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

---

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

Reports elsewhere demonstrated that Epimedin C, a constituent isolated from the leaves of Epimedium sagittatum, possessed anti-tumor activity. However, its mechanism of action remains unresolved. Using SK-Hep-1 cells, a poorly-differentiated hepatoma subline, as an experimental model, we present evidence here that the anti-tumor activity of Epimedin C may involve cell cycle blockage. Immunoblotting analyses demonstrated that Epimedin C caused a decreased expression of hyperphosphorylated retinoblastoma (Rb) protein, cyclin D1, c-Myc, and c-Fos. In parallel, we measured the kinase activities and found that CDK2 and CDK4 were suppressed with commensurate increased levels of CDK inhibitors, p21(Cip1) and p27(Kip1). These data suggested that Epimedin C arrested the proliferation of these cells at G0/G1 phase through inhibition of CDK2 and CDK4 activities via an increased induction of p21(Cip1) and p27(Kip1). Alternatively, we investigated whether the anti-proliferative effect of Epimedin C on these cells might involve MAP kinase cascade. Using western blotting technique, we demonstrated that Epimedin C also selectively decreased ERK1/2 phosphorylation. Among the downstream effectors of ERK examined, we found that Epimedin C selectively decreased the expression of c-Fos, but not c-Jun. By EMSA assay, we further demonstrated that decreased c-Fos resulted in the downregulation of AP-1/DNA binding activity. Taken together, the molecular mechanisms of anti-tumor activity of Epimedin C may be proceeded by the combined effects of the cell cycle blockage via either the inhibition of CDK2 and CDK4 activities, with commensurate increase in their inhibitors, p21(Cip1) and p27(Kip1) or negatively modulates the ERK/c-Fos/AP-1 signaling pathway.
...
PMID:Molecular mechanism of cell cycle blockage of hepatoma SK-Hep-1 cells by Epimedin C through suppression of mitogen-activated protein kinase activation and increased expression of CDK inhibitors p21(Cip1) and p27(Kip1). 1611 86

There appear to be two pathways involved in the pathogenesis of premalignant non-immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Nearly half of tumors are nonhyperdiploid, and mostly have one of five recurrent IgH translocations: 16% 11q13 (CCN D1), 3% 6p21 (CCN D3), 5% 16q23 (MAF), 2% 20q12 (MAFB), and 15% 4p16 (FGFR3 and MMSET). The remaining hyperdiploid tumors have multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21, and infrequently one of these five translocations. Although cyclin D1 is not expressed by healthy lymphoid cells, it is bi-allelically dysregulated in a majority of hyperdiploid tumors. Virtually all MM and MGUS tumors have dysregulated and/or increased expression of cyclin D1, D2, or D3, providing an apparent early, unifying event in pathogenesis. The patterns of translocations and cyclin D expression (TC) define a novel classification that includes eight groups: 11q; 6p; MAF; 4p; D1 (34%); D1+D2 (6%); D2 (17%); and none (2%). The hyperdiploid D1 group is virtually absent in extramedullary MM and MM cell lines, suggesting a particularly strong dependence on interaction with the bone marrow microenvironment. Despite shared progression events (RAS mutations, MYC dysregulation, p53 mutations, and additional disruption of the retinoblastoma pathway), the phenotypes of MGUS and MM tumors in the eight TC groups is determined mainly by early oncogenic events. Similar to acute lymphocytic leukemia, MM seems to include several diseases (groups) that have differences in early or initiating events, global gene expression patterns, bone marrow dependence, clinical features, prognosis, and response to therapy.
...
PMID:Molecular pathogenesis and a consequent classification of multiple myeloma. 1615 16

