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

Intracellular levels of phosphorylation are regulated by the coordinated action of protein kinases and phosphatases. Disregulation of this balance can lead to cellular transformation. Here we review knowledge of the mechanisms of one protein phosphatase, the tumour suppressor PTEN/MMAC/TEP 1 apropos its role in tumorigenesis and signal transduction. PTEN plays an important role in the phosphatidyl-inositol-3-kinase (PI3-K) pathway by catalyzing degradation of phosphatidylinositol-(3,4,5)-triphosphate generated by PI3-K. This inhibits downstream targets mainly protein kinase B (PKB/Akt), cell survival and proliferation. PTEN contributes to cell cycle regulation by blockade of cells entering the S phase of the cell cycle, and by upregulation of p27(Kip1) which is recruited into the cyclin E/cdk2 complex. PTEN also modulates cell migration and motility by regulation of the extracellular signal-related kinase - mitogen activated protein kinase (ERK-MAPK) pathway and by dephosphorylation of focal adhesion kinase (FAK). We also emphasize the increasingly important role that PTEN has from an evolutionary point of view. A number of PTEN functions have been elucidated but more information is needed for utilization in clinical application and potential cancer therapy.
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PMID:The mechanism of action of the tumour suppressor gene PTEN. 1503 1

The RAS-activated RAF-->MEK-->extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3'-kinase (PI3'-kinase)-->PDK1-->AKT signaling pathways are believed to cooperate to promote the proliferation of normal cells and the aberrant proliferation of cancer cells. To explore the mechanisms that underlie such cooperation, we have derived cells harboring conditionally active, steroid hormone-regulated forms of RAF and AKT. These cells permit the assessment of the biological and biochemical effects of activation of these protein kinases either alone or in combination with one another. Under conditions where activation of neither RAF nor AKT alone promoted S-phase progression, coactivation of both kinases elicited a robust proliferative response. Moreover, under conditions where high-level activation of RAF induced G(1) cell cycle arrest, activation of AKT bypassed the arrest and promoted S-phase progression. At the level of the cell cycle machinery, RAF and AKT cooperated to induce cyclin D1 and repress p27(Kip1) expression. Repression of p27(Kip1) was accompanied by a dramatic reduction in KIP1 mRNA and was observed in primary mouse embryo fibroblasts derived from mice either lacking SKP2 or expressing a T187A mutated form of p27(Kip1). Consistent with these observations, pharmacological inhibition of MEK or PI3'-kinase inhibited the effects of activated RAS on the expression of p27(Kip1) in NIH 3T3 fibroblasts and in a panel of bona fide human pancreatic cancer cell lines. Furthermore, we demonstrated that AKT activation led to sustained activation of cyclin/cdk2 complexes that occurred concomitantly with the removal of RAF-induced p21(Cip1) from cyclin E/cdk2 complexes. Cumulatively, these data strongly suggest that the RAF-->MEK-->ERK and PI3'K-->PDK-->AKT signaling pathways can cooperate to promote G(0)-->G(1)-->S-phase cell cycle progression in both normal and cancer cells.
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PMID:Cooperative regulation of the cell division cycle by the protein kinases RAF and AKT. 1557 89

Constitutive expression of cyclin D1 is a frequent abnormality in human cancer and sustains the transformed phenotype. We have previously demonstrated that cyclin D1 is constitutively expressed in human BON neuroendocrine tumour cells due to an autocrine insulin-like growth factor-I (IGF-I) loop. Here we examine the regulation of cyclin D1 expression by endogenously released IGF-I in BON cells. Cyclin D1 expression in these cells was found to be dependent on phosphatidylinositol 3-kinase (PI3-K), but independent of the extracellular signal-regulated kinase cascade. Ras- and Rac-GTPases were found to be upstream activators of cyclin D1 expression, whereas protein kinase B/AKT and nuclear factor kappa B (NFkappaB) could be established as downstream mediators of cyclin D1 transcription in response to endogenously released IGF-I in these cells. In addition, the Ras/PI3-K/AKT/Rac/NFkappaB/cyclin D1 signaling cascade triggered by endogenously released IGF-I is sufficient to sustain Rb phosphorylation and cdk4 kinase activity in BON cells. In conclusion, our data provide the first comprehensive map of the signaling events elicited by endogenously released IGF-I leading to constitutive cyclin D1 expression in human neuroendocrine tumour cells.
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PMID:Regulation of cyclin D1 expression by autocrine IGF-I in human BON neuroendocrine tumour cells. 1558 Feb 91

