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)

Deregulated cell cycle and defective genome-integrity checkpoints are among the hallmarks of cancer. Here we summarize our recent studies of key components of the GI/S machinery in normal human spermatogenesis, and their abnormalities in testicular germ cell tumours (TGCTs), with special emphasis on carcinoma in situ lesions (CIS). Our combined immunohistochemical and immunoblotting analyses of normal human adult and fetal testes, CIS, seminomas, embryonal carcinomas, and teratomas, revealed an 'unorthodox' spectrum of defects within the so-called RB pathway in TGCTs. The early aberrations included lack of expression of the retinoblastoma tumour suppressor (pRB) and the CDK inhibitor pl9ink4d, and overexpression of cyclin D2. Progression from CIS to invasive TGCTswas associated with loss of another two CDK inhibitors and tumour suppressors: pl6ink4a and pl8ink4c. We also found the lack of pRB and pl9ink4d in fetal gonocytes, the candidate target cell for all types of TGCTs. These findings, together with the status of the Chk2-p53 DNA-integrity checkpoint, are considered in relation to the origin, biology and pathogenesis of TGCTs, and potential implications of the GI/S defects for the curability of these tumours.
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PMID:Deregulation of the G1/S-phase control in human testicular germ cell tumours. 1276 Mar 79

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of growth arrested clonal B lymphocytes that undergo apoptosis when treated with fludarabine. To further explore the mechanism for the cell cycle arrest, we examined the expression and activity of cyclin-dependent kinases and inhibitors in primary B-CLL cells. We observed high levels of p27kip1, cyclin D2, cyclin E, cdk2, and cdk4 expression in freshly isolated B-CLL cells. Despite high levels of cyclins and cdks, little cdk2 or cdk4 activity was observed with p27kip1 in complex with cyclinD2/cdk4 and cyclin E/cdk2. Remarkably, when B-CLL cells were treated in vitro with fludarabine, p27kip1 underwent caspase-specific degradation accompanied by an increase in cdk4 activity. We conclude that the G0/G1 arrest of B-CLL cells may protect against apoptosis and that the decrease in p27kip1 expression by caspase cleavage may be a key step in chemotherapy-induced apoptosis in B-CLL.
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PMID:Fludarabine-induced apoptosis of B chronic lymphocytic leukemia cells includes early cleavage of p27kip1 by caspases. 1276 76

The three human D-type cyclins, cyclin D1, D2 and D3 share the ability to bind to and activate cdk4 and 6. MMTV-cyclin D1 transgenic mice develop mainly adenocarcinoma, while MMTV-cyclin D2 mice show a lack of alveologenesis during pregnancy and only develop carcinoma at low frequency. The effect of cyclin D3 overexpression in mammary glands remains hitherto unknown. We generated MMTV-cyclin D3 transgenic mice and report here that they develop exclusively squamous cell carcinoma. We show that although cyclin D3 transgene expression was detected early in puberty, postnatal development and mammary gland proliferation were normal in virgin animals. In contrast, multiparous mice develop multiple foci of abnormal growth that correspond to various stages of squamous metaplasia. Therefore, our results support a role for cyclin D3 in squamous differentiation. In addition, we found that p16 expression during involution is abolished, while p27 expression increased in MMTV-cyclin D3 mice, two modifications that have been reported in the other MMTV-D-type cyclin transgenic models. Our observations indicate that despite biochemical redundancy in vitro and in vivo, D-type cyclins promote distinct oncogenic pathways.
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PMID:Alternative mammary oncogenic pathways are induced by D-type cyclins; MMTV-cyclin D3 transgenic mice develop squamous cell carcinoma. 1285 79

Cyclin D2 affects B cell proliferation and differentiation in vivo. It is rate-limiting for B cell receptor (BCR)-dependent proliferation of B cells, and cyclin D2-/- mice lack CD5+(B1) B lymphocytes. We show here that the bone marrow (BM) of cyclin D2-/- mice contains half the numbers of Sca1+B220+ B cell progenitors but normal levels of Sca1+ progenitor cells of other lineages. In addition, clonal analysis of BM from the cyclin D2-/- and cyclin D2+/+ mice confirmed that there were fewer B cell progenitors (B220+) in the cyclin D2-/- mice. In addition, the colonies from cyclin D2-/- mice were less mature (CD19lo) than those from cyclin D2+/+ mice (CD19Hi). The number of mature B2 B cells in vivo is the same in cyclin D2-/- and cyclin D2+/+ animals. Lack of cyclin D2 protein may be compensated by cyclin D3, as cyclin-dependent kinase (cdk)6 coimmunoprecipitates with cyclin D3 but not cyclin D1 from BM mononuclear cells of cyclin D2-/- mice. It is active, as endogenous retinoblastoma protein is phosphorylated at the cdk6/4-cyclin D-specific sites, S807/811. We conclude that cyclin D2 is rate-limiting for the production of B lymphoid progenitor cells whose proliferation does not depend on BCR signaling.
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PMID:Cyclin D2 controls B cell progenitor numbers. 1461 31

