Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently several chromosomal translocations involved in myeloma cases and myeloma cell lines; i.e., t(11;14)(q13;q32), t('8;14)(q24;q32), t(4;14)(q16.3;q32.3), t(6;14)(p25;q32), and t(14;16)(q32.3;q23), have been identified. These translocations are considered to dysregulate genes which may be concerned with myelomagenesis; i.e., PRAD1/cyclin D1, the c-myc oncogene, FGFR3 (fibroblast growth factor receptor 3), MMSET (multiple myeloma SET domain), MUM1 (multiple myeloma oncogene 1)/IRF4 (interferon regulatory factor 4), and the c-maf oncogene, respectively. However, the cellular biological roles of these genes have not yet been elucidated in myeloma cells. Because two of the seven human myeloma cell lines which were established at Kawasaki Medical School, Okayama, Japan, KMS-11 and KMS-18, have been proven to possess t(4;14)(q16.3;q32.3), we studied the expression levels of the FGFR3 gene in these seven cell lines and 13 primary myeloma specimens. The expression levels of 12 known FGF family genes (FGF-1 to 12) and 4 FGFR genes (FGFR1 to 4) were also examined in seven cell lines. In addition, the growth status of the KMS-11 and KMS-18 lines with FGF-1 or anti-FGF-4 neutralizing monoclonal antibody (MoAb) supplementation was investigated because FGF-1 and 4 are known as the principal ligands for FGFR3. FGFR3 overexpression was observed in both of the cell lines possessing t(4;14)(q16.3;q32.3) and in 3 of 13 case specimens. Anti-FGF-4 neutralizing MoAb caused significant growth inhibition in these two cell lines possessing t(4;14)(q16.3;q32.3). These findings indicate that t(4;14) (q16. 3;q32.3) may provide myeloma cells with a growth advantage via an autocrine mechanism between FGFR3 and FGF-4.
 ...
PMID:Expression of fibroblast growth factor and FGF-receptor family genes in human myeloma cells, including lines possessing t(4;14)(q16.3;q32. 3) and FGFR3 translocation. 1056 29

Ginseng (the root of Panax ginseng C.A. Meyer, Araliaceae) has been used as a crude drug taken orally for preventive and therapeutic purposes in Asian countries as a traditional medicine. In the current study, we have investigated the antitumor effect of a novel ginseng protopanaxadiol saponin bacterial metabolic derivative, 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol (IH-901), in eight human myeloma cell lines. IH-901 inhibited the proliferation of all myeloma cell lines examined. Despite the fibroblast growth factor receptor 3 (FGFR3) overexpression due to a chromosomal translocation t(4;14)(q16.3;q32.3) in KMS-11 myeloma cells, IH-901 induced apoptosis in a dose- and time-dependent way in this cell line. Treatment of KMS-11 with IH-901 resulted in the formation of internucleosomal DNA fragments, poly (ADP-ribose) polymerase cleavage, and the activation of caspase-3. IH-901 also caused the down-regulation of FGFR3 mRNA and protein expression and inhibited ERK activity in KMS-11 cells. Our results demonstrate that IH-901 induces apoptosis and inhibits FGFR3 expression and signaling in KMS-11 cells, suggesting candidacy for the chemoprevention and the treatment of myeloma.
 ...
PMID:A novel ginseng saponin metabolite induces apoptosis and down-regulates fibroblast growth factor receptor 3 in myeloma cells. 1296 89

The t(4;14)(p16.3;q32), associated with 10-20% of cases of multiple myeloma (MM), deregulates the expression of MMSET and FGFR3. To assess the potential of FGFR3 as a drug target, we evaluated the effects of selective inhibitors on MM and control cell lines. SU5402 and PD173074 specifically inhibited the growth of the two t(4;14)-positive MM lines, KMS-11 and OPM-2. Importantly, inhibition was still observed in the presence of IL-6, a growth factor known to play an important role in MM. Both compounds induced a dose-dependent reduction in cell viability and an increase in apoptosis, accompanied by a decrease in extracellular signal-related kinase phosphorylation. In contrast, no inhibition was seen with either compound against t(4;14)-negative cell lines or NCI-H929, a t(4;14)-positive, FGFR3-negative MM cell line. FGFR3 is thus a plausible candidate for targeted therapy in a subset of MM patients.
 ...
PMID:Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074. 1502 11

