Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of early response genes by interferons (IFNs) requires tyrosine phosphorylation of the Stat transcription factors and is mediated by the Jak family of tyrosine kinases. Recent evidence suggests that ERK2 serine/threonine kinase modulates the IFN-stimulated Jak/Stat pathway. In this report we show that in the myeloma cell line U266 protein kinase A specifically interacts with the cytoplasmic domain of the IFNalpha/beta receptor. Treatment of cells with the adenylate cyclase activator forskolin inhibits IFNbeta-, IFNgamma-, and hydrogen peroxide/vanadate-induced formation of complexes that bind to enhancers known to stimulate the expression of IFN-regulated genes. Immunoprecipitations followed by anti-phosphotyrosine immunoblots indicate that tyrosine phosphorylation of the alpha chain of the IFNalpha/beta receptor, Jak1, Tyk2, as well as Stat1 and Stat2 is reduced as a consequence of incubation of cells with forskolin. In contrast, dideoxyforskolin, which fails to activate adenylate cyclase, has no effect on IFN induction of the Jak/Stat pathway. These results indicate a novel regulatory mechanism by which protein kinase A can modulate the Jak/Stat signaling cascade.
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PMID:Activation of protein kinase A inhibits interferon induction of the Jak/Stat pathway in U266 cells. 861 15

Mouse plasma cell tumor (PCT) and human multiple myeloma (MM) are terminal B-cell malignancies sharing many similarities. Our recent work demonstrated that activation of the insulin-like growth factor receptor (IGF-IR)/insulin receptor substrate (IRS)/phosphatidylinositol 3' kinase (PI 3'K) pathway was evident in the tumor lines derived from both species. Although PI 3'K activity was higher in mouse tumor lines than that in human tumors, activation of Akt serine/threonine kinase was markedly lower in mouse lines. This discrepancy prompted us to test the status of PTEN tumor suppressor gene, as it has been shown to be a negative regulator of PI 3'K activity. Although all the mouse lines expressed intact PTEN, 2 of the 4 human lines (Delta47 and OPM2) possessing the highest Akt activity lost PTEN expression. Sequencing analysis demonstrated that the PTEN gene contains a deletion spacing from exon 3 to exon 5 or 6 in the Delta47 line and from exon 3 to 7 in the OPM2 line. Restoration of PTEN expression suppressed IGF-I-induced Akt activity, suggesting that loss of PTEN is responsible for uncontrolled Akt activity in these 2 lines. Despite the expression of PTEN with the concomitant low Akt activity in all mouse PCT lines, their p70S6K activities were generally higher than those in 3 human MM lines, arguing for specific negative regulation of Akt, but not p70S6K by PTEN. These results suggest that p70S6K and Akt may be differentially used by the plasma cell tumors derived from mice and humans, respectively.
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PMID:Loss of PTEN expression leading to high Akt activation in human multiple myelomas. 1107 55

Interleukin-6 (IL-6) is a pleiotropic cytokine and acts as a growth factor for murine plasmacytoma and human myeloma. IL-6 activates multiple signal transduction pathways. Among them, signal transducer and activator of transcription3 (STAT3), and the SHP-2-mediated Erk/MAP kinase pathway are important. The roles for the two major pathways in the IL-6-induced growth of B cell hybridoma cells were examined. A mutational analysis of the cytoplasmic domain of exogenously expressed gp130, a signal transducing beta chain of the IL-6 receptor complex, revealed that the proximal 133 amino acid (AA) region of gp130 with the intact Y767 but not Y759 is necessary and sufficient for gp130-signal-induced cell proliferation. Interestingly, no requirement of the Y759-mediated signals, including SHP-2-mediated Erk/MAP kinase pathway, coincided with the failure of SHP-2, Gab1/Gab2, and Erk/MAP kinase activation by IL-6 in MH60 cells. Moreover, we show that another serine/threonine kinase pathway leading to STAT3 Ser727 phosphorylation, which seemed to be derived from the Y767 in the proximal 133 AA residues, is intact in MH60 cells. Since Erk/MAP kinases are known to inhibit the subsequent IL-6-induced STAT3 activation, the impaired activation of Erk/MAP kinases by IL-6 may contribute to the development of B cell neoplasia.
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PMID:No involvement of Erk/MAP kinases in IL-6-induced proliferation of a B cell hybridoma cell line. 1155 93

