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)

More than half of anaplastic large-cell lymphomas (ALCLs) have a chromosomal translocation t(2;5) that leads to the expression of a hybrid protein composed of the nucleolar phosphoprotein nucleophosmin (NPM) and the anaplastic lymphoma kinase (ALK) that exhibits an unregulated tyrosine kinase activity. We have previously identified PLC-gamma as a crucial downstream signaling molecule of NPM-ALK that contributes to its mitogenic potential. Here, we show that NPM-ALK recruits the C-terminal SH2 domain of the phosphatidylinositol 3-kinase (PI 3kinase) p85 subunit. PI 3-kinase assays revealed that the kinase is activated by NPM-ALK in vivo, in turn activating PKB/Akt in NPM-ALK-expressing cells. The use of 2 specific PI 3-kinase inhibitors, wortmannin and LY294002, demonstrated the requirement of PI 3-kinase for the growth of NPM-ALK-transformed cell lines, as well as a cell line established from a patient with ALCL. Primary murine bone marrow retrovirally transduced with NPM-ALK showed a transformed phenotype that was reversible on treatment with PI 3-kinase inhibitors. Flow cytometric analysis revealed that wortmannin-treated NPM-ALK-transformed cell lines underwent apoptosis. Furthermore, apoptosis induced by overexpression of the proapoptotic molecule Bad could be partially blocked by the overexpression of NPM-ALK. Thus, NPM-ALK activates the antiapoptotic PI 3-kinase/Akt pathway, which likely contributes to the molecular pathogenesis of ALCL. (Blood. 2000;96:4319-4327)
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PMID:Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. 1111 Jul 8

The NPM/ALK fusion gene, formed by the t(2;5) translocation in a subset of anaplastic large cell lymphomas, encodes a Mr 75,000 hybrid protein that contains the NH2-terminal portion of the nucleolar phosphoprotein nucleophosmin (NPM) joined to the entire cytoplasmic portion of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK). NPM/ALK encodes a constitutively activated tyrosine kinase that belongs to the family of tyrosine kinases activated by chromosomal translocations. Our studies showed that NPM/ALK, similar to other members of this family, activates phosphatidylinositol 3-kinase (PI3K) and its downstream effector, serine/threonine kinase (Akt). PI3K was found in complex with NPM/ALK. Both PI3K and Akt kinase were permanently activated in NPM/ALK-transfected BaF3 murine hematopoietic cells and in NPM/ALK-positive, but not in NPM/ALK-negative, patient-derived anaplastic large cell lymphoma cell lines. In addition, Akt was phosphorylated/activated in protein samples isolated from four patients diagnosed with ALK-positive T/null-cell lymphomas. The PI3K inhibitors wortmannin and LY294002 induced apoptosis in NPM/ALK+ cells but exerted only minor effects on the control BaF3 parental cells and peripheral blood mononuclear cells stimulated by growth factors. Furthermore, retroviral infection of NPM/ALK+ BaF3 cells with a dominant-negative PI3K mutant (delta p85) or a dominant-negative Akt mutant (K179M) inhibited proliferation and clonogenic properties of the infected cells. Finally, the Akt mutant (K179M) suppressed the tumorigenicity of NPM/ALK-transfected BaF3 cells injected into syngeneic mice. In conclusion, our data indicate that NPM/ALK constitutively activates the PI3K-Akt pathway and that this pathway plays an important role in the NPM/ALK-mediated malignant transformation.
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PMID:Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis. 1128 Jul 86

The majority of anaplastic large cell lymphomas (ALCL) are associated with chromosomal abnormalities affecting the anaplastic lymphoma kinase (ALK) gene which result in the expression of hybrid ALK fusion proteins in the tumor cells. In most of these tumors, the hybrid gene comprises the 5' region of nucleophosmin (NPM) fused in frame to the 3' portion of ALK, resulting in the expression of the chimeric oncogenic tyrosine kinase NPM-ALK. However, other variant rearrangements have been described in which ALK fuses to a partner other than NPM. Here we have identified the moesin (MSN) gene at Xq11-12 as a new partner of ALK in a case of ALCL which exhibited a distinctive membrane-restricted pattern of ALK labeling. The hybrid MSN-ALK protein had a molecular weight of 125 kd and contained an active tyrosine kinase domain. The unique membrane staining pattern of ALK is presumed to reflect association of moesin with cell membrane proteins. In contrast to other translocations involving the ALK gene, the ALK breakpoint in this case occurred within the exonic sequence coding for the juxtamembrane portion of ALK. Identification of the genomic breakpoint confirmed the in-frame fusion of the whole MSN intron 10 to a 17 bp shorter juxtamembrane exon of ALK. The breakpoint in der(2) chromosome showed a deletion, including 30 bp of ALK and 36 bp of MSN genes. These findings indicate that MSN may act as an alternative fusion partner for activation of ALK in ALCL and provide further evidence that oncogenic activation of ALK may occur at different intracellular locations.
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PMID:Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma. 1131 Aug 34

