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)

The heat shock proteins (HSPs) induced by cell stress are expressed at high levels in a wide range of tumors and are closely associated with a poor prognosis and resistance to therapy. The increased transcription of HSPs in tumor cells is due to loss of p53 function and to higher expression of the proto-oncogenes HER2 and c-Myc, and is crucial to tumorigenesis. The HSP family members play overlapping, essential roles in tumor growth both by promoting autonomous cell proliferation and by inhibiting death pathways. The HSPs have thus become targets for rational anti-cancer drug design: HSP90 inhibitors are currently showing much promise in clinical trials, whereas the increased expression of HSPs in tumors is forming the basis of chaperone-based immunotherapy.
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PMID:Heat shock proteins in cancer: chaperones of tumorigenesis. 1648 82

Aside from the well-established roles of c-Myc in the regulation of cell cycle, differentiation, and apoptosis, a recent picture is beginning to emerge linking c-Myc to the regulation of metabolic pathways. Here, we define a further function for c-Myc in determining cellular redox balance, identifying glutathione (GSH) as the leading molecule mediating this process. The link between c-Myc and GSH is gamma-glutamyl-cysteine synthetase (gamma-GCS), the rate-limiting enzyme catalyzing GSH biosynthesis. Indeed, c-Myc transcriptionally regulates gamma-GCS by binding and activating the promoters of both gamma-GCS heavy and light subunits. Exposure to H2O2 enhances c-Myc recruitment to gamma-GCS regulatory regions through ERK-dependent phosphorylation. Phosphorylation at Ser-62 is required for c-Myc recruitment to gamma-GCS promoters and determines the cellular response to oxidative stress induced by different stimuli. Thus, the c-Myc phosphorylation-dependent activation of the GSH-directed survival pathway can contribute to oxidative stress resistance in tumor cells, which generally exhibit deregulated c-Myc expression.
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PMID:c-Myc phosphorylation is required for cellular response to oxidative stress. 1648 32

We previously showed that prolonged and strong ERK phosphorylation induced by Compound 5 (Cpd 5), a Cdc25A protein phosphatase inhibitor, was involved in its mechanism of cell growth inhibition. To study the relationship between ERK phosphorylation and cell growth inhibition, we used Cpd 5 as a tool to investigate ERK-regulated c-Myc expression in Hep3B hepatoma cells. We found that ERK phosphorylation caused by Cpd 5 induced c-Myc phosphorylation, but suppressed c-Myc expression at the mRNA and protein levels. Furthermore, Cpd 5 inhibited c-Myc transcriptional activity and DNA binding ability, and this inhibition was antagonized by ERK kinase (MEK) inhibitor U-0126, implying that the ERK pathway was involved in regulating c-Myc expression. Since the participation of c-Myc protein in transcription requires its dimerization with Max protein, we examined the Myc-Max association in Cpd 5-treated cells and found that Cpd 5 suppressed Myc-Max dimerization. Transfection of Hep3B cells with mutated ERK (T188A/Y190F), which has lost its dual-phosphorylation sites, attenuated the actions of Cpd 5 on Myc-Max association. To further demonstrate whether Myc phosphorylation by Cpd 5-induced ERK activation was able to directly regulate c-myc gene expression, a chromatin immunoprecipitation (ChIP) assay was used to examine the binding of phospho-Myc to the c-myc promoter region. We found that phospho-Myc induced by Cpd 5 had lost its ability to bind to the c-myc promoter, whereas MEK inhibitor U-0126 antagonized this inhibitory effect. These data suggest that an increase in c-Myc phosphorylation in response to prolonged ERK phosphorylation negatively auto-regulates c-Myc gene expression, leading to the suppression of its target gene expression and cell cycle block.
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PMID:Phosphorylation regulates Myc expression via prolonged activation of the mitogen-activated protein kinase pathway. 1659 19

This study examined the effect of wild-type Smad3 gene on the osteoblastic differentiation of rat bone marrow-derived mesenchymal stem cells in vitro. Bone marrow-derived mesenchymal stem cells (MSCs) were stably transfected with the complexes of pcDNA3. 0-Myc-Smad3 or pcDNA3. 0-Myc-Smad3deltaC and Lipofectamine reagent. Immunofluorescence staining was performed to evaluate the c-Myc signal in MSCs. The cell proliferation was detected by MTT method. To clarify the osteoblastic characteristics in stably transfected MSCs, alkaline phosphatase (ALP) mRNA and core binding factor alpha1 (Cbfa1) mRNA were investigated by RT-PCR, and ALP activity and mineralization were examined by p-nitrophenolphosphate method and alizarin red staining respectively. PD98059, a specific inhibitor of the ERK signaling pathway, was used to determine the role of ERK in Smad3-MSCs osteoblastic differentiation. c-Myc signal was detected in Smad3-MSCs and Smad3 deltaC-MSCs. The proliferation of Smad3-MSCs was slower than that of Smad3deltaC-MSCs or V-MSCs. The relative levels of ALP mRNA and Cbfal mRNA in Smad3-MSCs, as well as ALP activity and mineralization, were markedly higher than those in Smad3deltaC-MSCs or V-MSCs. Although ALP activity and mineralization were slightly lower in Smad3-MSCs treated with PD98059 than in those without PD98059 treatment, no significant difference was found between them (P > 0.05). It is concluded that the wild-type Smad3 gene, which is a crucial component promoting bone formation, can inhibit the proliferation of MSCs and enhance the osteoblastic differentiation of uncommitted MSCs and the maturation of committed MSCs independent of the ERK signaling pathway.
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PMID:Wild-type Smad3 gene enhances the osteoblastic differentiation of rat bone marrow-derived mesenchymal stem cells in vitro. 1669 23

