Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signal transducer and activator of transcription 3 (STAT3), normally activated by Janus kinase (JAK) in response to cytokine stimulation, has been shown to have oncogenic potential. In addition to JAK, recent data suggest that STAT3 can also be activated by other proteins such as the aberrant fusion protein, NPM-ALK, which is expressed in a subset of systemic anaplastic large cell lymphoma (ALCL). In this study, we investigated the possible role of JAK in activating STAT3 in ALCL using two ALK-positive ALCL cell lines, Karpas 299 and SU-DHL-1. At the steady state, JAK3 showed detectable tyrosine phosphorylation by immunoprecipitation. Treatment with AG490, a JAK inhibitor, decreased but did not completely abrogate tyrosine phosphorylation of JAK3 and STAT3 in a concentration-dependent manner. Similar results were obtained using two other inhibitors of JAK3, WHI-P131 and WHI-P154. These biochemical changes were associated with apoptosis in both cell lines that was coupled with activation of caspase 3 and decreased bcl-xL and bcl-2. Cell cycle analysis revealed a decrease in the S phase, which may be attributed to cyclin D3 downregulation and p21(waf1) upregulation. Importantly, the tyrosine kinase activity of NPM-ALK, as assessed by an in vitro assay, decreased with increasing concentrations of AG490. Our findings highlight the importance of JAK3 in activating STAT3 in ALCL, and that NPM-ALK-mediated activation of STAT3 is influenced by the functional status of JAK3.
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PMID:Inhibition of JAK3 induces apoptosis and decreases anaplastic lymphoma kinase activity in anaplastic large cell lymphoma. 1293 99

Bag-1 is a novel multifunctional protein. It was identified based on its ability to bind the anti-apoptotic protein, bcl-2, and also reported to interact with the heat shock protein 70 kDa (Hsp70). Thus, bag-1 may modulate apoptosis and the chaperone activity. More interestingly, bag-1 can bind to several growth factor receptors or steroid hormone receptors and regulate their function and signaling. The receptor of hepatocyte growth factor (HGF), c-met, associated with bag-1 in a study measuring immunoprecipitation in endothelial cells, we decided to investigate the contribution of bag-1 to the anti-apoptotic action of HGF. Endogenous expression of bag-1 in endothelial cells was confirmed mainly in the cytosol fraction. The treatment of human recombinant HGF (rHGF) increased tyrosine kinase and ERK phosphorylation, whereas over-expression of bag-1 had no effect on this phosphorylation. In DNA synthesis as assessed by thymidine incorporation, over-expression of bag-1 also did not induce any additional increase. In contrast, in an assay of cell death as assessed by caspase activity and lactate dehydrogenase release, over-expression of bag-1 alone attenuated serum-free and tumor necrosis factor-alpha-induced cell death in endothelial cells. No synergistic effect was observed between bag-1 and rHGF. To further study the association of HGF and bag-1, we examined the effect of a deletion mutant of the bag-1 C-terminal region (CTR), because bag-1 CTR is necessary to bind to c-met. Unexpectedly, over-expression of bag-1 CTR also attenuated the endothelial cell death, similar to rHGF. Taken together, these results indicate that over-expression of bag-1 has an anti-apoptotic effect on endothelial cells independent of HGF signaling.
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PMID:Lack of association between the hepatocyte growth factor receptor, c-met, and the anti-apoptotic action of bag-1 in endothelial cells. 1519 84

Controversy still exists over the response to therapy and prognosis of patients with primary mediastinal B-cell lymphoma (PMBL). Recent data from the International Extranodal Lymphoma Study Group (IELSG) suggest that a MACOP-B (methotrexate, adriamycin, cyclophosphamide, vincristine, prednisone, bleomycin) chemotherapy regimen followed by radiotherapy may be a better induction strategy than other previously used treatments. Although the pathobiology of PMBL has been widely studied, its precise histology, phenotype, and molecular characteristics are still not clear. To date, phenotypic analysis has revealed the following phenotype: positivity for CD45 and CD20, but negativity for CD3, CD10, CD21, Class I/II major histocompatibility antigens, and a variety of other immunohistochemical markers. CD79a is generally detected, despite an absence of surface immunoglobulins (Igs). CD30 staining is observed in most cases, but is weaker and less homogeneous than in classic Hodgkin's lymphoma or anaplastic large cell lymphoma. BCL-2 protein is usually expressed but there are few data describing the expression of MUM1/IRF4, PAX5/BSAP, BCL-6, or the B-cell transcription factors BOB.1, Oct-2, and PU.1. Cytogenetic studies reveal gains in segments of chromosome 9p, including amplification of the REL proto-oncogene and the tyrosine kinase gene JAK2. Other molecular findings include: C-myc mutations or rearrangements, p53 mutations, IgV(H), gene mutations, and bcl-2 and mal over-expression. bcl-6 mutations and bcl-2 gene rearrangements are generally absent, suggesting that PMBL is of pre-germinal center (GC) origin. However, two recent reports show isotype-switched Ig genes with a high frequency of somatic hypermutations as well as variants in the 5' noncoding region of the bcl-6 gene. The IELSG collected 137 PMBL cases for extensive pathologic review. Histologically, the lymphomatous growth was predominantly diffuse with sclerosis that induced compartmentalized cell aggregation. It consisted of large cells with varying degrees of nuclear polymorphism and clear to basophilic cytoplasm. Molecular analysis was performed on 40 cases and showed novel findings. More than half of the cases displayed bcl-6 gene mutations, which usually occurred together with functioning somatic IgV(H) gene mutations, and BCL-6 and/or MUM1/IRF4 expression. The present study supports the concept that PBML is derived from activated GC or post-germinal center cells. However, it differs from other aggressive B-cell lymphomas in that it shows defective Ig production despite the expression of Oct-2, BOB.1, and PU.1 transcription factors, and a lack of IgV(H) gene crippling mutations.
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PMID:Pathobiology of primary mediastinal B-cell lymphoma. 1520 21