Anaplastic large cell lymphoma (ALCL) is frequently associated with the t(2;5)(p23;q35) translocation. It creates a NPM-ALK fusion gene, fusing the anaplastic lymphoma kinase (ALK) gene (2p23) and the nucleophosmin (NPM) gene (5q35). Other rearrangements involving the ALK gene have recently been shown to be associated with ALCL, among which the ATIC-ALK rearrangement resulting from the inv(2)(p23q35) translocation is probably the most recurrent. The aims of the present study were to investigate the presence of NPM-ALK and ATIC-ALK fusion genes in ALCL, using a real-time 5' exonuclease-based reverse-transcription polymerase chain reaction (RT-PCR). This sensitive technique was also applied to investigate whether both fusion genes might be detected in Hodgkin's disease cases and in reactive lymphoid tissue. Results of the RT-PCR were compared to ALK immunostaining, cytogenetics, and fluorescence in situ hybridization (FISH) results. RT-PCR detected the NPM-ALK and ATIC-ALK fusions at high levels in 8 and 3 of a total of 13 ALK-positive ALCL cases. One ALK-positive ALCL case was negative for both fusion genes analyzed but revealed a new ALK-related translocation t(2;17)(p23;q25) by cytogenetic and FISH analysis. In addition, of the eight ALK-positive ALCL cases that were strongly positive for the NPM-ALK fusion, three cases also showed the presence of the ATIC-ALK fusion, although at much lower levels. Similarly, out of the three strongly positive ATIC-ALK cases, one case was positive for the NPM-ALK fusion, at low levels. Finally, the NPM-ALK and the ATIC-ALK fusions were detected, at equally low levels, respectively in 13 and 5 ALK-negative ALCL cases, in 11 and 5 Hodgkin's disease cases and in 20 and 1 non-neoplastic lymphoid tissues. The distinction between the high- and low-level detection was confirmed by relative quantitative RT-PCR for a representative number of cases. Of interest is the fact that the high-level detection coincided with the presence of ALK gene rearrangement detected by cytogenetics and FISH and may reflect a central role of the transcript in the oncogenic mechanism of ALK-positive ALCL. Low-level detection is not supported by cytogenetics and FISH, presumably due to the presence of the transcripts in only a small minority of normal cells not detectable by these techniques. Our findings demonstrate that NPM-ALK and ATIC-ALK fusion transcripts may be detected in conditions other than ALK-positive ALCL including reactive lymphoid tissues, although at low levels, suggesting the presence of the transcripts in normal (bystander) cells. Moreover, they suggest that the ALK gene rearrangement by itself might be insufficient to induce tumor formation. They further question the validity of quantitative real-time RT-PCR for monitoring minimal residual disease in ALCL. Finally, the newly identified translocation t(2;17)(p23;q25) can be added to the list of ALK gene rearrangements occurring in ALK-positive ALCL.
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PMID:The NPM-ALK and the ATIC-ALK fusion genes can be detected in non-neoplastic cells. 1139 96

