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)

We have recently identified a novel gene, TACC1 (transforming acidic coiled coil-containing gene 1), which is located close to FGFR1 within a region amplified in breast cancer on human chromosome 8p11. The coiled coil domain of this gene identified a series of cDNAs in the expressed sequence tag database, which suggested the existence of a family of TACC genes comprising at least three family members. We have now characterized the human and mouse TACC3 cDNAs, and demonstrate that this gene is upregulated in various cancer cell lines, and at Embryonic Day 15 in mice, suggesting that the TACC3 protein is involved in the control of cell growth and differentiation. The TACC3 gene maps telomeric to the FGFR3 gene in 4p16.3, close to a region disrupted by translocation breakpoints associated with multiple myeloma. Thus, TACC1, TACC2, and TACC3 map close to the corresponding FGFR1, FGFR2, and FGFR3 genes. The phylogenetic relationship among the three TACC genes is similar to that of the three FGFR family members. These relationships suggest that the FGFR and TACC genes arose from a physically linked ancestral gene pair. Subsequently, this gene pair has undergone two successive rounds of gene duplication to give rise to the three FGFR/TACC gene pairs on chromosomes 4, 8, and 10.
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PMID:The third member of the transforming acidic coiled coil-containing gene family, TACC3, maps in 4p16, close to translocation breakpoints in multiple myeloma, and is upregulated in various cancer cell lines. 1036 48

The t(4;14)(p16;q32) translocation seen in c. 18% of newly diagnosed multiple myeloma (MM) cases, results in FGFR3 activation and creation of an IGH/MMSET fusion transcript. We have recently shown that FGFR3 is activated in only 75% of t(4;14)(+) cases, suggesting that alternative genes near the breakpoint may be involved in the transforming event. The gene, TACC3, located just 50 kb telomeric of FGFR3, with transforming capacity, therefore represented a candidate gene. Using a real-time quantitative polymerase chain reaction-based approach on a cohort of 54 patients, we found a statistically significant, twofold increase in TACC3 expression in t(4;14)(+) cases. TACC3, MMSET and p21 values were positively correlated in all cases and, of particular interest, six patient samples [three t(4;14)(-), three t(4;14)(+)] samples showed a joint up-regulation of TACC3, MMSET and p21. Although a poor prognosis is linked with elevated MMSET expression, an extended follow-up period will be required to evaluate the significance of elevated TACC3 and p21 expression in this subgroup of MM.
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PMID:Correlation of TACC3, FGFR3, MMSET and p21 expression with the t(4;14)(p16.3;q32) in multiple myeloma. 1519 34

The Transforming acidic coiled coil (TACC) proteins play a conserved role in normal development and tumorigenesis through interactions with multiple complexes involved in transcription, translation, and centrosomal dynamics. However, despite significant work on the function of TACC3 in the control of centrosomal mechanics, relatively little functional data is known about the family's founding member, TACC1. From a continued analysis of clones isolated by an unbiased yeast two-hybrid assay, we now show direct physical interactions between the TACC1 and the FHL (Four and a Half LIM-only) family of proteins. The authenticity of these interactions was validated both in vitro and in cellular systems. The FHLs exhibit diverse biological roles such as the regulation of the actin cytoskeleton and are promiscuous coregulators for several transcription factors. The interaction of the endogenous TACC-FHL proteins is primarily localized to the nucleus. However, similar to FHL2, overexpression of TACC1A in HEK293 is able to sequester serum activated ERK to the cytoplasm. This has the effect of reducing the serum induced transcriptional response of the c-fos and c-jun genes. The observation that TACCs can interact with the FHLs and alter their serum induced activities raises the possibility that the TACCs participate in crosstalk between cell signaling pathways important for cancer development and tumor progression. The transforming acidic coiled coil genes are known to be important prognostic indicators for breast, ovarian and lung cancer. In this manuscript, we identify a novel interaction between the TACCs and the FHL protein family. This interaction has an affect on ERK and may in part explain the variable associations and changes in subcellular locations of each family with specific subtypes of malignancy.
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PMID:Interaction of TACC proteins with the FHL family: implications for ERK signaling. 1848 Dec 6

Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
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PMID:A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer. 2141 68