PBK/TOPK is a recently cloned serine/threonine kinase which is phosphorylated during mitosis. Earlier work indicated that this kinase is upregulated in a Burkitt's lymphoma cell line (GA-10). To determine whether PBK/TOPK is upregulated in other mitotically active neoplastic cell lines and tissues, Northern analysis was performed on a panel of malignant cell lines and on clinical samples from patients with leukemia or lymphoma. While PBK/TOPK mRNA was not detectable in normal peripheral blood cells and was weakly expressed in hyperplastic tonsillar B-cells, significantly higher levels of mRNA were detected in 8 Burkitt's lymphoma cell lines, 10 other neoplastic cell lines, and 2 clinical samples-one derived from a patient with ALL and a second derived from a patient with relapsed myeloma. In addition, Northern analysis of fetal tissues showed upregulated expression of PBK/TOPK in fetal kidney, lung, spleen, brain, and testis. These data suggest that PBK/TOPK expression is increased in highly proliferative malignant cells and during normal fetal development.
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PMID:PBK/TOPK is a novel mitotic kinase which is upregulated in Burkitt's lymphoma and other highly proliferative malignant cells. 1178 45

Death associated protein kinase (DAP-kinase) is a pro-apoptotic calcium/calmodulin-regulated serine/threonine kinase with a multidomain structure that participates in a wide array of apoptotic systems initiated by IFN-gamma, TNF-alpha, activated Fas, and detachment from extracellular matrix. At various stages during tumor development, cells are subjected to apoptosis inducing stimuli and genetic mutations causing inhibition of apoptosis confer a selective advantage to cells. Thus, apoptosis and its regulation play an important role in tumor initiation, progression and metastasis. It has been demonstrated that the tumor-suppressive properties of DAP-kinase operate at two different apoptotic checkpoints in the course of tumor development; first, during the early oncogene-activated apoptotic checkpoint mediated by p19ARF-p53 pathway and second, during the late stages of metastasizing cells entering the circulation after detachment from extracellular matrix. Promoter hypermethylation of DAP-kinase has been observed in a high variety of primary tumors including head and neck tumors, and non-small cell lung cancers, where an association with poor prognosis was also noted. Notably, high frequencies of DAP-kinase methylation have been found in B cell lymphomas and myeloma, where loss of control of c-Myc induced hyperproliferation from inactivated DAP-kinase may possibly play an important role in the pathogenesis of these B cell neoplasms.
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PMID:Death associated protein kinase: from regulation of apoptosis to tumor suppressive functions and B cell malignancies. 1199 70

Circumvention of chemoresistance in the B-cell neoplasm multiple myeloma (MM) might be achieved by targeting certain intracellular signaling pathways crucial for survival of the malignant clone. The use of the macrolide rapamycin, selectively inhibiting the phosphoprotein mammalian target of rapamycin (mTOR) downstream of, for example, insulin-like growth factor-I receptor (IGF-IR), possibly represents such a molecular mode of therapy. By using a panel of MM cell lines we showed that rapamycin induced G0/G1 arrest, an effect being associated with an increase of the cyclin-dependent kinase inhibitor p27 and a decrease of cyclins D2 and D3. Interestingly, in primary, mainly noncycling MM cells, rapamycin, at clinically achievable concentrations, induced apoptosis. More important, rapamycin sensitized both MM cell lines and primary MM cells to dexamethasone-induced apoptosis. This effect was associated with a decreased expression of cyclin D2 and survivin. The phosphorylation of the serine/threonine kinase p70S6K at Thr389 and Thr421/Ser424 was down-regulated by rapamycin and/or dexamethasone. Strikingly, the combinatorial treatment with rapamycin and dexamethasone suppressed the antiapoptotic effects of exogenously added IGF-I and interleukin 6 (IL-6) as well as their stimulation of p70S6K phosphorylation. The induction of apoptosis by rapamycin and dexamethasone despite the presence of survival factors was also demonstrated in primary MM cells, thus suggesting this drug combination to be active also in vivo.
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PMID:Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone. 1507 Jun 96

