Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumor suppressor protein p53 is activated by distinct cellular stresses including radiation, hypoxia, type I interferon, and DNA/RNA virus infection. The transactivation domain of p53 contains a phosphorylation site at Ser20 whose modification stabilizes the binding of the transcriptional co-activator p300 and whose mutation in murine transgenics induces B-cell lymphoma. Although the checkpoint kinase CHK2 is implicated in promoting Ser20 site phosphorylation after irradiation, the enzyme that triggers this phosphorylation after DNA viral infection is undefined. Using human herpesvirus 6B (HHV-6B) as a virus that induces Ser20 site phosphorylation of p53 in T-cells, we sought to identify the kinase responsible for this virus-induced p53 modification. The p53 Ser20 kinase was fractionated and purified using cation, anion, and dye-ligand exchange chromatography. Mass spectrometry identified casein kinase 1 (CK1) and vaccinia-related kinase 1 (VRK1) as enzymes that coeluted with virus-induced Ser20 site kinase activity. Immunodepletion of CK1 but not VRK1 removed the kinase activity from the peak fraction, and bacterially expressed CK1 exhibited Ser20 site kinase activity equivalent to that of the virus-induced native CK1. CK1 modified p53 in a docking-dependent manner, which is similar to other known Ser20 site p53 kinases. Low levels of the CK1 inhibitor D4476 selectively inhibited HHV-6B-induced Ser20 site phosphorylation of p53. However, x-ray-induced Ser20 site phosphorylation of p53 was not blocked by D4476. These data highlight a central role for CK1 as the Ser20 site kinase for p53 in DNA virus-infected cells but also suggest that distinct stresses may selectively trigger different protein kinases to modify the transactivation domain of p53 at Ser20.
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PMID:A central role for CK1 in catalyzing phosphorylation of the p53 transactivation domain at serine 20 after HHV-6B viral infection. 1866 30

Here, we confirmed that stable expression of B-cell lymphoma-xL (Bcl-xL) in N18TG neuroglioma cells could suppress c-Jun N-terminal protein kinase (JNK) activation, nuclear fragmentation, and cell death caused by etoposide treatment. Moreover, additional overexpression of JNK1 led to partially antagonize the antiapoptotic environment attained by Bcl-xL, implying that JNK1-involved pathway may play a role in down-regulation of the antiapoptotic effect of Bcl-xL. However, the antagonistic effect of JNK1 on the antiapoptotic action of Bcl-xL was significantly weaker than that on the action of Bcl-2. Interestingly, we found that overexpression of JNK1 led to increase of Bcl-xL expression. Thus, these results suggest that Bcl-xL and Bcl-2 may induce its antiapoptotic effect in a different mechanism, provoking the possibility of involvement of JNK1-involved pathway in Bcl-xL expression.
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PMID:Differential regulation of the antiapoptotic action of B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma extra long (Bcl-xL) by c-Jun N-terminal protein kinase (JNK) 1-involved pathway in neuroglioma cells. 1875 60

The protein kinase Syk is a key mediator of proximal B-cell receptor (BCR) signaling. Following antigen stimulation, Syk is recruited to the BCR and becomes activated by phosphorylation at Y352. Recently, Syk was found to be constitutively phosphorylated in several common B-cell lymphoma subtypes, indicating a role for antigen-independent Syk activation in the pathogenesis of these diseases. We now report that Syk is constitutively phosphorylated on the activating Y352 residue in chronic lymphocytic leukemia (CLL) B cells. To examine the effects of constitutive Syk activity on intracellular signaling and leukemic cell survival, we performed in vitro studies with the Syk inhibitor R406. Treatment with R406 induced leukemic cell apoptosis in the majority of investigated cases and affected the basal activity or expression of several pro-survival molecules regulated by Syk, including the Akt and extracellular signal-regulated (ERK) kinases, and the anti-apoptotic protein Mcl-1. In addition, R406 prevented the increase in leukemic cell viability induced by sustained BCR engagement and inhibited BCR-induced Akt activation and Mcl-1 upregulation. Collectively, these data identify Syk as a potential target for CLL treatment and suggest that inhibition of this kinase could provide a double therapeutic benefit by disrupting both antigen-dependent and antigen-independent signaling pathways that regulate leukemic cell survival.
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PMID:Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells. 1909 49

