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)

Anaplastic large-cell lymphoma (ALCL) is frequently associated with the 2;5 translocation and expresses the NPM-ALK fusion protein, which possesses a constitutive tyrosine kinase activity. We analyzed SHP1 tyrosine phosphatase expression and activity in 3 ALK-positive ALCL cell lines (Karpas 299, Cost, and SU-DHL1) and in lymph node biopsies (n = 40). We found an inverse correlation between the level of NPM-ALK phosphorylation and SHP1 phosphatase activity. Pull-down and coimmunoprecipitation experiments demonstrated a SHP1/NPM-ALK association. Furthermore, confocal microscopy performed on ALCL cell lines and biopsy specimens showed the colocalization of the 2 proteins in cytoplasmic bodies containing Y664-phosphorylated NPM-ALK. Dephosphorylation of NPM-ALK by SHP1 demonstrated that NPM-ALK was a SHP1 substrate. Downregulation of SHP1 expression by RNAi in Karpas cells led to hyperphosphorylation of NPM-ALK, STAT3 activation, and increase in cell proliferation. Furthermore, SHP1 overexpression in 3T3 fibroblasts stably expressing NPM-ALK led to the decrease of NPM-ALK phosphorylation, lower cell proliferation, and tumor progression in nude mice. These findings show that SHP1 is a negative regulator of NPM-ALK signaling. The use of tissue microarrays revealed that 50% of ALK-positive ALCLs were positive for SHP1. Our results suggest that SHP1 could be a critical enzyme in ALCL biology and a potential therapeutic target.
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PMID:SHP1 tyrosine phosphatase negatively regulates NPM-ALK tyrosine kinase signaling. 1646 75

CCAAT/enhancer binding protein beta (C/EBPbeta) is one of a 6-member family of C/EBPs. These transcription factors are involved in the regulation of various aspects of cellular growth and differentiation. Although C/EBPbeta has important functions in B- and T-cell differentiation, its expression has not been well studied in lymphoid tissues. We, therefore, analyzed its expression by immunohistochemistry and Western blot in normal lymphoid tissues and in 248 well-characterized lymphomas and lymphoma cell lines. Nonneoplastic lymphoid tissues and most B-cell, T-cell, and Hodgkin lymphomas lacked detectable levels of C/EBPbeta. In contrast, most (40 of 45; 88%) cases of ALK-positive anaplastic large cell lymphoma (ALCL) strongly expressed C/EBPbeta. Western blot analysis confirmed C/EBPbeta expression in the ALK-positive ALCLs and demonstrated elevated levels of the LIP isoform, which has been associated with increased proliferation and aggressiveness in carcinomas. Transfection of Ba/F3 and 32D cells with NPM-ALK and a kinase-inhibitable modified NPM-ALK resulted in the induction of C/EBPbeta and demonstrated dependence on NPM-ALK kinase activity. In conclusion, we report the constitutive expression of C/EBPbeta in ALK-positive ALCL and show its relationship to NPM-ALK. We suggest that C/EBPbeta is likely to play an important role in the pathogenesis and unique phenotype of this lymphoma.
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PMID:NPM-ALK-dependent expression of the transcription factor CCAAT/enhancer binding protein beta in ALK-positive anaplastic large cell lymphoma. 1670 33

The aberrant fusion protein NPM-ALK plays an important pathogenetic role in ALK+ anaplastic large-cell lymphoma (ALCL). We previously demonstrated that Jak3 potentiates the activity of NPM-ALK. Jak3 activation is restricted to interleukins that recruit the common gamma chain (gammac) receptor, including IL-9. NPM-ALK was previously shown to promote widespread lymphomas in IL-9 transgenic mice by unknown mechanisms. We hypothesized that IL-9 plays an important role in ALK+ ALCL via Jak3 activation. Our studies demonstrate the expression of IL-9Ralpha and IL-9 in 3 ALK+ ALCL-cell lines and 75% and 83% of primary tumors, respectively. IL-9 was detected in serum-free culture medium harvested from ALK+ ALCL-cell lines, supporting autocrine release of IL-9. Treatment of these cells with an anti-IL-9-neutralizing antibody decreased pJak3 and its kinase activity, along with pStat3 and ALK kinase activity. These effects were associated with decreased cell proliferation and colony formation in soft agar and cell-cycle arrest. Evidence suggests that cell-cycle arrest can be attributed to up-regulation of p21 and down-regulation of Pim-1. Our results illustrate that IL-9/Jak3 signaling plays a significant role in the pathogenesis of ALK+ ALCL and that it represents a potential therapeutic target for treating patients with ALK+ ALCL.
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PMID:Autocrine release of interleukin-9 promotes Jak3-dependent survival of ALK+ anaplastic large-cell lymphoma cells. 1676 6

