Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signaling molecules such as p21(ras) (Ras), mitogen-activated protein kinase (MAPK), and Akt kinase play pivotal roles in the proliferation and survival of lymphoid cells in response to many kinds of stimulation. It is not fully understood, however, how these molecules participate in the growth of malignant lymphoid cells. We determined whether Ras, MAPKs such as extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38 MAPK, and Akt kinase are activated in B-cell tumors, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, Burkitt-like lymphoma, diffuse large B-cell lymphoma, and plasma cell leukemia. We found that Lyn protein tyrosine kinase was constitutively phosphorylated on tyrosine, and that ERK and p38 MAPK were constitutively active in all cases of the B-cell tumor. In contrast, activation of Ras and Akt kinase was found in limited cases, and JNK kinase activity was not observed in any case. These results suggest that ERK and p38 play roles in the oncogenesis of B-cell tumors.
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PMID:Constitutive activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase in B-cell lymphoproliferative disorders. 1277 25

B cell type chronic lymphocytic leukaemia (B-CLL) cells carry the Epstein-Barr virus (EBV) receptor CD21 and can be infected in vitro with the virus. The infected cells exhibit an unusual EBV program, they express the nuclear proteins but not latent membrane protein 1 (LMP-1). Similar cells were encountered in lymphoid tissues of infectious mononucleosis (IM) patients and in lymphoproliferations of immunosuppressed patients. EBV infected B-CLL cells can be regarded as model for this viral program. In B cells the regulation of LMP-1 is executed mainly by EBV encoded nuclear antigen 2 (EBNA-2), interacting with several cellular proteins and these complexes bind to specific sequences in the LMP-1 promoter. ATF2 and c-Jun were shown to be among the interacting partners of EBNA-2. These molecules can be detected in experimentally infected B lymphocytes. We found c-Jun and/or phosphorylated ATF-2 (p-ATF-2) expression in some B-CLL ex vivo samples. They disappeared or their expression declined promptly in explanted cells, even if they were infected with EBV in vitro. Activation of the infected B-CLL cells by exposure to CD40L was accompanied by p-ATF-2 and c-Jun but not by LMP-1 expression. In one of three clones tested, subsequent treatment with histone deacetylase inhibitors (HDACi), TSA or n-butyrate, could induce LMP-1. Treatment with phorbol-12, 13-dibutyrate (PDB) induced LMP-1 expression in three of four clones. Neither the HDACi nor the PDB treated cells survived.
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PMID:EBV infection induces expression of the transcription factors ATF-2/c-Jun in B lymphocytes but not in B-CLL cells. 1583 Jan 49

The fully human anti-HLA-DR antibody 1D09C3 has been shown to delay lymphoma cell growth in severe combined immunodeficient (SCID) mice. The present study was aimed at (a) investigating the mechanism(s) of 1D09C3-induced cell death and (b) further exploring the therapeutic efficacy of 1D09C3 in nonobese diabetic (NOD)/SCID mice. The chronic lymphocytic leukemia cell line JVM-2 and the mantle cell lymphoma cell line GRANTA-519 were used. Generation of reactive oxygen species (ROS) and mitochondrial membrane depolarization were measured by flow cytometry following cell incubation with dihydroethidium and TMRE, respectively. Western blot analysis was used to detect c-Jun-NH(2)-kinase (JNK) phosphorylation and apoptosis-inducing factor (AIF). NOD/SCID mice were used to investigate the activity of 1D09C3 in early- or advanced-stage tumor xenografts. In vitro, 1D09C3-induced cell death involves a cascade of events, including ROS increase, JNK activation, mitochondrial membrane depolarization, and AIF release from mitochondria. Inhibition of JNK activity significantly reduced 1D09C3-induced apoptosis, indicating that 1D09C3 activity involves activation of the kinase. In vivo, 1D09C3 induces long-term disease-free survival in a significant proportion of tumor-bearing mice treated at an early stage of disease. Treatment of mice bearing advanced-stage lymphoma results in a highly significant prolongation of survival. These data show that 1D09C3 (a) exerts a potent antitumor effect by activating ROS-dependent, JNK-driven cell death, (b) cures the great majority of mice treated at an early-stage of disease, and (c) significantly prolongs survival of mice with advanced-stage disease.
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PMID:The anti-human leukocyte antigen-DR monoclonal antibody 1D09C3 activates the mitochondrial cell death pathway and exerts a potent antitumor activity in lymphoma-bearing nonobese diabetic/severe combined immunodeficient mice. 1645 41