The transcription factor NF-kappaB is required for lymphocyte activation and proliferation as well as the survival of certain lymphoma types. Antigen receptor stimulation assembles an NF-kappaB activating platform containing the scaffold protein CARMA1 (also called CARD11), the adaptor BCL10 and the paracaspase MALT1 (the CBM complex), linked to the inhibitor of NF-kappaB kinase complex, but signal transduction is not fully understood. We conducted parallel screens involving a mass spectrometry analysis of CARMA1 binding partners and an RNA interference screen for growth inhibition of the CBM-dependent 'activated B-cell-like' (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Here we report that both screens identified casein kinase 1alpha (CK1alpha) as a bifunctional regulator of NF-kappaB. CK1alpha dynamically associates with the CBM complex on T-cell-receptor (TCR) engagement to participate in cytokine production and lymphocyte proliferation. However, CK1alpha kinase activity has a contrasting role by subsequently promoting the phosphorylation and inactivation of CARMA1. CK1alpha has thus a dual 'gating' function which first promotes and then terminates receptor-induced NF-kappaB. ABC DLBCL cells required CK1alpha for constitutive NF-kappaB activity, indicating that CK1alpha functions as a conditionally essential malignancy gene-a member of a new class of potential cancer therapeutic targets.
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PMID:Casein kinase 1alpha governs antigen-receptor-induced NF-kappaB activation and human lymphoma cell survival. 1911 83

Cyclin-dependent protein kinase 6 (CDK6), in cooperation with cyclin Ds, drives cell cycle progression from G1 to S phase through phosphorylation and subsequent inactivation of retinoblastoma 1 protein. Alteration of this pathway results in both nonhematologic and hematologic malignancies, which include a small subset of B-cell lymphoproliferative disorders (BLPDs). We identified 5 cases of BLPD that carried CDK6 chromosomal translocations and characterized their clinical, pathologic, immunophenotypic, and genetic features. Common clinical characteristics included marked neoplastic lymphocytosis, systemic lymphadenopathy, splenomegaly, and bone marrow involvement. Three patients were diagnosed with low-grade B-cell lymphoma and had an indolent clinical course, and 2 patients (one who transformed to large B-cell lymphoma, and the other who was initially diagnosed with a high-grade B-cell lymphoma) had an aggressive clinical course. Immunophenotypically, the neoplastic B cells expressed CD5, CDK6, and cytoplasmic retinoblastoma 1 protein in all cases, expressed phospho-RB, p27kip1, and cyclin D2 in most cases, and uniformly lacked expression of all other cyclins. In 4 cases, the CDK6 translocation partner was kappa immunoglobulin light-chain gene; and in the fifth case, the CDK6 translocation partner was unknown. These distinct clinicopathologic and cytogenetic features distinguish the CDK6 translocation-associated BLPDs (CDK6-BLPDs) from other mature B-cell lymphomas.
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PMID:Clinicopathologic features of CDK6 translocation-associated B-cell lymphoproliferative disorders. 1914 99

p70S6K/p85S6K and cdc2/cdk1 are members of the serine/threonine protein kinase family. p70S6K/p85S6K is one of the downstream effectors of the PI3K/Akt/mTOR signal transduction pathway. It phosphorylates S6 protein of 40S ribosomal subunit and thus functions in protein synthesis and cell growth. cdc2/cdk1 is a cyclin-dependent protein kinase that controls the cell cycle entry from G2 to M phase. Overexpression of phospho-p70S6K and cdc2/cdk1 has recently been identified in the majority of diffuse large B-cell lymphoma (DLBCL) specimens. Combination of small molecules that target phosphorylation of p70S6K and cdc2/cdk1 synergistically induced cell apoptosis and cell cycle G1 and G2 arrest, suggesting that they are potential molecular targets for DLBCL therapy. This review will summarize recent advances in the study of phospho-p70S6K and cdc2/cdk1 as molecular markers and therapeutic targets for DLBCL. We propose that multilevel inhibition of the PI3K/Akt/mTOR pathway and double brake at the G1 and G2 phases of the cell cycle progression are effective strategies in treating DLBCL that overexpress phospho-p70S6K and cdc2/cdk1.
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PMID:Phospho-p70S6K and cdc2/cdk1 as therapeutic targets for diffuse large B-cell lymphoma. 1961 61

This study explored the levels of Aurora B, a key regulator of mitosis, in 71 lymph nodes and tumor specimens excised operatively from individuals with various types of non-Hodgkin lymphoma (NHLs). Immunohistochemical examination found that diffuse large B-cell lymphoma (10/21, 48%) and Burkitt lymphoma (BL) (6/7, 86%) cells highly (percentage of positive cells, >20%) expressed Aurora B in their nuclei. On the other hand, none of the low-grade B-cell lymphoma (n=20), except for one case of follicular lymphoma, highly expressed this protein kinase, suggesting that levels of Aurora B correlated with histological grade in B-cell NHLs (P<0.01). Exposure of BL/leukemia cells to AZD1152-HQPA in vitro, a selective inhibitor of Aurora B kinase, potently induced growth arrest and apoptosis in a caspase-dependent, as well as -independent manner. Moreover, AZD1152 synergistically enhanced the effects of vincristine (VCR) to induce growth arrest of these cells. Further experiments found that VCR increased levels of the p-Aurora B through the activation of c-Jun N-terminal kinase, which was blocked in the presence of AZD1152-HQPA.
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PMID:Analysis of Aurora B kinase in non-Hodgkin lymphoma. 1982 68

