Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Whilst many studies have examined the role of the MAP Kinases in regulating the G1-->S transition, much less is known about the function of these pathways in regulating other cell cycle transitions. Stimulation of the conditional mutant Delta MEKK3:ER* in asynchronous hamster (CCl39) and rat (Rat-1) fibroblasts resulted in the strong activation of endogenous JNK and p38 but only a weak activation of ERK. Activation of Delta MEKK3:ER* inhibited cell proliferation through a combination of an initial G1 and G2 cell cycle arrest, followed by a delayed onset of apoptosis. When cells were synchronized in S phase with aphidicolin and then released, activation of Delta MEKK3:ER* resulted in the up-regulation of p21(CIP1) and a pronounced inhibition of cyclin A/CDK2 and cyclin B1/CDK1 kinase activity. Analysis of mitotic figures indicated that cells failed to enter mitosis, arresting late in G2. Delta MEKK3:ER*-mediated CDK inhibition and G2 arrest did not absolutely require p21(CIP1), since both events were observed in Rat-1 cells in which p21(CIP1) is transcriptionally silenced due to promoter methylation. Rather, CDK inhibition was associated with a down-regulation of cyclin A and B1 expression. Finally, application of the p38 inhibitor SB203580 partially restored cyclin B associated kinase activity and allowed cells to proceed through mitosis into the next G1 phase, suggesting that activation of the p38 alpha/beta 2 pathway can promote a G2 cell cycle arrest.
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PMID:Delta MEKK3:ER* activation induces a p38 alpha/beta 2-dependent cell cycle arrest at the G2 checkpoint. 1244 45

After a two-thirds hepatectomy, normally quiescent liver cells are stimulated to reenter the cell cycle and proliferate to restore the original liver mass. One of the most rapidly and highly induced genes and proteins in regenerating liver is insulin-like growth factor binding protein 1 (IGFBP-1), a secreted protein that may modulate the activities of insulin-like growth factors (IGFs) or signal via IGF-independent mechanisms. To assess the functional role of IGFBP-1 in liver regeneration, mice with a targeted disruption of the IGFBP-1 gene were generated. Although IGFBP-1(-/-) mice demonstrated normal development, they had abnormal liver regeneration after partial hepatectomy, characterized by liver necrosis and reduced and delayed hepatocyte DNA synthesis. The abnormal regenerative response was associated with blunted activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and a reduced induction of C/EBP beta protein expression posthepatectomy. Like cell cycle abnormalities observed in hepatectomized C/EBP beta(-/-) mice, cyclin A and cyclin B1 expression was delayed and reduced in IGFBP-1(-/-) livers, whereas cyclin D1 expression was normal. Treatment of IGFBP-1(-/-) mice with a preoperative dose of IGFBP-1 induced MAPK/ERK activation and C/EBP beta expression, suggesting that IGFBP-1 may support liver regeneration at least in part via its effect on MAPK/ERK and C/EBP beta activities. These findings are the first demonstration of the involvement of IGFBP-1 in the regulation of in vivo mitogenic signaling pathways.
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PMID:Impaired hepatocyte DNA synthetic response posthepatectomy in insulin-like growth factor binding protein 1-deficient mice with defects in C/EBP beta and mitogen-activated protein kinase/extracellular signal-regulated kinase regulation. 1255 85

A central function of the tumor suppressor retinoblastoma (Rb) is its ability to repress E2F transcriptional activity. Many cancers harbor inactivated Rb and consequently deregulated E2F. RXL peptides inhibit E2F recruitment and phosphorylation by CDK2/cyclin A. Here we report that RXL peptides selectively kill tumor cells with deregulated Rb/cyclin D pathways. We extend these observations to tumor models and demonstrate inhibition of tumor growth in SV40 large T transformed Balb/c 3T3 grafts and in HER2 transgenic tumors. Moreover, our observations reveal that RXL peptide-treated tumors undergo apoptosis. Our results indicate that RXL motif-based inhibitors will provide selective antiproliferative agents with in vivo efficacy in tumors with deregulated Rb/cyclin D pathways.
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PMID:Selective cyclin-dependent kinase 2/cyclin A antagonists that differ from ATP site inhibitors block tumor growth. 1261 17