The mechanisms underlying sperm protein 17 (Sp17) gene expression in myeloma cells remained unclear. Using reverse transcription-polymerase chain reaction (RT-PCR), Sp17 transcripts were detected in ARK-B, ARP-1, RPMI-8226 and KMS-11 but not in H929, IM-9, MM1-R and U266 cells. Using a panel of primer pairs in methylation-sensitive PCR to amplify overlapping gene segments, our screening studies showed that the HpaII sites at -359 and -350 are involved in the regulation of Sp17 gene expression. To confirm the differences in methylation status between Sp17-positive and Sp17-negative cell lines, KMS-11 cells (Sp17-positive) and IM-9 cells (Sp17-negative) were subjected to the more accurate method of bisulphite conversion. KMS-11 cells were more hypomethylated at these HpaII sites of exon 1 compared to IM-9 cells, indicating the association of hypomethylated promoter with Sp17 gene expression. In addition, the level of methylation at other CpG sites within the promoter sequence was also higher in IM-9 than KMS-11. Exon 1 was cloned into a reporter vector, pCAT*3 Enhancer. Chloramphenicol acetyl transferase (CAT) activity was restored in cells transfected with the recombinant plasmid, indicating the promoter function of exon 1. Exposure of Sp17-negative cell lines to the hypomethylating agent, 5-azacytidine, resulted in the upregulation of Sp17 gene expression. Our results therefore provide evidence for the regulation of Sp17 gene expression by promoter methylation.
 ...
PMID:Sp17 gene expression in myeloma cells is regulated by promoter methylation. 1538 30

Interleukin-6 (IL-6) is a cytokine that regulates the proliferation of some tumor cells including multiple myeloma (MM). Ectopic expression of fibroblast growth factor receptor 3 (FGFR 3) associated with the chromosomal translocation, t(4;14)(p16.3;q32), is frequently found in MM, and therefore, has been implicated in the neoplastic transformation of this disease. Here, we show that IL-6 together with FGF enhanced proliferation of a myeloma cell line, KMS-11 carrying t(4;14)(p16.3;q32) and the FGFR 3-transfected U 266 myeloma cell line which ectopically expressed FGFR 3 but responded to neither IL-6 nor FGF alone. In KMS-11, IL-6 activated signal transducer and activator of transcription 3 (STAT 3) while FGF activated extracellular signal-regulated kinase 1/2 (ERK 1/2) and phosphatidylinositol (PI)-3 kinase. As both MEK inhibitors and a PI 3-kinase inhibitor abolished the effect of IL-6 and FGF, the activation of both the ERK 1/2 and PI 3-kinase signaling cascades is essential for the proliferation of KMS-11 enhanced by IL-6 and FGF. Furthermore, the FGF-induced activation of ERK 1/2 contributed to the serine phosphorylation of STAT 3, suggesting that the signaling crosstalk between the cytokine receptor, IL-6 receptor alpha/gp 130 and the growth factor receptor tyrosine kinase, FGFR 3. These results indicate that FGFR 3 plays a crucial role in the accelerated proliferation of MM carrying t(4;14)(p16.3;q32).
 ...
PMID:Accelerated proliferation of myeloma cells by interleukin-6 cooperating with fibroblast growth factor receptor 3-mediated signals. 1594 Feb 50

Thalidomide (Thal), a novel agent in the treatment of multiple myeloma, is presumed to act through a variety of mechanisms. In the present study, we examined the relationship between fibroblast growth factor receptor 3 (FGFR3) expression and the therapeutic effect of Thal. The DNA synthesis of KMS-11 clone, which overexpresses FGFR3, was inhibited by Thal in a dose-dependent manner; whereas U266 cells, which lack FGFR3 expression, failed to respond to Thal inhibition. To further examine the intertwining of Thal's therapeutic effects, wild-type human full-length FGFR3 cDNA was transfected into U266 cells. FGFR3 transfected U266 clones revealed increased FGFR3 expression, but resulted in decreased DNA synthesis and increased apoptosis under Thal treatment. Under Thal treatment, the myeloma proliferation-related protein, vascular endothelial growth factor (VEGF), and interleukin-6 (IL-6) were decreased in U266 FGFR3 transfectant as well. These results suggest that Thal inhibits myeloma cell proliferation and may depend on FGFR3 expression status. To further confirm this observation, we transfected a plasmid constructed anti-FGFR3 ribozyme (Rz52) into KMS-11 cells. In the ribozyme transfectant KMS-11 clone, FGFR3 expression was decreased; whereas the effects of Thal in cell growth inhibition were abrogated in KMS-11 Rz52 clone. Further results suggested that Thal inhibition of DNA synthesis, induction of apoptosis, and down-regulation of VEGF and IL-6 might be dependent on FGFR3-associated signal transduction of the ERK and STAT3 phosphorylation pathway. Thus, FGFR3 may be a predictive/surrogate marker for selection of Thal treatment in myeloma.
 ...
PMID:Therapeutic effects of thalidomide in myeloma are associated with the expression of fibroblast growth factor receptor 3. 1836 May 64