Fludarabine is a nucleoside analogue that has been successfully employed for the treatment of low-grade lymphoid malignancies and, more recently, in nonmyeloablative preparative regimens for stem cell transplantation, due to its strong cytotoxic activity on lymphocytes. In this paper, we show that fludarabine can also induce pro-inflammatory stimulation of monocytic cells, as evaluated by increased expression of ICAM-1 and IL-8 release. To study the mechanisms involved, we employed selective inhibitors of MAPK and NF-kappaB pathways, both of which have been implicated in the modulation of ICAM-1 and IL-8. Our results showed that fludarabine effects were mediated through the activation of ERK and were independent on p38, JNK or NF-kappaB pathways. By Western blotting analysis we corroborated that fludarabine induced a rapid activation of ERK that was sustained for at least 30 min. Moreover, pro-inflammatory activation of monocytic cells by fludarabine was largely attenuated by coadministration of the free radical scavenger N-acetylcysteine suggesting the involvement of reactive oxygen species in fludarabine effects. Finally, we showed that fludarabine induced the activation of the transcription factor AP-1 not only in monocytic cells but also in non-proliferating lymphocytes from chronic lymphocytic leukemia. It is possible that some of fludarabine side effects in vivo may be attributed to cell activation/differentiation rather than induction of apoptosis.
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PMID:Fludarabine induces pro-inflammatory activation of human monocytic cells through a MAPK/ERK pathway. 1654 1

This study was undertaken to characterize preclinical cytotoxic interactions for human malignancies between the multikinase inhibitor sorafenib (BAY 43-9006) and proteasome inhibitors bortezomib or MG132. Multiple tumor cell lines of varying histiotypes, including A549 (lung adenocarcinoma), 786-O (renal cell carcinoma), HeLa (cervical carcinoma), MDA-MB-231 (breast), K562 (chronic myelogenous leukemia), Jurkat (acute T-cell leukemia), MEC-2 (B-chronic lymphocytic leukemia), and U251 and D37 (glioma), as well as cells derived from primary human glioma tumors that are likely a more clinically relevant model were treated with sorafenib or bortezomib alone or in combination. Sorafenib and bortezomib synergistically induced a marked increase in mitochondrial injury and apoptosis, reflected by cytochrome c release, caspase-3 cleavage, and poly(ADP-ribose) polymerase degradation in a broad range of solid tumor and leukemia cell lines. These findings were accompanied by several biochemical changes, including decreased phosphorylation of vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-beta, and Akt and increased phosphorylation of stress-related c-Jun NH2-terminal kinase (JNK). Inhibition of Akt was required for synergism, as a constitutively active Akt protected cells against apoptosis induced by the combination. Alternatively, the JNK inhibitor SP600125 could also protect cells from apoptosis induced by the combination, indicating that both inhibition of Akt and activation of JNK were required for the synergism. These findings show that sorafenib interacts synergistically with bortezomib to induce apoptosis in a broad spectrum of neoplastic cell lines and show an important role for the Akt and JNK pathways in mediating synergism. Further clinical development of this combination seems warranted.
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PMID:Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. 1698 72

