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)

The idiopathic hypereosinophilic syndrome (HES) has remained for a long time a diagnosis of exclusion. Differential diagnosis between the HES and the related chronic eosinophilic leukemia (CEL) relied on the identification of signs of clonality that allowed, when present, the reclassification of patients as CEL. Recently, a new acquired mutation was described in approximately 50% of the HES/CEL patients: a cryptic deletion on chromosome band 4q12 generating a FIP1L1-PDGFRA fusion gene. According to the World Health Organization classification, this clonal abnormality has been proposed as a new surrogate marker for chronic eosinophilic leukemia diagnosis. Fluorescence in situ hybridization and reverse transcriptase-polymerase chain reaction protocols were developed for an accurate del(4)(q12q12) and FIP1L1-PDGFRA fusion gene detection. Here, we report a patient with a rare FIP1L1 intron 16 breakpoint located outside of the reported FIP1L1 breakpoint region (ie, from FIP1L1 introns 9 to 13). This case illustrates the risk of false-negative results with diagnostic procedures that do not take into account the occurrence of rare FIP1L1 breakpoints. As targeted therapy with tyrosine kinase inhibitors has dramatically changed the prognosis of FIP1L1-PDGFRA (+) CEL, false-negative results could hamper accurate diagnosis and treatment.
...
PMID:A case of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia with a rare FIP1L1 breakpoint. 1759 42

Many substrates of ERK2 contain a D-site, a sequence recognized by ERK2 that is used to promote catalysis. Despite lacking a canonical D-site, the substrate Ets-1 is displaced from ERK2 by peptides containing one. This suggests that Ets-1 may contain a novel or cryptic D-site. To investigate this possibility a protein footprinting strategy was developed to elucidate ERK2-ligand interactions. Using this approach, single cysteine reporters were placed in the D-recruitment site (DRS) of ERK2 and the resulting ERK2 proteins subjected to alkylation by iodoacetamide. The ability of residues 1-138 of Ets-1 to protect the cysteines from alkylation was determined. The pattern of protection observed is consistent with Ets-1 occupying a hydrophobic binding site within the DRS of ERK2. Significantly, a peptide derived from the D-site of Elk-1, which is known to bind the DRS, exhibits a similar pattern of cysteine protection. This analysis expands the repertoire of the DRS on ERK2 and suggests that other targeting sequences remain to be identified. Furthermore, cysteine-footprinting is presented as a useful way to interrogate protein-ligand interactions at the resolution of a single amino acid.
...
PMID:Expanding the repertoire of an ERK2 recruitment site: cysteine footprinting identifies the D-recruitment site as a mediator of Ets-1 binding. 1765 91

Hypereosinophilic syndromes (HES) are a heterogeneous group of disorders characterized by marked peripheral blood and tissue eosinophilia resulting in organ damage. Recent advances in molecular biology have led to the identification of a FIP1L1-PDGFRA fusion gene as a recurrent abnormality in some patients with HES. This fusion gene results from a cryptic 4q12 interstitial deletion involving an 800 kb region. Recent reports indicate that this subtype of HES is imatinib responsive with rapid and complete haematological remissions. Here we report two patients successfully treated with imatinib.
...
PMID:[Efficacy of imatinib in FIP1L1-PDGFRA positive hypereosinophilic syndrome]. 1803 6

Patients with an apparently balanced translocation and an abnormal phenotype may carry a cryptic deletion/duplication at their translocation breakpoints that may explain their abnormalities. Using microarray CGH (aCGH) and gene expression arrays we studied a child with t(15;22)(q26.1;q11.2), developmental delay and mild dysmorphic features. A high density aCGH study with 244,000 oligo probes demonstrated a 3.3 Mb deletion immediately adjacent to the 15q breakpoint. Gene expression studies with 44,000 oligos displayed an approximately 50% reduction of the expression of IGF1R gene that was translocated to the der(22). There are 18 known or hypothetical protein coding genes within the deleted region according to UniProt, RefSeq, and GenBank mRNA (UCSC HG17, May 2004). Although two of these genes, RGMA and ST8SIA2, play an important role in neural development, the mild phenotype of our patient indicates that loss of one copy of these genes may not be critical developmentally. The 50% reduction of IGF1R expression could be responsible for the growth deficiency in the patient. Reviewing the few 15q26 microdeletion cases that have been characterized by aCGH, we discovered that deletion of the segment including distal 15q26.2 to the proximal part of 15q26.3 is associated with severe phenotypes. Our experience demonstrates that high-density oligonucleotide-based aCGH is a quick and precise way to identify cryptic copy number changes in "balanced translocations." Expression studies can also add valuable information regarding gene expression changes due to a chromosomal rearrangement. Both approaches can assist in the elucidation of the etiology of unexplained phenotypic differences in cases such as this one.
...
PMID:Characterization of a cryptic 3.3 Mb deletion in a patient with a "balanced t(15;22) translocation" using high density oligo array CGH and gene expression arrays. 1820 77