In this report we have examined changes in cell growth parameters, cell cycle effectors, and signaling pathways that accompany thyrotrope growth arrest by thyroid hormone (TH) and growth resumption after its withdrawal. Flow cytometry and immunohistochemistry of proliferation markers demonstrated that TH treatment of thyrotrope tumors resulted in a reduction in the fraction of cells in S-phase that is restored upon TH withdrawal. This is accompanied by dephosphorylation and rephosphorylation of retinoblastoma (Rb) protein. The expression levels of cyclin-dependent kinase 2 and cyclin A, as well as cyclin-dependent kinase 1 and cyclin B, were decreased by TH, and after withdrawal not only did these regulators of Rb phosphorylation and mitosis increase in their expression but so too did the D1 and D3 cyclins. We also noted a rapid induction and subsequent disappearance of the type 5 receptor for the growth inhibitor somatostatin with TH treatment and withdrawal, respectively. Because somatostatin can arrest growth by activating MAPK pathways, we examined these pathways in TtT-97 tumors and found that the ERK pathway and several of its upstream and downstream effectors, including cAMP response element binding protein, were activated with TH treatment and deactivated after its withdrawal. This led to the hypothesis that TH, acting through increased type 5 somatostatin receptor, could activate the ERK pathway leading to cAMP response element binding protein-dependent decreased expression of critical cell cycle proteins, specifically cyclin A, resulting in hypophosphorylation of Rb and its subsequent arrest of S-phase progression. These processes are reversed when TH is withdrawn, resulting in an increase in the fraction of S-phase cells.
...
PMID:The proliferative status of thyrotropes is dependent on modulation of specific cell cycle regulators by thyroid hormone. 1622 61

An important recent advance in anticancer therapy was the development of molecular-targeting drugs, such as the epidermal growth-factor receptor (EGFR)-targeting drug ZD1839 (Iressa) and the HER2-trageting anti-HER2 monoclonal antibody trastuzumab (Herceptin). ZD1839 and trastuzumab are reported to improve the therapeutic efficacy of treatment for non-small-cell lung cancer (NSCLC) and breast cancer, respectively, although the effectiveness of either drug alone is not satisfactory. NSCLC cells often express both EGFR and HER2. We therefore investigated whether a combination of ZD1839 and trastuzumab had an additive or synergistic antitumor effect. In culture ZD1839 inhibited the growth of four NSCLC cell lines (A549, NCI-H23, NCI-H727, and NCI-H661) that expressed various levels of EGFR, HER2, HER3, and HER4. A significant cytotoxic effect was observed when ZD1839 was combined with trastuzumab in A549 cells. However, this combination had no apparent effect in NCI-H23 cells. Significant G(1)-phase arrest, increased p27 expression and decreased cyclin E or D1 levels were detected in A549 cells treated with ZD1839 and trastuzumab. No significant effects were detected in NCI-H23 cells examined. The combination treatment significantly inhibited the phosphorylation of EGFR, HER2, retinoblastoma, extracellular signal-regulated kinase-1/2, and protein kinase B/Akt in A549 cells, but not in NCI-H23 cells. Our results indicated that increased levels of constitutive EGFR/HER2 heterodimers were formed in A549 cells in the presence of ZD1839, whereas no heterodimer formation was detected in NCI-H23 cells. We therefore suggest that combination treatment with ZD1839 and trastuzumab might have improved therapeutic efficacy against NSCLC cells expressing both EGFR and HER2.
...
PMID:Cooperative cell-growth inhibition by combination treatment with ZD1839 (Iressa) and trastuzumab (Herceptin) in non-small-cell lung cancer. 1625 59

Reflecting its critical role in integrating cell growth and division with the cellular nutritional environment, the mammalian target of rapamycin *(mTOR) is a highly conserved downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway. mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1. As a consequence of inhibiting its downstream messengers, mTOR inhibitors prevent cyclin-dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause GI phase arrest. Constitutive activation of the PI3K/Akt kinases occur in human leukemias. FLT3, VEGF, and BCR-ABL mediate their activities via mTOR. New rapamycin analogs including CCI-779, RAD001, and AP23573, are entering clinical studies for patients with hematologic malignancies.
...
PMID:Mammalian target of rapamycin as a therapeutic target in leukemia. 1630 91