Heme plays a central role in oxygen utilization and in the generation of cellular energy. Here we examined the effect of heme and heme deficiency on cell cycle progression and the expression of key regulators in HeLa cells. We found that inhibition of heme synthesis causes cell cycle arrest and induces the expression of molecular markers associated with senescence and apoptosis, such as increased formation of PML nuclear bodies. Our data show that succinyl acetone-induced heme deficiency increases the protein levels of the tumor suppressor gene product p53 and CDK inhibitor p21, and decreases the protein levels of Cdk4, Cdc2, and cyclin D2. Further, we found that heme deficiency diminishes the activation/phosphorylation of Raf, MEK1/2, and ERK1/2-components of the MAP kinase signaling pathway. Our results show that heme is a versatile molecule that can effectively control cell growth and survival by acting on multiple regulators.
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PMID:Heme controls the expression of cell cycle regulators and cell growth in HeLa cells. 1497 35

Retinoblastoma protein (pRB) controls the G1/S transition in the cell cycle by binding and inactivating E2F transcription factor. pRB changes the chromatin structure at the E2F-responsive promoter by recruiting histone deacetylase (HDAC) to the pRB-E2F complex, thus controlling the transcriptional activity of E2F. Cyclin-dependent kinases (Cdks) phosphorylate pRB and disrupt association between pRB and E2F. We investigated the effects of pRB phosphorylation on HDAC-1 binding in vitro. Phosphorylation of pRB by Cdk4-cyclin D2, Cdk2-cyclin E, and Cdk2-cyclin A inhibited association of pRB with HDAC. Among these Cdks, Cdk4-cyclin D2 showed particularly effective inhibition of pRB-HDAC complex formation. Using pRB mutants with various deletions in the N- and C-terminal domains, we found that both the pocket and C-terminal domains are important for regulating association between pRB and HDAC.
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PMID:Cdk-mediated phosphorylation of pRB regulates HDAC binding in vitro. 1500 38

Overexpression of fibroblast growth factor receptor (FGFR) tyrosine kinases has been found in many human breast cancers and has been associated with poor patient prognosis. In order to understand the mechanism by which FGFR mediates breast cancer cell proliferation, we used a low molecular weight compound, PD173074, that selectively inhibits FGFR tyrosine kinase activity and autophosphorylation. This potential anticancer agent caused a G1 growth arrest of MDA-MB-415, MDA-MB-453 and SUM 52 breast cancer cells. Our analyses revealed that FGFR signaling links to the cell cycle machinery via D-type cyclins. PD173074-mediated inhibition of FGFR activity caused downregulation of cyclin D1 and cyclin D2 expression, inhibition of cyclin D/cdk4 activity and, as a consequence, reduction of pRB phosphorylation. Retroviral-mediated ectopic expression of cyclin D1 prevented pRB hypophosphorylation and the cell cycle G1 block in PD173074-treated cells, suggesting a central role for D cyclins in proliferation of FGFR-driven breast cancer cells. The repression of FGFR activity caused downregulation of MAPK in MDA-MB-415 and MDA-MB-453 cells. In SUM 52 cells, both MAPK and PI3K signaling pathways were suppressed. In conclusion, results shown here describe a mechanism by which FGFR promotes proliferation of breast cancer cells.
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PMID:Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins. 1511 89