Accumulating evidence suggests that psychotropic agents such as mood stabilizers, antidepressants, and antipsychotics realize their neurotrophic/neuroprotective effects by activating the mitogen activated protein kinase/extracellular signal-related kinase, PI3-kinase, and wingless/glycogen synthase kinase (GSK) 3 signaling pathways. These agents also upregulate the expression of trophic/protective molecules such as brain-derived neurotrophic factor, nerve growth factor, B-cell lymphoma 2, serine-threonine kinase, and Bcl-2 associated athanogene 1, and inactivate proapoptotic molecules such as GSK-3. They also promote neurogenesis and are protective in models of neurodegenerative diseases and ischemia. Most if not all, of this evidence was collected from animal studies that used clinically relevant treatment regimens. Furthermore, human imaging studies have found that these agents increase the volume and density of brain tissue, as well as levels of N-acetyl aspartate and glutamate in selected brain regions. Taken together, these data suggest that the neurotrophic/neuroprotective effects of these agents have broad therapeutic potential in the treatment; not only of mood disorders and schizophrenia, but also neurodegenerative diseases and ischemia.
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PMID:The neurotrophic and neuroprotective effects of psychotropic agents. 1987

In diffuse large B-cell lymphoma (DLBCL), several recurrent chromosomal aberrations have been described where the presumed target genes remain unknown, including gain/amplification at 11q23-24. Here, we characterized amplification at 11q23 in the DLBCL cell line KARPAS-422. Quantitative genomic PCR and FISH analysis were used to define the region altered, thus showing an amplification peak at 111.1 Mb, the region hosting SIK2/SNF1LK2. Expression profiling, quantitative RT-PCR, Western blot, and immunocytology identified overexpression of SIK2, highlighting this gene as a likely key target of 11q23 amplification. SIK2 encodes a protein kinase that has been shown to inhibit transcription factor CREB via phosphorylation of its cofactor TORC2/CRTC2. Accordingly, siRNA-mediated downregulation of SIK2 expression resulted in upregulation of the CREB target gene BIM. Functional analysis by treatments with cAMP, the glucocorticoid dexamethasone, and 2-deoxy-d-glucose revealed a regulatory role for SIK2 in survival and glucose metabolism, respectively. However, overexpression of SIK2 was not detectable in primary DLBCL samples. Nevertheless, identification of SIK2 as an amplification target highlights this kinase along with its regulatory network as potential therapeutic targets in DLBCL.
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PMID:Amplification at 11q23 targets protein kinase SIK2 in diffuse large B-cell lymphoma. 2023 55

Neoplastic cells rely on key oncogenic pathways for their gain of proliferative and/or loss of apoptotic potential. Therapy targeted at specific points in these pathways has the potential to eliminate cancer cells by inducing differentiation or apoptosis. Concurrent immunophenotypic evaluation of survival pathways in nodular sclerosing classical Hodgkin lymphoma (cHL-NS) tissues has not previously been undertaken. We took the tissue microarray (TMA)-based approach to retrospectively evaluate the activation state of key oncogenic pathways by immunohisto-chemistry (IHC) in a series of 6 cases of cHL-NS (with predominantly syncitial areas). For comparison, 2 cases of diffuse large B-cell lymphoma (DLBCL), and 1 case of follicular hyperplasia (FH) were included in the study. Infiltration of T regulatory cells (Tregs) in the tumor microenvironment was assessed by expression of the Foxp3 transcription factor. Differential upregulation of the mitogen-activated protein kinase (MAPK)-extracellular signal related kinase (ERK), signal transducers and activators of transcription (STAT)3, and protein kinase c - alpha (PKC-alpha) pathways was seen among the cHL cases, whereas nuclear factor - kappa B (NF-kB) and phosphoinositide 3 kinase (PI3 K)-AKT-mammalian target of rapamycin (mTOR) pathways were equally activated in the neoplastic Reed-Sternberg cells of the 6 cHL-NS cases. Marked difference in the morphoproteomic profile was seen amongst the two cases of DLBCL. The amount of Foxp3+ T regulatory cells (Tregs) in the tumor microenvironment was highly variable ranging from 6/hpf to 120/hpf in cHL-NS, and 1/hpf to 82/hpf in DLBCL. In this pilot study, concurrent evaluation of oncogenic pathways in cHL-NS and DLBCL offers powerful insights in the putative therapeutic targets for an individualized approach to diagnosis and therapy.
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PMID:Tissue-microarray based immunohistochemical analysis of survival pathways in nodular sclerosing classical Hodgkin lymphoma as compared with Non-Hodgkin's lymphoma. 2036 41


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