Advances in our understanding of the pathophysiology of acute myeloid leukemia (AML) have not yet led to major improvements in disease-free and overall survival of adults with this disease. Only about one-third of those between ages 18-60 who are diagnosed with AML can be cured; disease-free survival is rare and current therapy devastating in older adults. In this chapter, challenges in the management of the adult with AML are discussed, including ongoing questions concerning the optimal choice of induction and postremission therapy such as the rationale for and role of allogeneic and autologous stem cell transplantation in a variety of settings, the special considerations pertaining to the older patient, and the development of new, so-called targeted therapies. In Section I, Dr. Richard Stone reviews state-of the-art therapy in AML in the era of change from a morphological to a genetically based classification system. Questions being addressed in ongoing randomized cooperative group trials include anthracycline dose during induction, the efficacy of drug-resistance modulators, and the utility of pro-apoptotic agents such as the anti-bcl-2 antisense oligonucloetide. Developmental therapeutics in AML include drug resistance modulation, anti-angiogenic strategies, immunotherapy, and signal transduction-active agents, particularly the farnesyl transferase inhibitors as well as those molecules that inhibit the FLT3 tyrosine kinase, activated via mutation in 30% of patients. In Section II Dr. Margaret O'Donnell discusses the role of stem cell transplantation in AML. Several advances including expanded donor pools, the movement toward peripheral blood stem cell collection, newer immunosuppressive drugs and antifungals, and particularly the advent of nonmyeloablative transplant have made the allogeneic option more viable. The subset-specific role for high-dose chemotherapy with autologous stem cell support and/or for allogeneic transplant in AML patients in first remission is outlined. Although preconceived notions about the role of transplant abound, the clinical data supporting a risk-adapted approach are covered. Finally, guidance concerning the use of nonmyeloablative or reduced-intensity allogeneic transplantation is provided. In Section III Dr. Mikkael Sekeres reviews the approach to the older patient with AML. Unique biological and therapeutic considerations make AML in this age group a vastly different disease than that in younger adults. The outcome data, including the role of specific anthracylines, hematopoietic growth factors, and drug-resistance modulators, are summarized. Communicating with older adults with AML and their families regarding selection of the optimal treatment strategy, often a stark choice between induction chemotherapy and palliative care, is covered.
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PMID:Acute myeloid leukemia. 1556 79

Current treatment options for ovarian cancer, which is one of the most widespread gynecological malignancies, are limited, mainly because patients with advanced-stage disease often develop resistance to chemotherapeutics. In breast cancer cells, several studies suggest that overexpression of the human epidermal growth factor receptor-2 (HER-2) leads to increased resistance against certain, but not all cytotoxic drugs. In ovarian carcinoma, conflicting data on the correlation of HER-2 expression and tumor cell sensitivity exist. In this paper, we explore the role of HER-2 expression and signaling levels pertaining to paclitaxel (Taxol) chemoresistance by applying three different and independent strategies in SKOV-3 ovarian carcinoma cells. Firstly, we show that treatment with the HER-2 inhibitory antibody trastuzumab (Herceptin), which is well established in tumor therapy, results in markedly increased, rather than decreased, cellular paclitaxel resistance. Next, we present two newly developed low molecular weight inhibitors of HER-2 tyrosine kinase activity, D-69491 and D-70166. With both drugs, the decrease in cellular paclitaxel sensitivity upon HER-2 inhibition is confirmed. Finally, for more detailed analysis we stably downregulate HER-2 expression by ribozyme-targeting. Using clonal ribozyme-transfected SKOV-3 cells with different residual HER-2 levels, we establish a 'HER-2 gene dose effect' of paclitaxel cytotoxicity. We show that this effect is due to differential induction of apoptosis and differential cell cycle inhibition by paclitaxel. Finally, paclitaxel- or HER-2-mediated alterations in the phosphorylation of MAP kinases p42/44, Stress-activated protein kinase/Jun-terminal kinase (SAPK/JNK), and p38, and effects on the activation of caspase-3, caspase-7, and bcl-2 are discussed. We conclude that paclitaxel cytotoxicity in SKOV-3 cells is 'HER-2 dose-dependent' and identify cell proliferation as one underlying cellular event of this effect.
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PMID:Inhibition of HER-2 by three independent targeting strategies increases paclitaxel resistance of SKOV-3 ovarian carcinoma cells. 1570 Jan 18

