Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The t(14;18)(q32;q21), resulting in deregulated expression of B-cell-leukemia/lymphoma-2 (Bcl-2), represents the genetic hallmark in human follicular lymphomas. Substantial evidence supports the hypothesis that the t(14;18) and Bcl-2 overexpression are necessary but not solely responsible for neoplastic transformation and require cooperating genetic derangements for neoplastic transformation to occur. To investigate genes that cooperate with Bcl-2 to influence cellular signaling pathways important for neoplastic transformation, we used oligonucleotide microarrays to determine differential gene expression patterns in CD19+ B cells isolated from Emu-Bcl-2 transgenic mice and wild-type littermate control mice. Fifty-seven genes were induced and 94 genes were repressed by > or =2-fold in Emu-Bcl-2 transgenic mice (P < 0.05). The suppressor of cytokine signaling-3 (SOCS3) gene was found to be overexpressed 5-fold in B cells from Emu-Bcl-2 transgenic mice. Overexpression of Bcl-2 in both mouse embryo fibroblast-1 and hematopoietic cell lines resulted in induction of SOCS3 protein, suggesting a Bcl-2-associated mechanism underlying SOCS3 induction. Immunohistochemistry with SOCS3 antisera on tissue from a cohort of patients with de novo follicular lymphoma revealed marked overexpression of SOCS3 protein that, within the follicular center cell region, was limited to neoplastic follicular lymphoma cells and colocalized with Bcl-2 expression in 9 of 12 de novo follicular lymphoma cases examined. In contrast, SOCS3 protein expression was not detected in the follicular center cell region of benign hyperplastic tonsil tissue. These data suggest that Bcl-2 overexpression leads to the induction of activated signal transducer and activator of transcription 3 (STAT3) and to the induction of SOCS3, which may contribute to the pathogenesis of follicular lymphoma.
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PMID:Bcl-2 overexpression leads to increases in suppressor of cytokine signaling-3 expression in B cells and de novo follicular lymphoma. 1556 78

Aberrant activity of the signal transducer and activator of transcription 3 (Stat3) is believed to be essential for neoplastic cell behaviour and thus for the malignancy of tumor cells [Bowman T, Garcia R, Turkson J, Jove R. STATs in oncogenesis. Oncogene 2000;19:2474-88]. Extravillous trophoblast cells resemble malignancies in their invasive and destructive features, excluding the fact of sequential restriction to the first trimester of pregnancy. Trophoblast cells from term placentas have reduced invasive capacity [Hohn HP, Denker HW. Experimental modulation of cell-cell adhesion, invasiveness and differentiation in trophoblast cells. Cells Tissues Organs 2002;172:218-36]. Constitutively activated Stat3 DNA-binding activity in choriocarcinoma cells, carcinomatous derivates of trophoblast cells, have been reported to correlate with its invasiveness [Corvinus FM, Fitzgerald JS, Friedrich K, Markert UR. Evidence for a correlation between trophoblast invasiveness and STAT3 activity. Am J Reprod Immunol 2003;50:316-21]. Here we demonstrate using RNAi that Stat3 activation is necessary in the invasive phenotype of trophoblast cells and can be controlled via Leukemia Inhibitory Factor (LIF). LIF provides a soluble extracellular signal that stimulates invasion in trophoblast and Jeg-3 choriocarcinoma cells. Loss of LIF-mediated invasion in these cells subsequent to STAT3 knock-down strongly suggests that STAT3 plays a crucial role in mediating this invasion.
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PMID:Trophoblast invasion: tuning through LIF, signalling via Stat3. 1583 65

