bipolar mitotic spindle. Aberrant centrosome number causes chromosome mis-segregation, and has been implicated in genomic instability and tumor development. Previous studies have demonstrated a role for the DNA replication factors MCM5 and Orc1 in preventing centrosome reduplication. Cyclin A-Cdk2 localizes on centrosomes by means of a modular centrosomal localization sequence (CLS) that is distinct from that of cyclin E. Here, we show that cyclin A interacts with both MCM5 and Orc1 in a CLS-dependent but Cdk-independent manner. Although the MRAIL hydrophobic patch is contained within the cyclin A CLS, binding of both MCM5 and Orc1 to cyclin A does not require a wild-type hydrophobic patch. The same domain in MCM5 that mediates interaction with cyclin E also binds cyclin A, resulting in centrosomal localization of MCM5. Finally, unlike its function in DNA synthesis, MCM5-mediated inhibition of centrosome reduplication in S-phase-arrested CHO cells does not require binding to other MCM family members. These results suggest that cyclins E and A sequentially prevent centrosome reduplication throughout interphase by recruitment of DNA replication factors such as MCM5 and Orc1.
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PMID:The cyclin A centrosomal localization sequence recruits MCM5 and Orc1 to regulate centrosome reduplication. 2066 15

MCM7 is one of the subunits of the MCM2-7 complex that plays a critical role in DNA replication initiation and cell proliferation of eukaryotic cells. After forming the pre-replication complex (pre-RC) with other components, the MCM2-7 complex is activated by DDK/cyclin-dependent kinase to initiate DNA replication. Each subunit of the MCM2-7 complex functions differently under regulation of various kinases on the specific site, which needs to be investigated in detail. In this study, we demonstrated that MCM7 is a substrate of cyclin E/Cdk2 and can be phosphorylated on Ser-121. We found that the distribution of MCM7-S121A is different from wild-type MCM7 and that the MCM7-S121A mutant is much less efficient to form a pre-RC complex with MCM3/MCM5/cdc45 compared with wild-type MCM7. By using the Tet-On inducible HeLa cell line, we revealed that overexpression of wild-type MCM7 but not MCM7-S121A can block S phase entry, suggesting that an excess of the pre-RC complex may activate the cell cycle checkpoint. Further analysis indicates that the Chk1 pathway is activated in MCM7-overexpressed cells in a p53-dependent manner. We performed experiments with the human normal cell line HL-7702 and also observed that overexpression of MCM7 can cause S phase block through checkpoint activation. In addition, we found that MCM7 could also be phosphorylated by cyclin B/Cdk1 on Ser-121 both in vitro and in vivo. Furthermore, overexpression of MCM7-S121A causes an obvious M phase exit delay, which suggests that phosphorylation of MCM7 on Ser-121 in M phase is very important for a proper mitotic exit. These data suggest that the phosphorylation of MCM7 on Ser-121 by cyclin/Cdks is involved in preventing DNA rereplication as well as in regulation of the mitotic exit.
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PMID:Phosphorylation of minichromosome maintenance protein 7 (MCM7) by cyclin/cyclin-dependent kinase affects its function in cell cycle regulation. 2372 Jul 38