An inverse correlation between p27(Kip1) expression and proliferation has been recently established in tissues derived from human lymphomas. The nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)/phospholipase C-gamma (PLCgamma) complex also appears to play an important role in cell proliferation and malignant transformation of anaplastic large cell lymphoma (ALCL). In this study, we report that SUDHL-1 and KARPAS 299 ALCL-derived cell lines present different sensitivity to the antiproliferative effect of recombinant adenovirus-mediated p27(Kip1) expression or to serum-starvation in culture media. The results indicate that exogenous p27(Kip1) may interact with the NPM-ALK/PLCgamma pathway in SUDHL-1 but not in KARPAS 299 cells. This interaction correlates with changes in cell cycle and cell morphology observed mainly in SUDHL-1 cells. The percentage of SUDHL-1 cells in S phase declines, whereas it is almost unchanged in KARPAS 299 cells as compared to the controls after 96 h of infection with the recombinant adenovirus. Furthermore KARPAS 299 cells are resistant to serum-starvation due to deficient p27(Kip1)-upregulation and G1 arrest, whereas SUDHL-1 cells respond with increased G1 phase and p27(Kip1)-upregulation after 48 h of serum-starvation. Both cell lines express appropriate variation of levels of cyclins E and A, and Rb-phosphorylation as expected by growing them in culture media with different FBS content. Although both cell lines express cyclin D2, SUDHL-1 cells only present high level of cyclin D3. Moreover SUDHL-1 cells express high level of PTEN and the PKB/Akt pathway is constitutively activated in both cell lines. Lastly SUDHL-1 cells show higher levels of phosphotyrosine-containing proteins that is correlated with a higher NPM-ALK-associated autophosphorylation activity compared to KARPAS 299 cells. Our study clearly identifies some of the biochemical differences that may explain the difference in sensitivity to antiproliferative stimuli shown by two cell lines derived from the same type of lymphoma.
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PMID:Biochemical differences between SUDHL-1 and KARPAS 299 cells derived from t(2;5)-positive anaplastic large cell lymphoma are responsible for the different sensitivity to the antiproliferative effect of p27(Kip1). 1149 42

The NPM/ALK fusion gene, formed by the t(2;5) translocation in anaplastic large-cell lymphoma, encodes a M(r) 75,000 hybrid protein that containsthe amino-terminal portion of the nucleolar phosphoprotein nucleophosmin(NPM) joined to the entire cytoplasmic portion of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK). NPM/ALK encodes a constitutively activated tyrosine kinase that belongs to the family of tyrosine kinases activated by chromosomal translocation. Our studies show that NPM/ALK, similar to other members of this family, activates signal transducer and activator of transcription 5 (STAT5) and that this activation is essential for lymphomagenesis. NPM/ALK-mediated activation of STAT5 was demonstrated by detection of: (a) constitutive tyrosine phosphorylation and enhanced DNA binding ability of STAT5 in NPM/ALK-transformed cells; and (b) NPM/ALK-dependent stimulation of STAT5-mediated transactivation of the beta-casein promoter. Retroviral infection of NPM/ALK+ cells with a dominant-negative STAT5B mutant (STAT5-DNM) inhibited the antiapoptotic activity of NPM/ALK in growth factor and serum-free medium. In addition, STAT5-DNM inhibited proliferation and diminished the clonogenic properties of NPM/ALK-positive cells. Finally, SCID mice injected with NPM/ALK+ cells infected with a virus carrying STAT5-DNM survived significantly longer than mice inoculated with NPM/ALK+ cells infected with the empty virus. Necropsy identified a widespread ALK+ lymphoma in lymph nodes and liver of the affected animals. Together, our data indicate that NPM/ALK-induced activation of STAT5 may play an important role in NPM/ALK-mediated lymphomagenesis.
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PMID:Role of signal transducer and activator of transcription 5 in nucleophosmin/ anaplastic lymphoma kinase-mediated malignant transformation of lymphoid cells. 1152 49

The anaplastic lymphoma kinase (ALK) gene fuses to the nucleophosmin (NPM) gene as a result of a (2;5) translocation associated with a subtype of human lymphoma (initially designated anaplastic large cell lymphoma [ALCL] or Ki-1/CD30-positive lymphoma). The immunocytochemical detection of NPM-ALK (and proteins encoded by other ALK fusion genes) has allowed the definition of a tumor entity, "ALK-positive lymphoma" (which shows only partial overlap with pathologists' diagnosis of ALCL), to be defined and is invaluable in distinguishing this disease from ALK-negative large cell lymphomas. Eight variant ALK fusion proteins have been identified. Some are expressed only in ALCL, some are found only in the nonhematopoietic neoplasm inflammatory myofibroblastic tumor (IMT), and some are present in both types of malignancy. The ALK gene is silent in adult tissues except for restricted sites within the nervous system (consequently, patients with ALK-positive lymphoma produce antibodies to the ALK protein) but is expressed in some neuroblastomas and rhabdomyosarcomas. Biochemical studies suggest an anti-apoptotic function of NPM-ALK, and this may contribute to oncogenesis. Although ALK-positive lymphomas have a generally good prognosis, new therapeutic regimens are still needed for patients whose disease is refractory to conventional treatment.
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PMID:Anaplastic lymphoma kinase proteins and malignancy. 1156 Nov 61