Mouse hepatitis virus (MHV) replication in actively growing DBT and 17Cl-1 cells resulted in the inhibition of host cellular DNA synthesis and the accumulation of infected cells in the G(0)/G(1) phase of the cell cycle. UV-irradiated MHV failed to inhibit host cellular DNA synthesis. MHV infection in quiescent 17Cl-1 cells that had been synchronized in the G(0) phase by serum deprivation prevented infected cells from entering the S phase after serum stimulation. MHV replication inhibited hyperphosphorylation of the retinoblastoma protein (pRb), the event that is necessary for cell cycle progression through late G(1) and into the S phase. While the amounts of the cellular cyclin-dependent kinase (Cdk) inhibitors p21(Cip1), p27(Kip1), and p16(INK4a) did not change in infected cells, MHV infection in asynchronous cultures induced a clear reduction in the amounts of Cdk4 and G(1) cyclins (cyclins D1, D2, D3, and E) in both DBT and 17Cl-1 cells and a reduction in Cdk6 levels in 17Cl-1 cells. Infection also resulted in a decrease in Cdk2 activity in both cell lines. MHV infection in quiescent 17Cl-1 cells prevented normal increases in Cdk4, Cdk6, cyclin D1, and cyclin D3 levels after serum stimulation. The amounts of cyclin D2 and cyclin E were not increased significantly after serum stimulation in mock-infected cells, whereas they were decreased in MHV-infected cells, suggesting the possibility that MHV infection may induce cyclin D2 and cyclin E degradation. Our data suggested that a reduction in the amounts of G(1) cyclin-Cdk complexes in MHV-infected cells led to a reduction in Cdk activities and insufficient hyperphosphorylation of pRb, resulting in inhibition of the cell cycle in the G(0)/G(1) phase.
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PMID:Murine coronavirus replication induces cell cycle arrest in G0/G1 phase. 1514 Sep 63

The specific functions of p57(Kip2) in lymphocytes have not yet been fully elucidated. In this study, it is shown that p57(Kip2), which is a member of the Cip/Kip family of cyclin-dependent kinase inhibitors, is present in the nuclei of normal resting (G(0)) T cells from peripheral blood and in the nuclei of the T cell-derived Jurkat cell line. Activation through the TCR results in rapid transport of cytoplasmic cyclin-dependent kinase 6 (cdk6) to nuclei, where it associates with cyclin D and p57(Kip2) in active enzyme complexes. Using purified recombinant proteins, it was shown in vitro that addition of p57(Kip2) protein to a mixture of cyclin D2 and cdk6 enhanced the association of the latter two proteins and resulted in phosphorylation of p57(Kip2). To probe further the function of p57(Kip2), Jurkat cells stably transfected with a plasmid encoding p57(Kip2) under control of an inducible (tetracycline) promoter were made. Induction of p57(Kip2) resulted in increased association of cdk6 with cyclin D3, without receptor-mediated T cell stimulation. The overall amounts of cdk6 and cyclin D3, and also of cdk4 and cyclin E, remained unchanged. Most notably, increased p57(Kip2) levels resulted in marked inhibition of both cyclin E- and cyclin A-associated cdk2 kinase activities and a decrease in cyclin A amounts. Therefore, although facilitating activation of cdk6, the ultimate outcome of p57(Kip2) induction was a decrease in DNA synthesis and cell proliferation. The results indicate that p57(Kip2) is involved in the regulation of several aspects of the T cell cycle.
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PMID:Identification of multiple cell cycle regulatory functions of p57Kip2 in human T lymphocytes. 1529 51

Granulosa cell proliferation during luteinization and terminal differentiation has historically been assumed to decline rapidly after an ovulatory stimulus. In contrast, terminal differentiation in other cell types has recently been associated with a transient increase in proliferation, suggesting that this may occur in the ovarian follicle. The goal of the current study was to test the hypothesis that an ovulatory stimulus to rats results in additional granulosa cell proliferation before cell cycle arrest. Immature rats were given a single injection of pregnant mare serum gonadotropin (PMSG) followed by human chorionic gonadotropin (hCG) to initiate periovulatory events. The proportion of granulosa cells in S phase did not change until 12 h after hCG, although the majority of the post-hCG proliferation was localized to cumulus granulosa cells for up to 10 h after hCG. The expression of cyclin D2 mRNA did not decline until 12 h after hCG, although both cyclin-dependent kinase (Cdk)4 and Cdk6 mRNA increased at 6 h. Protein levels of cyclin D2 and Cdk4 did not change as a result of hCG, whereas cyclin E increased 6 h after hCG. Kinase activity of Cdk2 dropped markedly by 4 h after hCG, but a slight increase in activity was evident 6-8 h after hCG. These data suggest that cumulus granulosa cells continue to proliferate for up to 10 h after an ovulatory stimulus, possibly via cyclin E/Cdk2. It is concluded that proliferation is maintained in granulosa cells in the proximity of the oocyte during luteinization of the rat follicle.
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PMID:Proliferation of rat granulosa cells during the periovulatory interval. 1537 25


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