The glioblastoma genome displays remarkable chromosomal aberrations, which harbor critical glioblastoma-specific genes contributing to several oncogenetic pathways. To identify glioblastoma-targeted genes, we completed a multifaceted genome-wide analysis to characterize the most significant aberrations of DNA content occurring in glioblastomas. We performed copy number analysis of 111 glioblastomas by Digital Karyotyping and Illumina BeadChip assays and validated our findings using data from the TCGA (The Cancer Genome Atlas) glioblastoma project. From this study, we identified recurrent focal copy number alterations in 1p36.23 and 4p16.3. Expression analyses of genes located in the two regions revealed genes which are dysregulated in glioblastomas. Specifically, we identify EGFR negative regulator, ERRFI1, within the minimal region of deletion in 1p36.23. In glioblastoma cells with a focal deletion of the ERRFI1 locus, restoration of ERRFI1 expression slowed cell migration. Furthermore, we demonstrate that TACC3, an Aurora-A kinase substrate, on 4p16.3, displays gain of copy number, is overexpressed in a glioma-grade-specific pattern, and correlates with Aurora kinase overexpression in glioblastomas. Our multifaceted genomic evaluation of glioblastoma establishes ERRFI1 as a potential candidate tumor suppressor gene and TACC3 as a potential oncogene, and provides insight on targets for oncogenic pathway-based therapy.
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PMID:Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes. 2130 75

In recent years, genome-wide association studies (GWAS) have identified more than 300 validated associations between genetic variants and risk of approximately 70 common diseases. A small number of rare variants with a frequency of usually less than 1% are associated with a strongly enhanced risk, such as genetic variants of TP53, RB1, BRCA1, and BRCA2. Only a very small number of SNPs (with a frequency of more that 1% of the rare allele) have effects of a factor of two or higher. Examples include APOE4 in Alzheimer's disease, LOXL1 in exfoliative glaucoma, and CFH in age-related macular degeneration. However, the majority of all identified SNPs have odds ratios between 1.1 and 1.5. In the case of urinary bladder cancer, all known SNPs that have been validated in sufficiently large populations are associated with odds ratios smaller than 1.5. These SNPs are located next to the following genes: MYC, TP63, PSCA, the TERT-CLPTM1L locus, FGFR3, TACC3, NAT2, CBX6, APOBEC3A, CCNE1, and UGT1A. It is likely that these moderate risk or "wimp SNPs" interact, and because of their high number, collectively have a strong influence on whether an individual will develop cancer or not. It should be considered that variants identified so far explain only approximately 5-10% of the overall inherited risk. Possibly, the remaining variance is due to an even higher number of SNPs with odds ratios smaller than 1.1. Recent studies have provided the following information: (1) The functions of genes identified as relevant for bladder cancer focus on detoxification of carcinogens, control of the cell cycle and apoptosis, as well as maintenance of DNA integrity. (2) Many novel SNPs are far away from the protein coding regions, suggesting that these SNPs are located on distant-acting transcriptional enhancers. (3) The low odds ratio of each individual bladder cancer-associated SNP is too low to justify reasonable preventive measures. However, if the recently identified SNPs interact, they may collectively result in a substantial risk that is of preventive relevance. In addition to the "novel SNPs" identified by the recent GWAS, at least 163 further variants have been reported in relation to bladder cancer, although they have not been consistently validated in independent case-control series. Moreover, given that only 60 of these 163 "old SNPs" are covered by the SNP chips used in the recent GWAS, there are in principle 103 published variants still awaiting validation or disproval. In future, besides identifying novel disease-associated rare variants by deep sequencing, it will also be important to understand how the already identified variants interact.
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PMID:Genetic variants in urinary bladder cancer: collective power of the "wimp SNPs". 2299 Jan 37

Larger imbalances on chromosome 4p in the form of deletions associated with Wolf-Hirschhorn syndrome (WHS) and duplications of chromosome 4p have a defined clinical phenotype. The critical region for both these clinical disorders has been narrowed based on the genotype-phenotype correlations. However, cryptic rearrangements in this region have been reported infrequently. We report on a male patient with a microduplication of chromosome 4p, who presents with findings of macrocephaly, irregular iris pigmentation-heterochromia, and preserved linear growth in addition to overlapping features of trisomy 4p such as seizures, delayed psychomotor development, and dysmorphic features including prominent glabella, low-set ears, and short neck. Using a high-density oligonucleotide microarray, we have identified a novel submicroscopic duplication involving dosage sensitive genes TACC3, FGFR3, and LETM1. The microduplication did not involve WHSC1 and WHSC2 which are considered in the critical region for WHS and trisomy 4p. This patient's presentation and genomic findings help further delineate clinical significance of re-arrangements in the 4p16 region without the involvement of WHS critical region.
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PMID:A novel 4p16.3 microduplication distal to WHSC1 and WHSC2 characterized by oligonucleotide array with new phenotypic features. 2181 51