Fibroblast growth factor receptors (FGFRs) can act as driving oncoproteins in certain cancers, making them attractive drug targets. Here we have characterized tumour cell responses to two new inhibitors of FGFR1-3, AZ12908010 and the clinical candidate AZD4547, making comparisons with the well-characterized FGFR inhibitor PD173074. In a panel of 16 human tumour cell lines, the anti-proliferative activity of AZ12908010 or AZD4547 was strongly linked to the presence of deregulated FGFR signalling, indicating that addiction to deregulated FGFRs provides a therapeutic opportunity for selective intervention. Acquired resistance to targeted tyrosine kinase inhibitors is a growing problem in the clinic but has not yet been explored for FGFR inhibitors. To assess how FGFR-dependent tumour cells adapt to long-term FGFR inhibition, we generated a derivative of the KMS-11 myeloma cell line (FGFR(Y373C)) with acquired resistance to AZ12908010 (KMS-11R cells). Basal phosphorylated FGFR and FGFR-dependent downstream signalling were constitutively elevated and refractory to drug in KMS-11R cells. Sequencing of FGFR3 in KMS-11R cells revealed the presence of a heterozygous mutation at the gatekeeper residue, encoding FGFR3(V555M); consistent with this, KMS-11R cells were cross-resistant to AZD4547 and PD173074. These results define the selectivity and efficacy of two new FGFR inhibitors and identify a secondary gatekeeper mutation as a mechanism of acquired resistance to FGFR inhibitors that should be anticipated as clinical evaluation proceeds.
 ...
PMID:Tumour cell responses to new fibroblast growth factor receptor tyrosine kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of acquired resistance. 2286 48

The anti-lymphoma activity and mechanism(s) of action of the multikinase inhibitor sorafenib were investigated using a panel of lymphoma cell lines, including SU-DHL-4V, Granta-519, HD-MyZ, and KMS-11 cell lines. In vitro, sorafenib significantly decreased cell proliferation and phosphorylation levels of MAPK and PI3K/Akt pathways while increased apoptotic cell death. In vivo, sorafenib treatment resulted in a cytostatic rather than cytotoxic effect on tumor cell growth associated with a limited inhibition of tumor volumes. However, sorafenib induced an average 50% reduction of tumor vessel density and a 2-fold increase of necrotic areas. Upon sorafenib treatment, endothelial and tumor cells from SU-DHL-4V, Granta-519, and KMS-11 nodules showed a potent inhibition of either phospho-ERK or phospho-AKT, whereas a concomitant inhibition of phospho-ERK and phospho-AKT was only observed in HD-MyZ nodules. In conclusion, sorafenib affects the growth of lymphoid cell lines by triggering antiangiogenic mechanism(s) and directly targeting tumor cells.
 ...
PMID:Sorafenib inhibits lymphoma xenografts by targeting MAPK/ERK and AKT pathways in tumor and vascular cells. 2362 Jul 75

The signaling lymphocytic activation molecule family 3 (SLAMF3) is highly expressed on plasma cells from patients with multiple myeloma (MM) and induces high malignant potential by ERK signaling mediated via the interaction with adaptor proteins SHP2 and GRB2. This study focused on the single-nucleotide polymorphism (SNP) of the SLAMF3 gene (rs509749, 1804A>G, M602V) in MM. The SNP G allele was a major type, and the frequencies of the GG, GA, and AA genotypes were 61.8%, 29.4%, and 8.8%, respectively, in patients with MM, which was almost the same as in healthy the control group in the Japanese population. Interestingly, patients with GG genotypes had significantly shorter overall survival times than patients with GA/AA genotypes. Consistent with those results, SLAMF3-overexpressing KMS-34 cells with the G allele (V602) had higher cell proliferation potential and were more resistant to anti-MM agents than those with the A allele (M602). When those cells were subcutaneously inoculated into NOG mice, tumor sizes in mice receiving V602 cells rapidly increased, and survival was significantly shorter than in mice injected with M602 cells. Furthermore, SLAMF3 V602 molecules bound more tightly to SHP2 and GRB2, with increased SHP2 and ERK phosphorylation compared with M602 cells. The mRNA expression of cell cycle-related genes (CCND1 and CCNE1) and anti-apoptotic genes (BCL2L and p21) was increased in V602 cells compared with M602 cells. The results thus suggested that the G allele of SLAMF3 SNP rs509749 may be associated with MM disease progression.
 ...
PMID:The SLAMF3 rs509749 polymorphism correlates with malignant potential in multiple myeloma. 3281 3