CD40, a tumor necrosis factor receptor family member, is expressed on B lymphocytes. Interaction between CD40 and its ligand (CD40L), expressed on activated T lymphocytes, is critical for B cell survival. Here, we demonstrate that CD40 signals B cell survival in part via transcriptional activation of the RelB NF-kappaB subunit. CD40L treatment of chronic lymphocytic leukemia cells induced levels of relB mRNA. Similarly, CD40L-mediated rescue of WEHI 231 B lymphoma cells from apoptosis induced upon B cell receptor (surface IgM) engagement led to increased relB mRNA levels. Recently, we characterized a new de novo synthesis pathway for the RelB NF-kappaB subunit, induced by the cytomegalovirus IE1 protein, in which binding of p50/p65 NF-kappaB and c-Jun/Fra-2 AP-1 complexes to the relB promoter works in synergy to potently activate transcription (Wang, X., and Sonenshein, G. E. (2005) J. Virol. 79, 95-105). CD40L treatment of WEHI 231 cells caused induction of AP-1 family members Fra-2, c-Jun, JunD, and JunB. Cotransfection of Fra-2 with the Jun AP-1 subunits and p50/c-Rel NF-kappaB led to synergistic activation of the relB promoter. Ectopic expression of relB or RelB knockdown using small interfering RNA demonstrated the important role of this subunit in control of WEHI 231 cell survival and implicated activation of the anti-apoptotic factors Survivin and manganese superoxide dismutase. Thus, CD40 engagement of transformed B cells activates relB gene transcription via a process we have termed the de novo RelB synthesis pathway, which protects these cells from apoptosis.
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PMID:CD40 ligand-mediated activation of the de novo RelB NF-kappaB synthesis pathway in transformed B cells promotes rescue from apoptosis. 1744 75

Vascular endothelial growth factor (VEGF) is a survival and angiogenesis factor that is a target for therapy in a variety of cancers. In many hematological malignancies, VEGF production is increased leading to cell survival responses. Herein, we demonstrate that lysophosphatidic acid (LPA) induces mRNA expression of VEGF in the multiple myeloma cell line, U266, the Burkitt's lymphoma cell line, BJAB, and the chronic lymphocytic leukemia (CLL)-like cell line, I-83. This increase in mRNA levels of VEGF corresponded with increased luciferase activity of the VEGF promoter in BJAB and I-83 cells and increased protein levels in I-83 cells. Secretion of VEGF was also increased in these cells following LPA treatment. LPA treatment also caused the activation of both VEGFR1 and VEGFR2. The increase in VEGF expression by LPA is mediated by the activation of c-Jun N-terminal Kinase (JNK) and transcription factor NFkappaB since blocking JNK or NFkappaB activation inhibited LPA induced VEGF expression. Furthermore, we have demonstrated that LPA protects cells from apoptosis and blocking activation of both VEGFR1 and VEGFR2 using a VEGF receptor kinase inhibitor prevented LPA survival responses. Knocking down expression of VEGFR1 and inhibiting activation of NFkappaB and JNK also blocked LPA induced protection against apoptosis. Taken together, this indicates that LPA contributes to VEGF production in B cell malignancies leading to cell survival.
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PMID:Lysophosphatidic acid (LPA) induces the expression of VEGF leading to protection against apoptosis in B-cell derived malignancies. 1839 13