Pim-2 is a transcriptionally regulated oncogenic kinase that promotes cell survival in response to a wide variety of proliferative signals. Deregulation of Pim-2 expression has been documented in several human malignancies, including leukemia, lymphoma, and multiple myeloma. Here, we show that the ability of Pim-2 to promote survival of cells is dependent on nuclear factor (NF)-kappaB activation. Pim-2 activates NF-kappaB-dependent gene expression by inducing phosphorylation of the oncogenic serine/threonine kinase Cot, leading to both augmentation of IkappaB kinase activity and a shift in nuclear NF-kappaB from predominantly p50 homodimers to p50/p65 heterodimers. Blockade of NF-kappaB function eliminates Pim-2-mediated survival in both cell lines and primary cells, and both Cot phosphorylation and expression are required for the prosurvival effects of Pim-2. Although Pim-2 cooperates with Myc to promote growth factor-independent cell proliferation, this feature is abrogated by NF-kappaB blockade. The ability of Pim-2 to serve as an oncogene in vivo depends on sustained NF-kappaB activity. Thus, the transcriptional induction of Pim-2 initiates a novel NF-kappaB activation pathway that regulates cell survival.
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PMID:Lymphocyte transformation by Pim-2 is dependent on nuclear factor-kappaB activation. 1554 3

The tyrosine kinase receptor FGFR3 is thought to play a role in hematopoietic malignancies. A new study in this issue of Cancer Cell identifies the serine/threonine kinase RSK2 as a key substrate of FGFR3 in human t(4;14)-positive multiple myeloma (MM) cells. Constitutively active FGFR3 directly phosphorylates RSK2 on Tyr529, which primes RSK2 for activation by the kinases ERK1 and ERK2 (ERK1/2). In turn, RSK2 activity plays an important role in the survival of FGFR3-expressing MM cells.
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PMID:New insights into RSK activation and hematopoietic cancer. 1778 2

To better understand the signaling properties of oncogenic FGFR3, we performed phospho-proteomics studies to identify potential downstream signaling effectors that are tyrosine phosphorylated in hematopoietic cells expressing constitutively activated leukemogenic FGFR3 mutants. We found that FGFR3 directly tyrosine phosphorylates the serine/threonine kinase p90RSK2 at Y529, which consequently regulates RSK2 activation by facilitating inactive ERK binding to RSK2 that is required for ERK-dependent phosphorylation and activation of RSK2. Moreover, inhibition of RSK2 by siRNA or a specific RSK inhibitor fmk effectively induced apoptosis in FGFR3-expressing human t(4;14)-positive myeloma cells. Our findings suggest that FGFR3 mediates hematopoietic transformation by activating RSK2 in a two-step fashion, promoting both the ERK-RSK2 interaction and subsequent phosphorylation of RSK2 by ERK.
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PMID:FGFR3 activates RSK2 to mediate hematopoietic transformation through tyrosine phosphorylation of RSK2 and activation of the MEK/ERK pathway. 1778 99

Abstract Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays a critical role in the regulation of basic cellular functions, including cellular growth and proliferation. In this study we describe the generation and characterization of novel monoclonal antibodies directed against mTOR protein kinase. A GST-tagged fragment of mTOR expressed in bacteria was used as an antigen. Antibody-producing hybridoma cells were obtained by fusing SP2/0 myeloma cells with splenocytes from immunized mice. Anti-mTOR antibody-producing hybridoma cell lines were first identified by enzyme-linked immunosorbent assay and then subcloned by limiting dilution. Antibodies produced by selected clones were further tested for their reactivity towards the GST/mTOR 1334-1504 recombinant protein. Furthermore, antibody produced by F11 clone was shown to recognize specifically mTOR in different tissues and cell lines in Western blotting, immunoprecipitation, and immunohistochemistry. In addition, mTOR F11 antibody was suitable for immunoprecipitating and testing mTOR activity in in vitro kinase assay. In summary, generated antibodies will be useful for investigating mTOR signaling complexes in normal and pathological states.
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PMID:Generation and characterization of monoclonal antibodies to mTOR kinase. 1880 7


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