Anaplastic large-cell lymphoma (ALCL) comprises a group of non-Hodgkin's lymphomas (NHLs) that were first described in 1985 by Stein and co-workers and are characterized by the expression of the CD30/Ki-1 antigen (Stein et al., 1985). Approximately half of these lymphomas are associated with a typical chromosomal translocation, t(2;5)(p23;q35). Much confusion about the exact classification and clinicopathological features of this subgroup of NHL was clarified with the identification of NPM-ALK (nucleophosmin-anaplastic lymphoma kinase) as the oncogene created by the t(2;5) (Morris et al., 1994). With the discovery of NPM-ALK as the specific lymphoma gene mutation, this NHL subtype could be redefined on the molecular level. This achievement was enhanced by the availability of specific antibodies that recognize ALK fusion proteins in paraffin-embedded lymphoma tissues. Several excellent recent reviews have summarized the histopathological and molecular findings of ALCL and their use in the classification of this lymphoma entity (Anagnostopoulos and Stein, 2000; Benharroch et al., 1998; Drexler et al., 2000; Foss et al., 2000; Gogusev and Nezelof, 1998; Kadin and Morris, 1998; Ladanyi, 1997; Morris et al., 2001; Shiota and Mori, 1996; Skinnider et al., 1999; Stein et al., 2000). This review will focus on the molecular function and signal transduction pathways activated by ALK fusion oncogenes, with recent advances and possible clinical implications to be discussed.
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PMID:Translocations involving anaplastic lymphoma kinase (ALK). 1160 14

Anaplastic large cell lymphomas (ALCLs) are frequently associated with the t(2;5)(p23;q35) translocation, leading to the expression of NPM-ALK, a fusion protein linking nucleophosmin and anaplastic lymphoma kinase, a receptor tyrosine kinase. In ALCLs, dimerization of NPM-ALK leads to constitutive autophosphorylation and activation of the kinase, necessary for NPM-ALK oncogenicity. To investigate whether NPM-ALK, like other oncogenic tyrosine kinases, can inhibit drug-induced apoptosis, we permanently transfected NPM-ALK into Jurkat T-cells. As in ALCLs, NPM-ALK was expressed as a constitutively kinase-active 80 kDa protein, and could be detected by immunocytochemistry in nucleoli, nuclei and cytoplasm. Doxorubicin-induced apoptosis (assessed by cell morphology and annexin V-FITC binding) was significantly inhibited in two independent NPM-ALK-expressing clones (5.2+/-1.8 and 7.5+/-0.8% apoptosis), compared to control vector-transduced cells (36+/-6.7%). Similar results were observed with etoposide. In contrast, Fas-induced apoptosis was not inhibited. Cytochrome c release into the cytosol was delayed in doxorubicin-, but not anti-Fas-treated transfectant cells, indicating that apoptosis inhibition occurred upstream of mitochondrial events. Using NPM-ALK mutants, we demonstrated that inhibition of drug-induced apoptosis: (1) requires functional kinase activity, (2) does not involve phospholipase C-gamma, essential for NPM-ALK-mediated mitogenicity and (3) appears to be phosphoinositide 3-kinase independent, despite a strong Akt/PKB activation observed in wild type NPM-ALK-expressing cells. These results suggest that the NPM-ALK antiapoptotic and mitogenic pathways are distinct.
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PMID:Expression of the oncogenic NPM-ALK chimeric protein in human lymphoid T-cells inhibits drug-induced, but not Fas-induced apoptosis. 1170 68

In 1985, Stein et al demonstrated the expression of the lymphoid activation antigen CD30/Ki by neoplastic cells. Fifteen years after the first description, anaplastic large-cell lymphomas (ALCL) are now thought to be a heterogeneous group in terms of their clinical, morphologic, phenotypic, cytogenetic, and molecular biology features. However, on the basis of a specific genetic anomaly and expression of a chimeric nucleophosmin anaplastic lymphoma kinase (NPM-ALK) protein and its variants, a distinct clinicopathologic entity defined as "ALK-positive lymphoma" or "ALKoma" can be recognized. Based on molecular and clinical criteria, 3 entities of primary ALCL can be identified: primary systemic ALK positive, primary systemic ALK negative, and primary cutaneous ALCL. This review focuses on advances in the knowledge of primary systemic ALCL biology and discusses therapeutic approaches based on ALK expression. The presence of this protein appears to be an important prognostic factor and, combined with an age-adjusted International Prognostic Index, could allow researchers to design more specific clinical trials aimed at finding new, more efficacious and less toxic treatments.
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PMID:Primary systemic anaplastic large-cell lymphoma (CD30+): advances in biology and current therapeutic approaches. 1170 67


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