Emodin (1,3,8-trihydroxy-6-methylanthraquinone), an active component in the root and rhizome of Rheum palmatum, is a tyrosine kinase inhibitor with a number of biological activities, including antitumor effects. Here, we examine the effects of emodin on vascular endothelial growth factor (VEGF)-A-induced angiogenesis, both in vitro and in vivo. In vitro, emodin dose-dependently inhibits proliferation, migration into the denuded area, invasion through a layer of Matrigel and tube formation of human umbilical vein endothelial cells (HUVECs) stimulated with VEGF-A. Emodin also inhibits basic fibroblast growth factor-induced proliferation and migration of HUVECs and VEGF-A-induced tube formation of human dermal microvascular endothelial cells. Specifically, emodin induces the cell cycle arrest of HUVECs in the G0/G1 phase by suppressing cyclin D1 and E expression and retinoblastoma protein phosphorylation, and suppresses Matrigel invasion by inhibiting the basal secretion of matrix metalloproteinase-2 and VEGF-A-stimulated urokinase plasminogen activator receptor expression. Additionally, emodin effectively inhibits phosphorylation of VEGF-A receptor-2 (KDR/Flk-1) and downstream effector molecules, including focal adhesion kinase, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, Akt and endothelial nitric oxide synthase. In vivo, emodin strongly suppresses neovessel formation in the chorioallantoic membrane of chick and VEGF-A-induced angiogenesis of the Matrigel plug in mice. Our data collectively demonstrate that emodin effectively inhibits VEGF-A-induced angiogenesis in vitro and in vivo. Moreover, inhibition of phosphorylation of KDR/Flk-1 and downstream effector molecules is a possible underlying mechanism of the anti-angiogenic activity of emodin. Based on these data, we propose that an interaction of emodin with KDR/Flk-1 may be involved in the inhibitory function of emodin toward VEGF-A-induced angiogenesis in vitro and responsible for its potent anti-angiogenic in vivo.
...
PMID:Emodin inhibits vascular endothelial growth factor-A-induced angiogenesis by blocking receptor-2 (KDR/Flk-1) phosphorylation. 1638 16

RNA polymerase (pol) III transcription decreases when primary cultures of rat neonatal cardiomyocytes are exposed to low oxygen tension. Previous studies in fibroblasts have shown that the pol III-specific transcription factor IIIB (TFIIIB) is bound and regulated by the proto-oncogene product c-Myc, the mitogen-activated protein kinase ERK and the retinoblastoma tumour suppressor protein, RB. The principal function of TFIIIB is to recruit pol III to its cognate gene template, an activity that is known to be inhibited by RB and stimulated by ERK. We demonstrate by chromatin immunoprecipitation (ChIP) that c-Myc also stimulates pol III recruitment by TFIIIB. However, hypoxic conditions cause TFIIIB dissociation from c-Myc and ERK, at the same time as increasing its interaction with RB. Consistent with this, ChIP assays indicate that the occupancy of tRNA genes by pol III is significantly reduced, whereas promoter binding by TFIIIB is undiminished. The data suggest that hypoxia can inhibit pol III transcription by altering the interactions between TFIIIB and its regulators and thus compromising its ability to recruit the polymerase. These effects are independent of cell cycle changes.
...
PMID:Hypoxic stress suppresses RNA polymerase III recruitment and tRNA gene transcription in cardiomyocytes. 1640 35

Sarcomatoid squamous cell carcinoma (SSCC) of the uterine cervix, characterized by biphasic components of sarcomatoid and squamous neoplastic cells, is a rare entity with uncertain pathogenesis. To date, less than 20 cases have been mentioned. Although the rarity of this diagnosis makes it difficult to draw firm conclusions from limited data, it does seem that SSCC is an aggressive tumor. In this study, we present a 31-year-old patient with abnormal vaginal bleeding. The diagnosis of SSCC was confirmed through pathologic examinations from hysterectomy specimen. Its epithelial origin was demonstrated by immunohistochemical studies. The expression of p53, HER2/neu, and c-kit was not enhanced in this tumor. Importantly, it was human papillomavirus type 16, positive by polymerase chain reaction and in situ hybridization studies. Enhanced immunostaining for phospho-retinoblastoma protein and decreased apoptosis compared with the squamous cell carcinoma counterpart were observed. This report characterizes the first description of molecular features in SSCC that may account for its aggressive behavior.
...
PMID:Evidence of human papillomavirus infection, enhanced phosphorylation of retinoblastoma protein, and decreased apoptosis in sarcomatoid squamous cell carcinoma of uterine cervix. 1644 55