Obesity has been recognized as a risk factor for breast cancer. Adipocyte-derived leptin may play as a paracrine regulator on the growth of breast cancer cells. Expression of both leptin and its OB-Rb receptor was detected in human breast cancer ZR-75-1 cells and further induced by leptin, suggesting that both expression and message mediation of leptin were autoregulated by itself. With cell counting and MTT assay, we had observed leptin stimulated ZR-75-1 growth in dose- and time-dependent manners. To study what steps of cell cycle progression leptin may involve in, we analyzed cell-cycle profile with flow cytometric analysis, mRNA and protein expressions of four cell-cycle regulators with RT-PCR and Western blotting analysis. Under the treatment of leptin, the G1 arrest of cells was reduced accompanied with up-regulation of G1 phase-specific cyclin D1 and proto-oncogene c-Myc, but down-regulation of cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and tumor suppressor p53. Furthermore, JAK2 inhibitor AG490, PI3K/Akt inhibitor Wortmannin, and MEK/ERK1/2 inhibitor PD98059 were efficiently prevented leptin-promoted cell growth. Effect of cooperation between leptin and estrogen on ZR-75-1 growth had been observed. Collectively, the results showed that the proliferative effect of leptin on ZR-75-1 was associated with the up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21(WAF1/CIP1) plausibly through a hypothesized JAK2-PI3K/Akt-MEK/ERK pathway. The leptin- and OB-Rb-expressing capability of ZR-75-1 created a possible autocrine control of leptin, in which signal could be effectively amplified by itself, on cell growth.
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PMID:Leptin-induced growth of human ZR-75-1 breast cancer cells is associated with up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21WAF1/CIP1. 1675 79

Ovine pulmonary adenocarcinoma (OPA) and enzootic nasal adenocarcinoma (ENA) are two contagious neoplastic diseases of secretory epithelial cells in the respiratory system of sheep and goats. Jaagsiekte sheep retrovirus (JSRV) is the aetiological agent of OPA, and enzootic nasal tumour virus (ENTV) is associated with ENA. The genomes of these retroviruses do not contain known oncogenes but products of the env gene are important in the generation of transforming stimuli. However, the cell signalling pathways activated in vivo are not completely understood. This study was based on the use of activation stage antibodies specifically detecting proteins of the extracellular signal regulated kinase Erk 1/2 cell signalling pathway and transcription factors. Tissue sections were collected from four natural cases of OPA, four experimentally induced OPA tumours, four ENA tumours in sheep, four ENA tumours in goats, two normal sheep lungs and two lungs with chronic inflammation. Routine immunohistochemical procedures with phosphorylation stage-specific antibodies were carried out. Representative proteins of the Erk1/2 pathway (Raf-1, Mek1/2 and p44/42MAPK) were activated in natural cases of OPA and ENA in sheep and goats and also in experimentally induced OPA. Transcription factors 90Rsk and Elk-1 were activated in OPA and ENA tumours. However, c-Myc was activated only in OPA tumours. In contagious respiratory neoplasms of sheep and goats the Erk1/2 pathway appears to be important for the in-vivo generation of the transforming stimuli.
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PMID:In-situ demonstration of mitogen-activated protein kinase Erk 1/2 signalling pathway in contagious respiratory tumours of sheep and goats. 1681 1

U1 bladder cancer cells of high malignancy exhibited higher proliferation capacity than U4 premalignant cells. Higher expression of Ras, c-Myc, and nucleophosmin/B23 and greater c-Myc transactivation and nucleophosmin/B23 promoter activities were detected in U1 cells compared with U4 cells. Moreover, c-Myc and nucleophosmin/B23 were increased in U1 but not in U4 cells upon serum stimulation from quiescence. Likewise, only in U1 cells could serum stimulate transcriptional activity of nucleophosmin/B23 promoter and c-Myc response element. The increase of nucleophosmin/B23 promoter activity could be abrogated by mitogen-activated protein kinase/extracellular signal-regulated kinase activating kinase inhibitor and was associated with recruitment of c-Myc to the promoter. U1 cells constitutively expressing dominant-negative Ras reduced the levels of Ras, nucleophosmin/B23, and p-ERK, and consequently abolished the serum-induced up-regulation of nucleophosmin/B23 promoter activity and c-Myc promoter recruitment. Our results indicate that Ras and c-Myc play important roles in the up-regulation of nucleophosmin/B23 during proliferation of cells associated with a high degree of malignancy, thus outlining a signaling cascade involving these factors in the cancer cells.
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PMID:Ras-dependent recruitment of c-Myc for transcriptional activation of nucleophosmin/B23 in highly malignant U1 bladder cancer cells. 1685 42