Ciliary neurotrophic factor (CNTF), a cytokine of the interleukin-6 superfamily, is known to exert pleiotropic actions, including regulation of food intake and permissive effects on reproduction, by facilitating the release of gonadotrophin-releasing hormone (GnRH) and gonadotrophins. CNTF activates membrane receptors (CNTF-Rs) composed of one ligand-specific binding subunit, defined CNTFR alpha, and two signal transducing subunits, termed leukaemia inhibitory factor receptor (LIFR) and gp130. However, it is not clear whether the effects of CNTF on GnRH release result from either a direct or an indirect action on GnRH-secreting hypothalamic neurones, or from a combination of these events. The hypothesis of a direct effect of CNTF was thus tested using the GT1-7 GnRH-secreting cell line. CNTF-R expression and CNTF-induced modulation of the Janus kinase (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway and of GnRH release were evaluated. GT1-7 cells were found to express CNTFR alpha, LIFR and gp130 genes, as shown by reverse transcription-polymerase chain reaction analysis, and the corresponding proteins, analysed by immunofluorescence and western blot. CNTFR alpha, LIFR and gp130 immunoreactive bands had an approximate size of 50, 190 and 130 kDa, respectively. Treatment of GT1-7 cells with 10(-12) M CNTF for 15-60 min resulted in a marked and transient increase of STAT3 phosphorylation via activation of JAK2. A 30-min exposure of GT1-7 cells to different CNTF concentrations increased the accumulation of GnRH into the culture medium, with a maximal effect at 10(-11) M. In conclusion, the present results provide new information about the regulation of the reproductive axis by CNTF, and suggest that it might operate at the hypothalamic level by directly influencing the activity of GnRH-secreting neurones, in addition to the possible indirect effects via interneurones proposed by previous studies.
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PMID:Expression of functional ciliary neurotrophic factor receptors in immortalized gonadotrophin-releasing hormone-secreting neurones. 1586 63

Growth and survival of chronic lymphocytic leukemia (CLL) B cells are favored by interactions between CLL and nontumoral accessory cells. CLL cells express CXCR4 chemokine receptors that direct leukemia cell chemotaxis. Marrow stromal cells or nurselike cells constitutively secrete CXCL12, the ligand for CXCR4, thereby attracting and rescuing CLL B cells from apoptosis in a contact-dependent fashion. Therefore, the CXCR4-CXCL12 axis represents a potential therapeutic target in CLL. We evaluated the most active CXCR4-specific antagonists (T140, TC14012, TN14003) for their capacity to inhibit CXCL12 responses in CLL cells. T140, or its analogs, inhibited actin polymerization, chemotaxis, and migration of CLL cells beneath stromal cells. CXCL12-induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) was abolished by CXCR4 antagonists. TC14012 and TN14003 antagonized the antiapoptotic effect of synthetic CXCL12 and stromal cell-mediated protection of CLL cells from spontaneous apoptosis. Furthermore, we found that stromal cells protected CLL cells from chemotherapy-induced apoptosis. Treatment with CXCR4 antagonists resensitized CLL cells cultured with stromal cells to fludarabine-induced apoptosis. These findings demonstrate that CXCR4 blocking agents effectively antagonize CXCL12-induced migratory and signaling responses and stromal protection of CLL cells from spontaneous or fludarabine-induced apoptosis. As such, small molecular CXCR4 antagonists may have activity in the treatment of patients with this disease.
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PMID:Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. 1590 92

Activation of STAT3 (signal transducer and activator of transcription 3) plays a crucial role in cell survival and proliferation. The aim of the present study was to clarify the role of STAT3 signalling in the protection of polyamine-depleted intestinal epithelial cells against TNF-alpha (tumour necrosis factor-alpha)-induced apoptosis. Polyamine depletion by DFMO (alpha-difluoromethylornithine) caused phosphorylation of STAT3 at Tyr-705 and Ser-727. Phospho-Tyr-705 STAT3 was immunolocalized at the cell periphery and nucleus, whereas phospho-Ser-727 STAT3 was predominantly detected in the nucleus of polyamine-depleted cells. Sustained phosphorylation of STAT3 at tyrosine residues was observed in polyamine-depleted cells after exposure to TNF-alpha. Inhibition of STAT3 activation by AG490 or cell-membrane-permeant inhibitory peptide (PpYLKTK; where pY represents phospho-Tyr) increased the sensitivity of polyamine-depleted cells to apoptosis. Expression of DN-STAT3 (dominant negative-STAT3) completely eliminated the protective effect of DFMO against TNF-alpha-induced apoptosis. Polyamine depletion increased mRNA and protein levels for Bcl-2, Mcl-1 (myeloid cell leukaemia-1) and c-IAP2 (inhibitor of apoptosis protein-2). Significantly higher levels of Bcl-2 and c-IAP2 proteins were observed in polyamine-depleted cells before and after 9 h of TNF-alpha treatment. Inhibition of STAT3 by AG490 and DN-STAT3 decreased Bcl-2 promoter activity. DN-STAT3 decreased mRNA and protein levels for Bcl-2, Mcl-1 and c-IAP2 in polyamine-depleted cells. siRNA (small interfering RNA)-mediated inhibition of Bcl-2, Mcl-1 and c-IAP2 protein levels increased TNF-alpha-induced apoptosis. DN-STAT3 induced the activation of caspase-3 and PARP [poly(ADP-ribose) polymerase] cleavage in polyamine-depleted cells. These results suggest that activation of STAT3 in response to polyamine depletion increases the transcription and subsequent expression of anti-apoptotic Bcl-2 and IAP family proteins and thereby promotes survival of cells against TNF-alpha-induced apoptosis.
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PMID:STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells. 1604 38