The question remains open whether the signaling pathways shown to be important for growth and transformation in adherent cultures proceed similarly and play similar roles for cells grown under anchorage-independent conditions. Chicken embryo fibroblasts (CEF) infected with the avian sarcoma virus UR2, encoding the oncogenic receptor protein-tyrosine kinase (RPTK) v-Ros, or with two of its transformation-impaired mutants were grown in nonadherent conditions in methylcellulose (MC)-containing medium, and the signaling functions essential for Ros-induced anchorage-independent growth were analyzed. We found that the overall tyrosine phosphorylation of cellular proteins in CEF transformed by v-Ros or by two oncogenic nonreceptor protein-tyrosine kinases (PTKs), v-Src and v-Yes, was dramatically reduced in nonadherent conditions compared with that in adherent conditions, indicating that cell adhesion to the extracellular matrix plays an important role in efficient substrate phosphorylation by these constitutively activated PTKs. The UR2 transformation-defective mutants were differentially impaired compared with UR2 in the activation of phosphatidylinositol 3-kinase (PI 3-kinase) and Stat3 in nonadherent conditions. Consistently, the constitutively activated mutants of PI 3-kinase and Stat3 rescued the ability of the UR2 mutants to promote anchorage-independent growth. Conversely, dominant negative mutants of PI 3-kinase and Stat3 inhibited UR2-induced anchorage-independent growth. UR2-infected CEF grown in nonadherent conditions displayed faster cell cycle progression than the control or the UR2 mutant-infected cells, and this appeared to correlate with a PI 3-kinase-dependent increase in cyclin A-associated Cdk2 activity. Treatment of UR2-infected cells with Cdk2 inhibitors led to the loss of the anchorage-independent growth-promoting activity of UR2. In conclusion, we have adopted an experimental system enabling us to study the signaling pathways in cells grown under anchorage-independent conditions and have identified matrix-independent activation of PI 3-kinase and Stat3 signaling functions, as well as the PI 3-kinase-dependent increase of cyclin A-associated Cdk2 kinase activity, to be critical for the Ros-PTK-induced anchorage-independent growth.
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PMID:Matrix-independent activation of phosphatidylinositol 3-kinase, Stat3, and cyclin A-associated Cdk2 Is essential for anchorage-independent growth of v-Ros-transformed chicken embryo fibroblasts. 1264 74

Previously, we showed that monensin, Na+ ionophore, potently inhibited the growth of acute myelogenous leukemia and lymphoma cells. Here, we investigated the antiproliferative effect of monensin on human myeloma cell lines. Monensin significantly inhibited the proliferation of myeloma cell lines examined with IC50 of about 1 micro M. Cell cycle analysis indicated that monensin induced a G1 and/or a G2-M phase arrest in these cell lines. To address the mechanism of the antiproliferative effect of monensin, we examined the effect of this drug on cell cycle-related proteins in NCI-H929 cells. Monensin decreased the levels of CDK2, CDK6, cdc2, cyclin A, cyclin B1, cyclin D1 and cyclin E proteins but did not alter CDK4 protein. While p21 was increased by monensin, p27 was not. In addition, monensin markedly enhanced the binding of p21 with CDK6 and cdc2. Furthermore, the activities of CDK2- and CDK6-associated kinases were reduced in association with hypophosphorylation of Rb protein. The activity of cdc2-associated kinase was decreased, which was accompanied by reduction of cdc25C phosphatase. Also, monensin induced apoptosis in myeloma cells, as evidenced by annexin V binding assay and flow cytometric detection of sub-G1 DNA content. This apoptotic process was associated with down-regulation of Bcl-2, loss of mitochondria transmembrane potential (Deltapsim) and an increase of caspase-3 activity. In addition, monensin caused the up-regulation of ERK and p38 kinase activities. Taken together, these results have demonstrated for the first time that monensin potently inhibited the proliferation of human myeloma cell lines, especially NCI-H929 cells, via cell cycle arrest in association with p21 and apoptosis.
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PMID:Monensin-mediated growth inhibition in NCI-H929 myeloma cells via cell cycle arrest and apoptosis. 1279 94