The brain tumor glioblastoma multiforme (GBM) is among the most lethal forms of human cancer. Here, we report that a small subset of GBMs (3.1%; 3 of 97 tumors examined) harbors oncogenic chromosomal translocations that fuse in-frame the tyrosine kinase coding domains of fibroblast growth factor receptor (FGFR) genes (FGFR1 or FGFR3) to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively. The FGFR-TACC fusion protein displays oncogenic activity when introduced into astrocytes or stereotactically transduced in the mouse brain. The fusion protein, which localizes to mitotic spindle poles, has constitutive kinase activity and induces mitotic and chromosomal segregation defects and triggers aneuploidy. Inhibition of FGFR kinase corrects the aneuploidy, and oral administration of an FGFR inhibitor prolongs survival of mice harboring intracranial FGFR3-TACC3-initiated glioma. FGFR-TACC fusions could potentially identify a subset of GBM patients who would benefit from targeted FGFR kinase inhibition.
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PMID:Transforming fusions of FGFR and TACC genes in human glioblastoma. 2287 21

Currently, multiple myeloma (MM) patients are broadly grouped into a non-hyperdiploid (nh-MM) group, highly enriched for IgH translocations, or into a hyperdiploid (h-MM) group, which is typically characterized by trisomies of some odd-numbered chromosomes. We compared the micro RNA (miRNA) expression profiles of these two groups and we identified 16 miRNAs that were downregulated in the h-MM group, relative to the nh-MM group. We found that target genes of the most differentially expressed miRNAs are directly involved in the pathogenesis of MM; specifically, the inhibition of hsa-miR-425, hsa-miR-152 and hsa-miR-24, which are all downregulated in h-MM, leads to the overexpression of CCND1, TACC3, MAFB, FGFR3 and MYC, which are the also the oncogenes upregulated by the most frequent IgH chromosomal translocations occurring in nh-MM. Importantly, we showed that the downregulation of these specific miRNAs and the upregulation of their targets also occur simultaneously in primary cases of h-MM. These data provide further evidence on the unifying role of cyclin D pathways deregulation as the key mechanism involved in the development of both groups of MM. Finally, they establish the importance of miRNA deregulation in the context of MM, thereby opening up the potential for future therapeutic approaches based on this molecular mechanism.
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PMID:Downregulation of specific miRNAs in hyperdiploid multiple myeloma mimics the oncogenic effect of IgH translocations occurring in the non-hyperdiploid subtype. 2317 83

Fusion genes are chromosomal aberrations that are found in many cancers and can be used as prognostic markers and drug targets in clinical practice. Fusions can lead to production of oncogenic fusion proteins or to enhanced expression of oncogenes. Several recent studies have reported that some fusion genes can escape microRNA regulation via 3'-untranslated region (3'-UTR) deletion. We performed whole transcriptome sequencing to identify fusion genes in glioma and discovered FGFR3-TACC3 fusions in 4 of 48 glioblastoma samples from patients both of mixed European and of Asian descent, but not in any of 43 low-grade glioma samples tested. The fusion, caused by tandem duplication on 4p16.3, led to the loss of the 3'-UTR of FGFR3, blocking gene regulation of miR-99a and enhancing expression of the fusion gene. The fusion gene was mutually exclusive with EGFR, PDGFR, or MET amplification. Using cultured glioblastoma cells and a mouse xenograft model, we found that fusion protein expression promoted cell proliferation and tumor progression, while WT FGFR3 protein was not tumorigenic, even under forced overexpression. These results demonstrated that the FGFR3-TACC3 gene fusion is expressed in human cancer and generates an oncogenic protein that promotes tumorigenesis in glioblastoma.
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PMID:The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma. 2329 39


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