Previous studies showed that most cases of ALK(+) anaplastic large-cell lymphoma (ALK(+)ALCL) do not express SHP1, a tyrosine phosphatase and an important negative regulator for cellular signaling pathways such as that of JAK/STAT. To fully assess the biologic significance of loss of SHP1 in ALK(+)ALCL, we transfected SHP1 plasmids into 2 SHP1(-), ALK(+)ALCL cell lines, Karpas 299 and SU-DHL-1. After 24 hours of transfection, pJAK3 and pSTAT3 were decreased, and these changes correlated with down-regulation of STAT3 downstream targets including cyclin D3, mcl-1, and bcl-2. Expression of SHP1 in these 2 cell lines also resulted in marked decreases in the protein levels of JAK3 and NPM-ALK, and these effects were reversible by proteosome inhibitor MG132. Conversely, when SHP1 expression in SUP-M2 (a SHP1(+) ALK(+)ALCL cell line) was inhibited using siRNA, pSTAT3, pJAK3, JAK3, and NPM-ALK were all up-regulated. Coimmunoprecipitation studies showed that SHP1 was physically associated with JAK3 and NPM-ALK. SHP1 expression in Karpas 299 and SU-DHL-1 led to significant G(1) cell cycle arrest but not apoptosis. To conclude, loss of SHP1 contributes to the pathogenesis of ALK(+)ALCL by 2 mechanisms: (1) it leaves the tyrosine phosphorylation and activation of JAK3/STAT3 unchecked and (2) it decreases proteosome degradation of JAK3 and NPM-ALK.
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PMID:Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma. 1682 95

Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a chimeric protein expressed in a subset of cases of anaplastic large cell lymphoma (ALCL) for which constitutive expression represents a key oncogenic event. The ALK signaling pathway is complex and probably involves functional redundancy between various signaling substrates of ALK. Despite numerous studies on signaling mediators, the molecular mechanisms contributing to the distinct oncogenic features of NPM-ALK remain incompletely understood. The search for additional interacting partners of NPM-ALK led to the discovery of AUF1/hnRNPD, a protein implicated in AU-rich element (ARE)-directed mRNA decay. AUF1 was immunoprecipitated with ALK both in ALCL-derived cells and in NIH3T3 cells stably expressing NPM-ALK or other X-ALK fusion proteins. AUF1 and NPM-ALK were found concentrated in the same cytoplasmic foci, whose formation required NPM-ALK tyrosine kinase activity. AUF1 was phosphorylated by ALK in vitro and was hyperphosphorylated in NPM-ALK-expressing cells. Its hyperphosphorylation was correlated with increased stability of several AUF1 target mRNAs encoding key regulators of cell proliferation and with increased cell survival after transcriptional arrest. Thus, AUF1 could function in a novel pathway mediating the oncogenic effects of NPM-ALK. Our data establish an important link between oncogenic kinases and mRNA turnover, which could constitute a critical aspect of tumorigenesis.
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PMID:A "liaison dangereuse" between AUF1/hnRNPD and the oncogenic tyrosine kinase NPM-ALK. 1683 82

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

Anaplastic large cell lymphoma (ALCL) is a distinct subtype of non-Hodgkin's lymphoma. Most of ALCLs (85%) carry a chromosomal translocation involving different partners in the 5' portion, and the anaplastic lymphoma kinase (ALK) receptor kinase domain in the 3' portion. These translocations induce the ectopic expression of X-ALK proteins, thought to be involved in lymphomagenesis, through the dysregulation of cell proliferation and apoptotic pathways. In the present study, based on several ALK+ and ALK- ALCL cell lines and biopsy specimens, we showed that serpin A1, a secretory glycoprotein, was overexpressed in ALK+ ALCL cell lines and ALK+ tumors at both the transcriptional and translational levels. The crucial role of NPM-ALK in the regulation of serpin A1 expression was further demonstrated by using both ectopic expression and downregulation, by RNA interference, of the NPM-ALK oncogene. In addition, in ALK+ tumors, serpin A1 expression appeared to be correlated with the clinical status of the patients as the serpin A1 mRNA level was higher in patients presenting with extranodal dissemination. These data, together with the pattern of expression of serpin A1 we observed in ALK+ tumors, suggest that serpin A1 has an invasion-promoting effect in ALK+ ALCL.
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PMID:Serpin A1 is overexpressed in ALK+ anaplastic large cell lymphoma and its expression correlates with extranodal dissemination. 1690 Feb 11