We show that Cdc6, an essential initiation factor for DNA replication, undergoes caspase-3-mediated cleavage in the early stages of apoptosis in HeLa cells and SK-HEP-1 cells induced by etoposide, paclitaxel, ginsenoside Rh2, or tumor necrosis factor-related apoptosis-inducing ligand. The cleavage occurs at the SEVD442/G motif and generates an N-terminal truncated Cdc6 fragment (p49-tCdc6) that lacks the carboxy-terminal nuclear export sequence. Cdc6 is known to be phosphorylated by cyclin A-cyclin dependent kinase 2 (Cdk2), an event that promotes its exit from the nucleus and probably blocks it from initiating inappropriate DNA replication. In contrast, p49-tCdc6 translocation to the cytoplasm is markedly reduced under the up-regulated conditions of Cdk2 activity, which is possibly due to the loss of nuclear export sequence. Thus, truncation of Cdc6 results in an increased nuclear retention of p49-tCdc6 that could act as a dominant negative inhibitor of DNA replication and its accumulation in the nucleus could promote apoptosis. Supporting this is that the ectopic expression of p49-tCdc6 not only promotes apoptosis of etoposide-induced HeLa cells but also induces apoptosis in untreated cells. Thus, the caspase-mediated cleavage of Cdc6 creates a truncated Cdc6 fragment that is retained in the nucleus and induces apoptosis.
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PMID:Caspase-3-mediated cleavage of Cdc6 induces nuclear localization of p49-truncated Cdc6 and apoptosis. 1451 33

DeltaNp73alpha is an isoform of the p53 homologue p73 that lacks an amino-terminal transactivation domain and antagonizes the induction of gene expression by p53. Here, we examined whether DeltaNp73alpha might also modulate cellular transcription in the absence of p53. The expression of DeltaNp73alpha in the p53-/- cell line H1299 reduced the mRNA levels of p21/CDKN1A, but did not affect other p53-responsive genes. Correspondingly, the p21/CDKN1A promoter was downregulated by DeltaNp73alpha in reporter assays, whereas other p53-responsive promoters were not inhibited. To identify additional genes that respond to DeltaNp73alpha in the absence of p53, microarrays carrying 4600 cDNA clones were hybridized. The expression of 30 genes was found to be altered more than threefold by overexpressed DeltaNp73alpha. For instance, DeltaNp73alpha increased the expression of EGR1 and CDC6, whereas it decreased the mRNA levels of c-MYC, cyclin A2/CCNA2, NF-kappaB1, ODC1, and RET finger protein/RFP. Semiquantitative reverse transcription-PCR confirmed these results and further revealed that the influence of DeltaNp73alpha on the regulation of these genes differs from other p73 isoforms and p53. We conclude that the impact of DeltaNp73alpha on gene expression is not limited to p53-responsive genes. Rather, DeltaNp73alpha can regulate the expression of a variety of genes independently of p53.
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PMID:DeltaNp73 can modulate the expression of various genes in a p53-independent fashion. 1461 48

Xylocydine (4-amino-6-bromo-7-(beta-l-xylofuranosyl)pyrrolo[2,3-d]pyrimidine-5-carboxamide) blocks cyclin-dependent kinase CDK1 and CDK2/cyclin A activity in vitro (IC(50) 1.4 and 61 nM, respectively) while minimally inhibiting the three other Ser/Thr protein kinases tested (IC(50) 21-86 microM). Reduced phosphorylated nucleolin and retinoblastoma protein levels showed it also efficiently inhibited cellular CDK1 and CDK2 activity (IC(50) 50-100 and 200-500 nM, respectively). Moreover, it blocked the functional activity of CDKs in tumor necrosis factor-related apoptosis-inducing ligand-induced SK-HEP-1 cell apoptosis 20 to 1000-fold more potently than olomoucine and roscovitine. Xylocydine is thus a novel and potent CDK inhibitor that could be used to interfere with cell cycle- and apoptosis-related CDK activity in various diseases.
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PMID:Xylocydine, a novel inhibitor of cyclin-dependent kinases, prevents the tumor necrosis factor-related apoptosis-inducing ligand-induced apoptotic cell death of SK-HEP-1 cells. 1461 91