Patients with acute myeloid leukemia (AML) harboring three or more acquired chromosome aberrations in the absence of the prognostically favorable t(8;21)(q22;q22), inv(16)(p13q22)/t(6;16)(p13;q22), and t(15;17)(q22;q21) aberrations form a separate category - AML with a complex karyotype. They constitute 10% to 12% of all AML patents, with the incidence of complex karyotypes increasing with the more advanced age. Recent studies using molecular-cytogenetic techniques (spectral karyotyping [SKY], multiplex fluorescence in situ hybridization [M-FISH]) and array comparative genomic hybridization (a-CGH) considerably improved characterization of previously unidentified, partially identified, or cryptic chromosome aberrations, and allowed precise delineation of genomic imbalances. The emerging nonrandom pattern of abnormalities includes relative paucity, but not absence, of balanced rearrangements (translocations, insertions, or inversions), predominance of aberrations leading to loss of chromosome material (monosomies, deletions, and unbalanced translocations) that involve, in decreasing order, chromosome arms 5q, 17p, 7q, 18q, 16q, 17q, 12p, 20q, 18p, and 3p, and the presence of recurrent, albeit less frequent and often hidden (in marker chromosomes and unbalanced translocations) aberrations leading to overrepresentation of segments from 8q, 11q, 21q, 22q, 1p, 9p, and 13q. Several candidate genes have been identified as targets of genomic losses, for example, TP53, CTNNA1, NF1, ETV6, and TCF4, and amplifications, for example, ERG, ETS2, APP, ETS1, FLI1, MLL, DDX6, GAB2, MYC, TRIB1, and CDX2. Treatment outcomes of complex karyotype patients receiving chemotherapy are very poor. They can be improved to some extent by allogeneic stem cell transplantation in younger patients. It is hoped that better understanding of genomic alterations will result in identification of novel therapeutic targets and improved prognosis in patients with complex karyotypes.
...
PMID:Cytogenetic, molecular genetic, and clinical characteristics of acute myeloid leukemia with a complex karyotype. 1869 87

Carcinoma ex pleomorphic adenoma (Ca-ex-PA) is an epithelial malignancy developing within a benign salivary gland pleomorphic adenoma (PA). Here we have used genome-wide, high-resolution array-CGH, and fluorescence in situ hybridization to identify genes amplified in double min chromosomes and homogeneously staining regions in PA and Ca-ex-PA and to identify additional genomic imbalances characteristic of these tumor types. Ten of the 16 tumors analyzed showed amplification/gain of a 30-kb minimal common region, consisting of the 5'-part of HMGA2 (encoding the three DNA-binding domains). Coamplification of MDM2 was found in nine tumors. Five tumors had cryptic HMGA2-WIF1 gene fusions with amplification of the fusion oncogene in four tumors. Expression analysis of eight amplified candidate genes in 12q revealed that tumors with amplification/rearrangement of HMGA2 and MDM2 had significantly higher expression levels when compared with tumors without amplification. Analysis of individual HMGA2 exons showed that the expression of exons 3-5 were substantially reduced when compared with exons 1-2 in 9 of 10 tumors with HMGA2 activation, indicating that gene fusions and rearrangements of HMGA2 are common in tumors with amplification. In addition, recurrent amplifications/gains of 1q11-q32.1, 2p16.1-p12, 8q12.1, 8q22-24.1, and 20, and losses of 1p21.3-p21.1, 5q23.2-q31.2, 8p, 10q21.3, and 15q11.2 were identified. Collectively, our results identify HMGA2 and MDM2 as amplification targets in PA and Ca-ex-PA and suggest that amplification of 12q genes (in particular MDM2), deletions of 5q23.2-q31.2, gains of 8q12.1 (PLAG1) and 8q22.1-q24.1 (MYC), and amplification of ERBB2 may be of importance for malignant transformation of benign PA.
...
PMID:High-resolution genomic profiling of adenomas and carcinomas of the salivary glands reveals amplification, rearrangement, and fusion of HMGA2. 1882 59

The FIP1L1-PDGFRA fusion gene is a recurrent molecular abnormality in patients with eosinophilia-associated myeloproliferative neoplasms. We characterized FIP1L1-PDGFRA junction sequences from 113 patients at the mRNA (n=113) and genomic DNA (n=85) levels. Transcript types could be assigned in 109 patients as type A (n=50, 46%) or B (n=47, 43%), which were created by cryptic acceptor splice sites in different introns of FIP1L1 (type A) or within PDGFRA exon 12 (type B). We also characterized a new transcript type C (n=12, 11%) in which both genomic breakpoints fell within coding sequences creating a hybrid exon without use of a cryptic acceptor splice site. The location of genomic breakpoints within PDGFRA and the availability of AG splice sites determine the transcript type and restrict the FIP1L1 exons used for the creation of the fusion. Stretches of overlapping sequences were identified at the genomic junction site, suggesting that the FIP1L1-PDGFRA fusion is created by illegitimate non-homologous end-joining. Statistical analyses provided evidence for clustering of breakpoints within FIP1L1 that may be related to DNA- or chromatin-related structural features. The variability in the anatomy of the FIP1L1-PDGFRA fusion has important implications for strategies to detect the fusion at diagnosis or for monitoring response to treatment.
...
PMID:The molecular anatomy of the FIP1L1-PDGFRA fusion gene. 1898 51