Hirschsprung's disease (HSCR) is a complex congenital disorder which, from a molecular perspective, appears to result due to disruption of normal signalling during development of enteric nerve cells, resulting in aganglionosis of the distal bowel. Associated congenital anomalies occur in at least 5-32% (mean 21%) of patients and certain syndromic phenotypes have been linked to distinct genetic sites, indicating underlying genetic associations of the disease and probable gene-gene interaction in its pathogenesis. Clear-cut associations with HSCR include Down's syndrome, dominant sensorineural deafness, Waardenburg syndrome, neurofibromatosis, neuroblastoma, phaeochromocytoma, the MEN type IIB syndrome and other abnormalities. Individual anomalies vary from 2.97% to 8%, the most frequent being the gastrointestinal tract (GIT) (8.05%), the central nervous system (CNS) and sensorineural anomalies (6.79%) and the genito-urinary tract (6.05%). Other associated systems include the musculoskeletal (5.12%), cardiovascular systems (4.99%), craniofacial and eye abnormalities (3%) and less frequently the skin and integumentary system (ectodermal dysplasia) and syndromes related to cholesterol and fat metabolism. In addition to associations with neuroblastoma and tumours related to MEN2B, HSCR may also be associated with tumours of neural origin such as ganglioneuroma, ganglioneuroblastoma, retinoblastoma and tumours associated with neurofibromatosis and other autonomic nervous system disturbances. The contribution of the major susceptibility genes on chromosome 10 (RET) and chromosome 13 (EDNRB) is well established in the phenotypic expression of HSCR. Whereas major RET mutations may result in HSCR by haploinsufficiency in 20-25% of cases, the etiology of the majority of sporadic HSCR is not as clear, appearing to arise from the combined cumulative effects of susceptibility loci at critical genes controlling the mechanisms of cell proliferation, differentiation and maturation. In addition, potential "modifying" associations exist with chromosome 2, 9, 20, 21 and 22, and we explore the importance of certain flanking genes of critical areas in the final phenotypic expression of HSCR.
...
PMID:The contribution of associated congenital anomalies in understanding Hirschsprung's disease. 1651 96

The development and progression of malignancies is a complex multistage process that involves the contribution of a number of genes giving growth advantage to cells when transformed. The role of transforming growth factor-beta (TGF-beta) in carcinogenesis is complex with tumor-suppressor or prooncogenic activities depending on the cell type and the stage of the disease. We have previously reported the identification of a novel WD-domain protein, STRAP, that associates with both TGF-beta receptors and that synergizes with the inhibitory Smad, Smad7, in the negative regulation of TGF-beta-induced transcription. Here, we show that STRAP is ubiquitously expressed and is localized in both cytoplasm and nucleus. STRAP is up-regulated in 60% colon and in 78% lung carcinomas. Stable expression of STRAP results in activation of mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and in down-regulation of the cyclin-dependent kinase inhibitor p21(Cip1), which results in retinoblastoma protein hyperphosphorylation. In addition, we have observed that Smad2/3 phosphorylation, TGF-beta-mediated transcription, and growth inhibition are induced in STRAP-knockout mouse embryonic fibroblasts compared with wild-type cells. Ectopic expression of STRAP in A549 lung adenocarcinoma cell line inhibits TGF-beta-induced growth inhibition and enhances anchorage-independent growth of these cells. Moreover, overexpression of STRAP increases tumorigenicity in athymic nude mice. Knockdown of endogenous STRAP by small interfering RNA increases TGF-beta signaling, reduces ERK activity, increases p21(Cip1) expression, and decreases tumorigenicity. Taken together, these results suggest that up-regulation of STRAP in human cancers may provide growth advantage to tumor cells via TGF-beta-dependent and TGF-beta-independent mechanisms, thus demonstrating the oncogenic function of STRAP.
...
PMID:Oncogenic function of a novel WD-domain protein, STRAP, in human carcinogenesis. 1677 89


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---