We explored, by cDNA mini-arrays, gene expression measurements of MVLN, a human breast carcinoma cell line derived from MCF-7, after 4 days of exposure to 17beta-estradiol (E(2)) treatment, in order to extend our understanding of the mechanism of the pharmacological action of estrogens. We focused on 22 genes involved in estrogen metabolism, cell proliferation regulation and cell transformation. The specificity of the E(2) response was reinforced by comparison with 4-hydroxytamoxifen (OH-Tam), ICI 182,780 and E(2)+OH-Tam expression profiles. Real-time quantitative PCR (RTQ-PCR) confirmed the variation of expression of known (TFF1, AREG, IRS1, IGFBP4, PCNA, ERBB2, CTSD, MYC) as well as novel (DLEU2, CCNA2, UGT1A1, ABCC3, ABCC5, TACC1, EFNA1, NOV, CSTA, MMP15, ZNF217) genes. The temporal response of these gene expression regulations was then investigated after 6 and 18 h of E(2) treatment and this allowed the identification of different time-course patterns. Cycloheximide treatment studies indicated first that estrogen affected the transcript levels of ABCC3 and ABCC5 through dissimilar pathways, and secondly that protein synthesis was needed for modulation of the expression of the CCNA2 and TACC1 genes by estrogens. Western blot analysis performed on TFF1, IRS1, IGFBP4, amphiregulin, PCNA, cyclin A2, TACC1 and ABCC5 proteins confirmed the mini-array and RTQ-PCR data, even for genes harboring low variations of mRNA expression. Our findings should enhance the understanding of changes induced by E(2) on the transcriptional program of human E(2)-responsive cells and permit the identification of new potential diagnostic/prognostic tools for the monitoring of estrogen-related disease conditions such as breast cancer.
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PMID:Estrogen regulation in human breast cancer cells of new downstream gene targets involved in estrogen metabolism, cell proliferation and cell transformation. 1507 47

We showed previously that exogenous overexpression of C3G, a guanine nucleotide releasing factor (GEF) for Rap1 and R-Ras proteins, blocks the focus-forming activity of cotransfected, activated, sis, ras and v-raf oncogenes in NIH 3T3 cells. In this report, we show that C3G also interferes with dbl and R-Ras focus-forming activity and demonstrate that the transformation suppressor ability of C3G maps to its Crk-binding region (SH3-b domain). Using full-length C3G and C3GDeltaCat mutant, lacking catalytic domain, we showed here that overexpression of cotransfected C3G or C3GDeltaCat inhibited oncogenic Hraslys12-mediated phosphorylation of ERK, without altering Ras and Raf-1 kinase activation. We also showed that, overexpressed C3G and C3GdeltaCat inhibited the viability of oncogenic Ras-induced colonies in soft agar, indicating that C3G interferes with the anchorage-independent growth of Ras-transformed cells in a Rap1-independent manner. Consistent with both observations, overexpression of exogenous C3G and C3GDeltaCat also caused downregulation of Ras-induced cyclin A expression. Altogether, our results indicate that C3G interferes with at least two separate aspects of oncogenic transformation - cell cycle progression and loss of contact inhibition - and that these inhibitory effects probably account for its transformation suppressor activity.
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PMID:C3G-mediated suppression of oncogene-induced focus formation in fibroblasts involves inhibition of ERK activation, cyclin A expression and alterations of anchorage-independent growth. 1507 65


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