Despite being implicated as a mechanism driving gastrulation and body axis elongation in mouse embryos, the cellular mechanisms underlying mammalian convergent extension (CE) are unknown. Here we show, with high-resolution time-lapse imaging of living mouse embryos, that mesodermal CE occurs by mediolateral cell intercalation, driven by mediolaterally polarized cell behavior. The initial events in the onset of CE are mediolateral elongation, alignment and orientation of mesoderm cells as they exit the primitive streak. This cell shape change occurs prior to, and is required for, the subsequent onset of mediolaterally polarized protrusive activity. In embryos mutant for PTK7, a novel cell polarity protein, the normal cell elongation and alignment upon leaving the primitive streak, the subsequent polarized protrusive activity, and CE and axial elongation all failed. The mesoderm normally thickens and extends, but on failure of convergence movements in Ptk7 mutants, the mesoderm underwent radial intercalation and excessive thinning, which suggests that a cryptic radial cell intercalation behavior resists excessive convergence-driven mesodermal thickening in normal embryos. When unimpeded by convergence forces in Ptk7 mutants, this unopposed radial intercalation resulted in excessive thinning of the mesoderm. These results show for the first time the polarized cell behaviors underlying CE in the mouse, demonstrate unique aspects of these behaviors compared with those of other vertebrates, and clearly define specific roles for planar polarity and for the novel planar cell polarity gene, Ptk7, as essential regulators of mediolateral cell intercalation during mammalian CE.
...
PMID:PTK7 is essential for polarized cell motility and convergent extension during mouse gastrulation. 1943 96

Ror2 is an orphan receptor tyrosine kinase with expression normally restricted to early stages of development. However, emerging evidence has placed aberrantly expressed Ror2, leading to an invasive phenotype, in several cancers including renal cell carcinoma (RCC). Although Ror2 is currently identified as up-regulated in an assortment of cancers, neither the regulatory role or mechanism of action have been delineated. We sought to place Ror2 in the most commonly mutated pathway of RCC, the loss of the tumor suppressor von Hippel-Lindau (VHL), which causes hypoxia-inducible factor (HIF)-1alpha and -2alpha stabilization and the transcriptional activation of a broad repertoire of response genes. We found that Ror2 was indeed associated with the pVHL loss in RCC as well as with VHL somatic mutations tightly coordinated with the induction of RCC. Additionally, knockdown and rescue analysis of HIF expression suggests that Ror2 is dependent on pathologic stabilization of either HIF-1alpha or HIF-2alpha. Subsequent evaluation of the ROR2 promoter suggests that HIF-2alpha and its dimerization partner, aryl hydrocarbon nuclear transferase localize to the ROR2 promoter via a cryptic transcriptional element. This data substantiates a unique regulation pattern for Ror2 in the VHL-HIF axis that has the potential to be applied to other cancer etiologies.
...
PMID:Identification of Ror2 as a hypoxia-inducible factor target in von Hippel-Lindau-associated renal cell carcinoma. 2018 29

We report 2 ALK-positive large B-cell lymphoma cases showing granular cytoplasmic and cytoplasmic/nuclear ALK immunostaining in which cryptic ALK rearrangements were identified by fluorescent in situ hybridization and molecular analysis. In the first case, the ALK-involving t(2;3)(p23;q27) masked the cryptic SEC31A-ALK fusion generated by an insertion of the 5' end of SEC31A (4q21) upstream of the 3' end of ALK. This rearrangement was associated with loss of the 5' end of ALK and duplication of SEC31A-ALK on der(20). In the second case with complex rearrangements of both chromosomes 2, a submicroscopic NPM1-ALK fusion created by insertion of the 3' end of ALK into the NPM1 locus was evidenced. Further studies of SEC31A-ALK showed that this variant fusion transforms IL3-dependent Ba/F3 cells to growth factor independence, and that the ALK inhibitor TAE-684 reduces cell proliferation and kinase activity of SEC31A-ALK and its downstream effectors ERK1/2, AKT, STAT3 and STAT5.
...
PMID:ALK-positive large B-cell lymphomas with cryptic SEC31A-ALK and NPM1-ALK fusions. 2020 48


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

---