Item request has been placed!
×
Item request cannot be made.
×
![loading](/sites/all/modules/hf_eds/images/loading.gif)
Processing Request
Deregulated FGFR3 mutants in multiple myeloma cell lines with t(4;14): comparative analysis of Y373C, K650E and the novel G384D mutations.
Item request has been placed!
×
Item request cannot be made.
×
![loading](/sites/all/modules/hf_eds/images/loading.gif)
Processing Request
- معلومة اضافية
- المصدر:
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print Cited Medium: Print ISSN: 0950-9232 (Print) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE
- بيانات النشر:
Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-
- الموضوع:
Chromosomes, Human, Pair 14* ;
Chromosomes, Human, Pair 4* ;
Mutation* ;
Protein-Tyrosine Kinases* ;
Translocation, Genetic*;
Multiple Myeloma/
*genetics ;
Receptors, Fibroblast Growth Factor/
*genetics;
3T3 Cells ;
Amino Acid Substitution ;
Animals ;
Cell Line ;
Chromosome Mapping ;
Fibroblast Growth Factors/
metabolism ;
Gene Expression Regulation, Neoplastic ;
Humans ;
Mice ;
Mutagenesis, Site-Directed ;
Phosphorylation ;
Polymerase Chain Reaction ;
Polymorphism, Single-Stranded Conformational ;
Receptor, Fibroblast Growth Factor, Type 3 ;
Receptors, Fibroblast Growth Factor/
chemistry ;
Receptors, Fibroblast Growth Factor/
metabolism ;
Transfection ;
Tumor Cells, Cultured - نبذة مختصرة :
The t(4;14)(p16.3;q32) chromosomal translocation occurs in approximately 20% of multiple myelomas (MM) and leads to the apparent deregulation of two genes located on 4p16.3: the fibroblast growth factor receptor 3 (FGFR3) and the putative transcription factor WHSC1/MMSET. Interestingly, FGFR3 mutations known to be associated with autosomal dominant human skeletal disorders have also been found in some MM cell lines with t(4;14) but their pathogenetic role in MM is still controversial. Since cell lines may represent useful models for investigating the effects of deregulated FGFR3 mutants in MM, we analysed the expression, activation, signaling pathways and oncogenic potential of three mutants identified so far: the Y373C and K650E in the KMS-11 and OPM-2 cell lines respectively, and the novel G384D mutation here identified in the KMS-18 cell line. All of the cell lines present a heterozygous FGFR3 gene mutation and transcribe the mutated allele; unlike KMS-11 and OPM-2 (which express the IIIc isoform), the KMS-18 cell line expresses prevalently the isoform IIIb. We demonstrated that, under serum-starved conditions, KMS-11 and OPM-2 cells express appreciable levels of phosphorylated FGFR3 mutants indicating a constitutive activation of the Y373C and K650E receptors; the addition of the aFGF ligand further increased the level of receptor phosphorylation. Conversely, the FGFR3 mutant in KMS-18 does not seem to be constitutively activated since it was phosphorylated only in the presence of the ligand. In all three MM cell lines, ligand-stimulated FGFR3 mutants activated the MAP kinase signaling pathway but did not apparently involve either the STAT1 or STAT3 cascades. However, when transfected in 293T cells, G384D, like Y373C and K650E, was capable of activating MAPK, STAT1 and STAT3 under serum-starved condition. Finally, a focus formation assay of NIH3T3 cells transfected with FGFR3-expressing plasmid vectors showed that Y373C and K650E (albeit at different levels) but not G384D or the wild-type receptor, can induce transformed foci. Overall, our results support the idea that FGFR3 mutations are graded in terms of their activation capability, thus suggesting that they may play a critical role in the tumor progression of MM patients with t(4;14).
- الرقم المعرف:
0 (Receptors, Fibroblast Growth Factor)
62031-54-3 (Fibroblast Growth Factors)
EC 2.7.10.1 (FGFR3 protein, human)
EC 2.7.10.1 (Fgfr3 protein, mouse)
EC 2.7.10.1 (Protein-Tyrosine Kinases)
EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 3)
- الموضوع:
Date Created: 20010629 Date Completed: 20010719 Latest Revision: 20120605
- الموضوع:
20240628
- الرقم المعرف:
10.1038/sj.onc.1204465
- الرقم المعرف:
11429702
No Comments.