Anaplastic large cell lymphoma (ALCL) is an entity of non-Hodgkin lymphomas (NHL) that often occurs in young children and adolescents. In the majority of cases, ALCL are of T-cell origin and contain the t(2;5)(p23;q35) leading to an NPM-ALK fusion or variant ALK translocations. In addition, there is an ALK-negative subtype of ALCL. The anaplastic lymphoid cell line TS1G6 established by interleukin (IL)-9 transfection of T-helper cells represents a murine model of this subtype. Here, we describe the cytogenetic features of this cell line using spectral karyotyping (SKY) and single-color fluorescence in situ hybridization (FISH). We show that TS1G6 cells exhibit a hypotetraploid karyotype with complex structural alterations. Several unbalanced translocations involved the chromosomal region 14E5, and different translocation partners, i.e. X?A6, 3A3 and 8A1. FISH analysis using a BAC clone containing c-myc confirmed the presence of six copies, but also demonstrated that two loci were irregularly located, indicating that additional intrachromosomal rearrangements had occurred. Moreover, a duplication of the region XF2 approximately 3 was identified. Furthermore, six chromosomes 15 were found, representing a trisomy 15 in a tetraploid chromosome complement, indicating an altered gene dosage of the oncogene c-myc located in region 15D3.
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PMID:Cytogenetic characteristics of a murine in vitro model for the human anaplastic large cell lymphoma (ALCL). 1695 69

Chromosomal translocation t(2;5) and the resulting fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) are detected in 50% to 70% of anaplastic large cell lymphoma (ALCL), which is a T/null cell non-Hodgkin's lymphoma showing anaplastic morphology with cell surface expression of CD30. Because aberrant CD30 expression was also observed in the T-cell lymphoma derived from lineage-specific NPM-ALK transgenic mice, we tested the hypothesis that there might be a functional relationship between the two neoplastic-related proteins: NPM-ALK and CD30. In this study, we used the RNA interference method to modulate NPM-ALK protein expression in ALCL-derived, t(2;5)-positive Karpas 299 cells. We observed decreased CD30 expression when NPM-ALK was repressed. Further analysis suggested that JunB functioned as the mediator of NPM-ALK-derived CD30 transcriptional regulation. The NPM-ALK-repressed cells, which had low CD30 expression, were characterized with lower cell proliferation compared with cells in the control group, suggesting that altered CD30 expression may correlate to NPM-ALK-mediated tumor cell growth inhibition. Combination of NPM-ALK repression and CD30 ligand leads to significantly increased tumor cell growth inhibition compared with one method alone, suggesting its potential application for ALCL-specific cancer treatment.
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PMID:The expression of CD30 in anaplastic large cell lymphoma is regulated by nucleophosmin-anaplastic lymphoma kinase-mediated JunB level in a cell type-specific manner. 1698 41

The nucleophosmin (NPM1) gene encodes for a multifunctional nucleocytoplasmic shuttling protein that is localized mainly in the nucleolus. NPM1 mutations occur in 50% to 60% of adult acute myeloid leukemia with normal karyotype (AML-NK) and generate NPM mutants that localize aberrantly in the leukemic-cell cytoplasm, hence the term NPM-cytoplasmic positive (NPMc+ AML). Cytoplasmic NPM accumulation is caused by the concerted action of 2 alterations at mutant C-terminus, that is, changes of tryptophan(s) 288 and 290 (or only 290) and creation of an additional nuclear export signal (NES) motif. NPMc+ AML shows increased frequency in adults and females, wide morphologic spectrum, multilineage involvement, high frequency of FLT3-ITD, CD34 negativity, and a distinct gene-expression profile. Analysis of mutated NPM has important clinical and pathologic applications. Immunohistochemical detection of cytoplasmic NPM predicts NPM1 mutations and helps rationalize cytogenetic/molecular studies in AML. NPM1 mutations in absence of FLT3-ITD identify a prognostically favorable subgroup in the heterogeneous AML-NK category. Due to their frequency and stability, NPM1 mutations may become a new tool for monitoring minimal residual disease in AML-NK. Future studies should focus on clarifying how NPM mutants promote leukemia, integrating NPMc+ AML in the upcoming World Health Organization leukemia classification, and eventually developing specific antileukemic drugs.
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PMID:Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. 1700 39


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