The target gene(s) required for Myc-mediated tumorigenesis are still elusive. Here we show that while endogenous c-Myc is surprisingly dispensable for skin homeostasis and TPA-induced hyperplasia, c-Myc-deficient epidermis is resistant to Ras-mediated DMBA/TPAinduced tumorigenesis. This is mechanistically linked to p21(Cip1), which is induced in tumors by the activated Ras-ERK pathway but repressed by c-Myc. Acute elimination of c-Myc in established tumors leads to the up-regulation of p21(Cip1), and epidermis lacking both p21(Cip1) and c-Myc reacquires normal sensitivity to DMBA/TPA-induced tumorigenesis. This identifies c-Myc-mediated repression of p21(Cip1) as a key step for Ras-driven epidermal tumorigenesis.
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PMID:Skin epidermis lacking the c-Myc gene is resistant to Ras-driven tumorigenesis but can reacquire sensitivity upon additional loss of the p21Cip1 gene. 1688 80

Transitional cell carcinoma of the bladder is a common tumor. While most patients presenting superficial disease can be expected to do well following treatment, still many patients will return to our office with muscle invasive and metastatic disease. Survival in advanced bladder cancer is less than 50%. Tumors of similar histologic grade and stage have variable behavior, suggesting that genetic alterations must be present to explain the diverse behavior of bladder cancer. It is hoped that through the study of the subtle genetic alterations in bladder cancer, important prognostic and therapeutic targets can be exploited. Many new diagnostic tests and gene therapy approaches rely on the identification and targeting of these unique genetic alterations. A review of literature published on the molecular genetics of bladder cancer from 1970 to the present was conducted. A variety of molecular genetic alterations have been identified in bladder cancer. Oncogenes (H-ras, erbB-2, EGFR, MDM2, C-MYC, CCND1), tumor suppressor genes (p53, Rb, p21, p27/KIP1, p16, PTEN, STK15, FHIT, FEZ1/LZTS1, bc10), telomerase, and methylation have all been studied in bladder cancer. Several have proven to be potentially useful clinical targets in the prognosis and therapy of bladder cancer such as staining for p53 and gene therapy strategies such as p53 and fez1. Clinical trials targeting HER2/neu and the EGFR pathways are underway. The UroVysion bladder cancer assay relies on FISH to detect genetic alterations in this disease. Continuing identification of the molecular genetic alterations in bladder cancer will enhance future diagnostic and therapeutic approaches to bladder cancer. Capitalizing on these alterations will allow early detection, providing important prognostic information and unique targets for gene therapy and other therapeutic approaches.
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PMID:Molecular genetics of bladder cancer: targets for diagnosis and therapy. 1691 24

Glucocorticoids are extensively used in combination chemotherapy of advanced prostate cancer (PC). Little is known, however, about the status of the glucocorticoid receptor (GR) in PC. We evaluated over 200 prostate samples and determined that GR expression was strongly decreased or absent in 70-85% of PC. Similar to PC tumors, some PC cell lines, including LNCaP, also lack GR. To understand the role of GR, we reconstituted its expression in LNCaP cells using lentiviral approach. Treatment of LNCaP-GR cells with the glucocorticoids strongly inhibited proliferation in the monolayer cultures and blocked anchorage-independent growth. This was accompanied by upregulation of p21 and p27, down-regulation of cyclin D1 expression and c-Myc phosphorylation. Importantly, the activation of GR resulted in normalized expression of PC markers hepsin, AMACR, and maspin. On the signaling level, GR decreased expression and inhibited activity of the MAP-kinases (MAPKs) including p38, JNK/SAPK, Mek1/2 and Erk1/2. We also found that activation of GR inhibited activity of numerous transcription factors (TF) including AP-1, SRF, NF-kappaB, p53, ATF-2, CEBPalpha, Ets-1, Elk-1, STAT1 and others, many of which are regulated via MAPK cascade. The structural analysis of hepsin and AMACR promoters provided the mechanistic rationale for PC marker downregulation by glucocorticoids via inhibition of specific TFs. Our data suggest that GR functions as a tumor suppressor in prostate, and inhibits multiple signaling pathways and transcriptional factors involved in proliferation and transformation.
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PMID:Tumor suppressor activity of glucocorticoid receptor in the prostate. 1701 46


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