Vesicular stomatitis virus (VSV) is a candidate oncolytic virus that replicates and induces cell death in cancer cells while sparing normal cells. Although defects in the interferon antiviral response facilitate VSV oncolysis, other host factors, including translational and growth regulatory mechanisms, also appear to influence oncolytic virus activity. We previously demonstrated that VSV infection induces apoptosis in proliferating CD4(+) T lymphocytes from adult T-cell leukemia samples but not in resting T lymphocytes or primary chronic lymphocytic leukemia cells that remain arrested in G(0). Activation of primary CD4(+) T lymphocytes with anti-CD3/CD28 is sufficient to induce VSV replication and cell death in a manner dependent on activation of the MEK1/2, c-Jun NH(2)-terminal kinase, or phosphatidylinositol 3-kinase pathway but not p38. VSV replication is specifically impaired by the cell cycle inhibitor olomoucine or rapamycin, which induces early G(1) arrest, but not by aphidicolin or Taxol, which blocks at the G(1)1S or G(2)1M phase, respectively; this result suggests a requirement for cell cycle entry for efficient VSV replication. The relationship between increased protein translation following G(0)/G(1) transition and VSV permissiveness is highlighted by the absence of mTOR and/or eIF4E phosphorylation whenever VSV replication is impaired. Furthermore, VSV protein production in activated T cells is diminished by small interfering RNA-mediated eIF4E knockdown. These results demonstrate that VSV replication in primary T lymphocytes relies on cell cycle transition from the G(0) phase to the G(1) phase, which is characterized by a sharp increase in ribogenesis and protein synthesis.
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PMID:Vesicular stomatitis virus oncolysis of T lymphocytes requires cell cycle entry and translation initiation. 1841 67

Activation of transcription factor nuclear factor-kappaB (NF-kappaB) and Jun N-terminal kinase (JNK) play the pivotal roles in regulation of lymphocyte activation and proliferation. Deregulation of these signaling pathways leads to inappropriate immune response and contributes to the development of leukemia/lymphoma. The scaffold protein CARMA1 [caspase-recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1] has a central role in regulation of NF-kappaB and the JNK2/c-Jun complex in both B and T lymphocytes. During last several years, tremendous work has been done to reveal the mechanism by which CARMA1 and its signaling partners, B cell CLL-lymphoma 10 and mucosa-associated lymphoid tissue 1, are activated and mediate NF-kappaB and JNK activation. In this review, we summarize our findings in revealing the roles of CARMA1 in the NF-kappaB and JNK signaling pathways in the context of recent advances in this field.
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PMID:CARMA1-mediated NF-kappaB and JNK activation in lymphocytes. 1929 Sep 29

Chemotherapeutic agents modify intracellular signaling that culminates in the inhibition of Bcl-2 family members and initiates apoptosis. Inhibition of the extracellular signal-regulated kinase by PD98059 dramatically accelerates vinblastine-mediated apoptosis in ML-1 leukemia with cells dying in 4 hours from all phases of the cell cycle. Inhibition of protein synthesis by cycloheximide also markedly accelerated vinblastine-induced apoptosis, showing that the proteins required for this acute apoptosis are constitutively expressed. Vinblastine induced the rapid induction of Mcl-1 that was inhibited by PD98059 and cycloheximide. No change in Bcl-2 or Bcl-X was observed. We hypothesize that ML-1 cells use Mcl-1 for protection from the rapid vinblastine-induced apoptosis. This was confirmed by targeting Mcl-1 with short hairpin RNA. We also investigated the response of 13 other leukemia and lymphoma cell lines and cells from seven chronic lymphocytic leukemia patients. Four cell lines and all chronic lymphocytic leukemia cells were killed in 6 hours by vinblastine alone. Two additional cell lines were sensitized to vinblastine by PD98059, which suppressed Mcl-1. This acute apoptosis either alone or in combination with PD98059 required vinblastine-mediated activation of c-Jun-NH(2)-terminal kinase. PD98059 did not suppress Mcl-1 in other cell lines whereas sorafenib did, but this did not sensitize the cells to vinblastine, suggesting that the acute apoptosis varies depending on which Bcl-2 protein mediates protection. Most of the cell lines were sensitized to vinblastine by cycloheximide, suggesting that inhibition of a short-lived protein in addition to Mcl-1 can acutely sensitize cells. These results suggest several clinical strategies that might provide an effective therapy for selected patients. Mol Cancer Ther; 9(4); 791-802. (c)2010 AACR.
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PMID:Vinblastine induces acute, cell cycle phase-independent apoptosis in some leukemias and lymphomas and can induce acute apoptosis in others when Mcl-1 is suppressed. 2037 26


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