Epidemiological evidences suggest that the progression and promotion of prostate cancer (CaP) can be modulated by diet. Since all men die with prostate cancer rather than of the disease, it is of particular interest to prevent or delay the progression of the disease by chemopreventive strategies. We have been studying the anticancer properties of compounds present in cruciferous vegetables such as indole-3-carbinol (I3C). Diindolylmethane (DIM) is a dimer of I3C that is formed under acidic conditions and unlike I3C is more stable with higher anti-cancer effects. In the present report, we demonstrate that DIM is a potent anti-proliferative agent compared to I3C in the hormone independent DU 145 CaP cells. The anti-prostate cancer effect is mediated by the inhibition of the Akt signal transduction pathway as DIM, in sharp contrast to I3C, induces the downregulation of Akt, p-Akt, and PI3 kinase. DIM also induced a G1 arrest in DU 145 cells by flow cytometry and downstream concurrent inhibition of cell cycle parameters such as cyclin D1, cdk4, and cdk6. Our data suggest a need for further development of DIM, as a chemopreventive agent for CaP, which justifies epidemiological evidences and molecular targets that are determinants for CaP dissemination/progression. The ingestion of DIM may benefit CaP patients and reduce disease recurrence by eliminating micro-metastases that may be present in patients who undergo radical prostatectomy.
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PMID:3,3'-Diindolylmethane downregulates pro-survival pathway in hormone independent prostate cancer. 1638 95

The effects of PRIMA-1 on wild-type (WT) mouse leukemia L1210 cells and drug-resistant L1210 cells (Y8) were studied with respect to the induction of apoptosis and necrosis in these cell lines. The WT L1210 cells express mutant p53 while the Y8 L1210 cells do not express p53 mRNA or protein, but do express WAF1/p21 and Gadd 45 mRNA's and proteins. It was found that, in response to treatment with PRIMA-1, the WT L1210 cells became necrotic with little apoptosis while the Y8 L1210 cells showed a much higher level of apoptosis than necrosis. Flavopiridol in combination with PRIMA-1 caused a synergistic increase in necrosis in the WT L1210 cells while LY 294002 in combination with PRIMA-1 caused a synergistic increase in apoptosis in the Y8 L1210 cells. These studies showed that PRIMA-1 had an effect not only on cells expressing mutant p53, but also on cells that do not express p53, suggesting that PRIMA-1 and PRIMA-1-like molecules have multiple sites of action independent of restoring p53 function and that these can interact with other signaling pathways involving CDK's and PI3 kinases.
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PMID:Effects of PRIMA-1 on wild-type L1210 cells expressing mutant p53 and drug-resistant L1210 cells lacking expression of p53: necrosis vs. apoptosis. 1661 36

Cyclin D1 overexpression is a frequent change in hepatocellular carcinomas (HCCs). Our present study demonstrated that cyclin D1 overexpression with abundant cyclin E, cdk4, cdk2, and p27Kip1 (p27) occurred in neoplastic hepatocytes from the early stage of mouse hepatocarcinogenesis. While cyclin D1 expression was mainly found in the cytoplasm of the tumor cells, it shifted to the nucleus in association with cell proliferation after the animals were subjected to a partial hepatectomy (PH), and then returned once more to the cytoplasm when the cells became quiescent. Inhibition of PI3 kinase (PI3K) by Ly294002 in mouse HCC cells in vitro suppressed the nuclear shift of cyclin D1 as well as cell proliferation, while PI3K activation by PTEN suppression failed to induce nuclear shift of cyclin D1, suggesting that PI3K activation is essential but not sufficient for the cyclin D1 nuclear shift. While MEK-ERK1/2 inhibition by PD98059 and mTOR inhibition by rapamycin affected the cyclin D1 nuclear shift and cell proliferation to a lesser extent, both these inhibitors reduced cyclin D1 levels. Finally, although p27, cdk4 and calmodulin (CaM) were detected in the cyclin D1 immunoprecipitates from both quiescent and proliferating HCC cells, Hsc70 and SSeCKS were detected only in the immunoprecipitate from quiescent cells, and p21Waf1/Cip1 (p21) was detected only in that from proliferating cells, suggesting that the cyclin D1 complex is different in quiescent and proliferating cells. These observations indicate that the nuclear/cytoplasmic localization of cyclin D1 plays an important role in the proliferation/quiescence of neoplastic hepatocytes.
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PMID:Neoplastic hepatocyte growth associated with cyclin D1 redistribution from the cytoplasm to the nucleus in mouse hepatocarcinogenesis. 1701 36

Mouse embryonic stem (mES) cells have short duration of their cell cycle and are capable of proliferating in the absence of growth factors. To find out which signaling pathways contribute to the regulation of the mES cell cycle, we used pharmacological inhibitors of MAP and PI3 kinase cascades. The MAP kinase inhibitors as well as serum withdrawal did not affect mES cell cycle distribution, whereas the inhibitor of PI3K activity, LY294002, induced accumulation of cells in G(1) phase followed by apoptotic cell death. Serum withdrawal also causes apoptosis, but it does not change the content and activity of cell cycle regulators. In contrast, in mES cells treated with LY294002, the activities of Cdk2 and E2F were significantly decreased. Interestingly, LY294002had a much stronger effect on cell cycle distribution in low serum conditions, implying that serum can promote G(1)-->S transition of mES cells by a LY294002-resistant mechanism. Thus, proliferation of mES cells is maintained by at least two separate mechanisms: a LY294002-sensitive pathway, which is active even in the absence of serum, and LY294002-resistant, but serum-dependent, pathway.
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PMID:Phosphoinositide 3-kinase inhibitor LY294002 but not serum withdrawal suppresses proliferation of murine embryonic stem cells. 1732 Nov 71