Leukemia-inhibitory factor (LIF) is indispensable for maintaining the undifferentiated state when propagating mouse embryonic stem (ES) cells. We previously cloned chicken LIF (chLIF) cDNA and demonstrated that it maintained chicken ES cell cultures in an undifferentiated state. Here, we developed two monoclonal antibodies, HUL-1 and HUL-2, against chLIF, which specifically recognized recombinant chLIF (rchLIF) produced by Escherichia coli and Chinese hamster ovary K1 cells, in enzyme-linked immunosorbent assays and Western blot analysis. In addition, HUL-2 inhibited the phosphorylation of signal transducer and activator of transcription 3 by rchLIF in chicken blastodermal cells (CBCs), but not that of mitogen-activated protein kinase kinase. Furthermore, the addition of HUL-2 to CBC cultures resulted in embryoid bodies forming earlier than in normal cultures. These results indicated that HUL-2 recognized not only rchLIF but also native chLIF, and suggested that CBCs in culture produce LIF, which functions in autocrine signaling.
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PMID:Effect of novel monoclonal antibodies on LIF-induced signaling in chicken blastodermal cells. 1615 Apr 88

Emodin is an active component of a traditional Chinese and Japanese medicine isolated from the root and rhizomes of Rheum palmatum L. Here, we show that emodin significantly induces cytotoxicity in the human myeloma cells through the elimination of myeloid cell leukemia 1 (Mcl-1). Emodin inhibited interleukin-6-induced activation of Janus-activated kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription 3 (STAT3), followed by the decreased expression of Mcl-1. Activation of caspase-3 and caspase-9 was triggered by emodin, but the expression of other antiapoptotic Bcl-2 family members, except Mcl-1, did not change in the presence of emodin. To clarify the importance of Mcl-1 in emodin-induced apoptosis, the Mcl-1 expression vector was introduced into the human myeloma cells by electroporation. Induction of apoptosis by emodin was almost abrogated in Mcl-1-overexpressing myeloma cells as the same level as in parental cells, which were not treated with emodin. In conclusion, emodin inhibits interleukin-6-induced JAK2/STAT3 pathway selectively and induces apoptosis in myeloma cells via down-regulation of Mcl-1, which is a good target for treating myeloma. Taken together, our results show emodin as a new potent anticancer agent for the treatment of multiple myeloma patients.
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PMID:Emodin has a cytotoxic activity against human multiple myeloma as a Janus-activated kinase 2 inhibitor. 1736 92

Bruton's tyrosine kinase (BTK) was previously demonstrated to be a mediator of oxidative stress-induced apoptosis in irradiated neoplastic B-cells and B-cell precursors. Defective BTK expression in leukaemic B-cell precursors from infants with t(4;11) acute lymphoblastic leukaemia has been associated with radiation resistance. The present study examined whether BTK mediates apoptosis during oxidative stress by interfering with the anti-apoptotic function of signal transducer and activator of transcription 3 (STAT3). BTK physically associated with and tyrosine phosphorylated STAT3; this association was promoted by pervanadate (PV)-induced oxidative stress. The BTK/STAT3 interaction appeared to prevent STAT3 response to oxidative stress, because PV-induced STAT3 activation was markedly enhanced in DT40 chicken lymphoma B-cells that were rendered BTK-deficient by targeted disruption of the btk gene as well as in BTK-deficient RAMOS-1 human lymphoma B-cells. These BTK-deficient cells were highly resistant to oxidative stress-induced apoptosis triggered by PV treatment. Reconstitution of BTK-deficient DT40 cells with wild-type human BTK gene eliminated the amplification of the STAT3 response and restored the PV-induced apoptotic signal. Similarly, while the BTK-positive NALM-6 human leukaemic B-cell precursor cell line showed no STAT3 activation after PV treatment and was exquisitely sensitive to PV-induced apoptosis, PV failed to induce apoptosis in BTK-deficient RAMOS-1 human lymphoma B-cells that showed a robust STAT3 response. These results provide unprecedented biochemical and genetic evidence for a unique mode of cross-talk that occurs between BTK and STAT3 pathways during oxidative stress, whereby BTK may trigger apoptosis via negative regulation of the anti-apoptotic STAT3 activity.
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PMID:Bruton's tyrosine kinase prevents activation of the anti-apoptotic transcription factor STAT3 and promotes apoptosis in neoplastic B-cells and B-cell precursors exposed to oxidative stress. 1736 10