D-type cyclins are direct targets of extracellular signals and critical regulators of G(1) progression. Our previous data demonstrated that IGF-I and FGF-2 synergize to enhance cyclin D1 expression, cyclin E/cdk2 complex activation, and S-phase entry in OP cells. Here, we provide a mechanistic explanation for how two growth factor signaling pathways converge on a major cell cycle regulator. IGF-I and FGF-2 differentially activate signaling pathways to coordinately promote cyclin D1 expression. We show that the p44/p42 MAPK signaling pathway is essential for FGF-2 induction of cyclin D1 mRNA. In contrast, blocking the PI3-Kinase pathway results in loss of IGF-I/FGF-2 synergistic induction of cyclin D1 protein levels. Moreover, the presence of IGF-I significantly enhances nuclear localization of cyclin D1, which also requires PI3K signaling. GSK-3beta, a downstream target of the PI3K/Akt pathway, is phosphorylated in the presence of IGF-I in OPs. Consistent with a known role for GSK-3beta in cyclin D1 degradation, we show that proteasome inhibition in OPs exposed to FGF-2 increased cyclin D1 levels, equivalent to levels seen in IGF-I/FGF-2 treated cells. Thus, we provide a model for cyclin D1 coordinate regulation where FGF-2 stimulation of the MAPK pathway promotes cyclin D1 mRNA expression while IGF-I activation of the PI3K pathway inhibits proteasome degradation of cyclin D1 and enhances nuclear localization of cyclin D1.
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PMID:Synergistic induction of cyclin D1 in oligodendrocyte progenitor cells by IGF-I and FGF-2 requires differential stimulation of multiple signaling pathways. 1750 24

This study examined the mechanisms by which transforming growth factor (TGF)-alpha regulates proliferation of mouse embryonic stem (ES) cells. TGF-alpha increased [3H] thymidine and BrdU incorporation in a time- (0-72 h) and dose-dependent (0-10 ng/ml) manner. TGF-alpha stimulated the phosphorylation of Akt, mammalian target of rapamycin (mTOR), p70S6K1 and p44/42 mitogen-activated protein kinases (MAPKs). TGF-alpha also increased the protein levels of Notch, Notch intracellular domain, Hes-1 and Wnt1. However, TGF-alpha-induced DNA synthesis was blocked by inhibition of Akt, mTOR, p44/42 MAPKs and Notch. TGF-alpha increased the gene expression of c-jun, c-myc and c-fos. Moreover, TGF-alpha increased cyclin D/CDK 4 and cyclin E/CDK 2 levels, while decreasing p21cip1/waf1 and p27kip1, which were blocked by the inhibition of Akt, mTOR and Notch. In conclusion, TGF-alpha regulated DNA synthesis of mouse ES cells via PI3-K/Akt, p44/42 MAPKs and Notch/Wnt pathways.
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PMID:Regulation of DNA synthesis in mouse embryonic stem cells by transforming growth factor-alpha: involvement of the PI3-K/Akt and Notch/Wnt signaling pathways. 1842 29

Previously, we observed that in vitro germinal vesicle breakdown (GVBD) in Cyprinus carpio oocytes was induced by recombinant human insulin-like growth factor-I (IGF-I) and bovine insulin (b-insulin) and this induction was steroid-independent. To investigate further the early signal transduction components involved in this process, the possible role of phosphatidylinositol 3-kinase (PI3 kinase) during oocyte maturation was examined. IGF-I- and b-insulin-induced oocyte maturation was significantly inhibited by Wortmannin and LY294002, two mechanistically different specific inhibitors of PI3 kinase. IGF-I and b-insulin were shown to activate PI3 kinase after 90 min of their treatment. Both IGF-I and b-insulin were found to activate cdc2 kinase at 21h of treatment. We examined the relative involvement of PI3 kinase, MAP kinase and cdc2 kinase in IGF-I- and b-insulin-induced oocyte maturation in C. carpio. MAP kinase was rapidly phosphorylated and activated (30-150 min) in response to exposure of the oocytes with IGF-I and b-insulin. This response preceded the phosphorylation and activation of cdc2 by several hours (almost 19h). A potent and selective inhibitor of MEK, PD98059, the protein kinase that phosphorylates and activate MAP kinase, blocked the phosphorylation and activation of MAP kinase and cdc2 kinase and GVBD induction. Likewise, PI3 kinase inhibitors strongly inhibited phosphorylation and activation of MAP kinase, which was increased during oocyte maturation. Taken together, these results suggest that PI3 kinase is an initial component of the signal transduction pathway which precedes MAP kinase, and MPF activation during IGF-I- and b-insulin-induced oocyte maturation in C. carpio.
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PMID:Involvement of PI3 kinase and MAP kinase in IGF-I- and insulin-induced oocyte maturation in Cyprinus carpio. 1948 57


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