How diverse stimuli control hemopoietic lineage development is unknown. An early event during induction of macrophage differentiation in the myeloblastic leukemia M1 cell line by different stimuli, such as leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), is expression of the colony-stimulating factor-1 receptor (CSF-1R). We report that expression of active CSF-1R in M1 cells accelerated their subsequent terminal differentiation into macrophages in response to LIF and IL-6 when compared with cells lacking the CSF-1R or expressing the receptor with compromised kinase activity; however, there was no requirement for signaling through the CSF-1R, for example, via endogenous CSF-1, during the actual LIF-induced and IL-6-induced differentiation stage. Differences were noted in the signaling pathways downstream of the LIF receptor depending on the presence of the CSF-1R. Both LIF and IL-6 gave an additive response with CSF-1, consistent with LIF and IL-6 acting via a different signaling pathway (signal transducer and activator of transcription 3 dependent) than CSF-1 (extracellular signal-regulated kinase dependent). Based at least on this cell model, we propose that terminal macrophage differentiation involves a critical priming or deterministic phase in which signaling by the CSF-1R prepares a precursor population for subsequent rapid terminal macrophage differentiation by diverse stimuli. We also propose that expression and activation of the CSF-1R explain much prior literature on macrophage lineage commitment in M1 leukemic cells and may be important in controlling the progression of certain myeloid leukemias.
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PMID:The critical role of the colony-stimulating factor-1 receptor in the differentiation of myeloblastic leukemia cells. 1833 52

Suppressor of cytokine signaling 3 (SOCS3) inhibits leukemia-inhibitory factor (LIF) signaling and acts as a negative regulator. Deletion of SOCS3 causes embryonic lethality because of placental failure, and genetic reduction of LIF or the LIF receptor (LIFR) in SOCS3-deficient mice rescues placental defects and embryonic lethality; this indicates that SOCS3 is an essential inhibitor of LIFR signaling. However, the downstream signaling molecule that acts as a link between the LIFR and SOCS3 has not been identified. In this study we explored the downstream signaling of LIFR. The administration of LIF to SOCS3-heterozygous pregnant mice promotes trophoblast giant cell differentiation and accelerates placental failure in SOCS3-deficient mice. SOCS3-deficient trophoblast stem cells show enhanced and prolonged signal transducer and activator of transcription 3 (Stat3) activation by LIF stimulation. Further, in the trophoblasts of SOCS3-deficient placenta and differentiating cells from the choriocarcinoma-derived cell line Rcho-1 cells, constitutive activation of Stat3 is observed. The forced expression of SOCS3, dominant-negative Stat3, and dominant-negative Janus kinase 1 (JAK1) in Rcho-1 cells significantly suppressed the trophoblast giant cell differentiation of these cells. In addition, the number of trophoblast giant cells is significantly reduced concomitant with an increased number of precursor trophoblasts in JAK1-deficient placentas. Finally, JAK1 deficiency rescues placental defects and embryonic lethality in SOCS3-deficient mice. These results indicate that the LIFR signaling is finely coordinated by JAK1, Stat3, and SOCS3 and regulates trophoblast giant cell differentiation. In addition, these data establish that LIFR-JAK1-Stat3-SOCS3 signaling is an essential pathway for the regulation of trophoblast giant cell differentiation.
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PMID:Leukemia inhibitory factor regulates trophoblast giant cell differentiation via Janus kinase 1-signal transducer and activator of transcription 3-suppressor of cytokine signaling 3 pathway. 1845 Oct 94


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