N-Methyl-D-aspartate (NMDA) at a subtoxic concentration (100 microM) promotes neuronal survival against glutamate-mediated excitotoxicity via a brain-derived neurotrophic factor (BDNF) autocrine loop in cultured cerebellar granule cells. The signal transduction mechanism(s) underlying NMDA neuroprotection, however, remains elusive. The mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3-K) pathways alter gene expression and are involved in synaptic plasticity and neuronal survival. This study tested whether neuroprotective activation of NMDA receptors, together with TrkB receptors, coactivated the MAPK or PI3-K pathways to protect rat cerebellar neurons. NMDA receptor activation caused a concentration- and time-dependent activation of MAPK lasting 24 hr. This activation was blocked by the NMDA receptor antagonist MK-801 but was attenuated only partially by the tyrosine kinase inhibitor k252a, suggesting that activation of both NMDA and TrkB receptors are required for maximal neuroprotection. The MAPK kinase (MEK) inhibitor U0126 (10 microM) partially blocked NMDA neuroprotection, whereas LY294002, a selective inhibitor of the PI3-K pathway, did not affect the neuroprotective activity of NMDA. Glutamate excitotoxicity decreased bcl-2, bcl-X(L), and bax mRNA levels,. NMDA increases Bcl-2 and Bcl-X(L) protein levels and decreases Bax protein levels. NMDA and TrkB receptor activation thus converge on the extracellular signal-regulated kinase (ERK) 1/2 signaling pathway to protect neurons against glutamate-mediated excitotoxicity. By increasing antiapoptotic proteins of the Bcl-2 family, NMDA receptor activation may also promote neuronal survival by preventing apoptosis.
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PMID:N-methyl-D-aspartate and TrkB receptors protect neurons against glutamate excitotoxicity through an extracellular signal-regulated kinase pathway. 1574 43

Acute myeloid leukaemia (AML) is a heterogenous malignant disease with diverse biological features in which disease progression at the level of CD34+ cells has a major impact on the resistance to chemotherapy and relapse. The AML blast cells in these elderly patients are often characterised by several unfavourable covariates that predict the poor treatment outcome, including high stem cell marker CD34 expression, minimally or undifferentiated features, high P-glycoprotein expression, high bcl-2/bax ratio, unfavourable karyotype and more frequent internal tandem duplications (ITDs) and mutations of class III receptor-type tyrosine kinase for key haematopoietic cytokines: Flt-3 (receptor for Flt-ligand), c-kit (receptor for stem cell factor) and fms (receptor for M-CSF). Testing the new and more specific molecular-targeted therapeutic approaches in CD34+ AML cells can provide the basis for a more effective combined molecular/chemotherapy regimen and may consequently improve the treatment outcome in elderly AML patients. Therefore, the present study was performed to evaluate whether stem cell factor-antibody (anti-SCF) can enhance the efficacy of the two main chemotherapeutic drugs used in AML therapy: cytarabine and daunorubicin at low doses in human-resistant CD34+ AML cells, in an attempt to identify a novel effective regimen with tolerable side-effects for elderly AML patients. The effect of anti-SCF on each of the two chemotherapeutic drugs-induced apoptosis and necrosis was investigated in KG1a human-resistant CD34+ AML cells expressing P-glycoprotein to determine its enhancing activity. Anti-SCF has significantly enhanced the low dose cytarabine- and daunorubicin-induced apoptosis+necrosis in KG1a CD34+ AML cells from 12.0+/-1.7 to 40.9+/-5.9% and from 16.3+/-0.9 to 48.9+/-1.0%, respectively, p<0.01. It has also exerted its significant enhancement activity on the low dose cytarabine- and daunorubicin-induced apoptosis+necrosis in KG1a CD34+ AML cells in the presence of SCF, p<0.05. Anti-SCF has significantly enhanced the low dose cytarabine- and daunorubicin-induced bcl-2 reduction in KG1a CD34+ AML cells from 26.7+/-0.6 to 64.6+/-1.0% and from 59.8+/-3.1 to 80.1+/-7.9%, respectively, p<0.01. The addition of SCF has not altered the low dose cytarabine- and daunorubicin-induced bcl-2 reduction in KG1a CD34+ AML cells (Table 4). Anti-SCF has also significantly enhanced the low dose cytarabine- and daunorubicin-induced bcl-2 reduction in KG1a CD34+ AML cells in the presence of SCF, p<0.05. The unique potent enhancing activity of anti-SCF on low dose chemotherapy-induced apoptosis and necrosis in extremely resistant AML cells suggest a novel promising role for the treatment of elderly AML patients. Further studies are warranted to evaluate a similar enhancing effect for anti-SCF in blast cells from elderly AML patients in primary cultures before its introduction in a pilot clinical study. In conclusion, the combination of anti-SCF and the low dose cytarabine provides a promising solution for the dilemma of therapy in elderly AML patients.
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PMID:Human stem cell factor-antibody [anti-SCF] enhances chemotherapy cytotoxicity in human CD34+ resistant myeloid leukaemia cells. 1611 92

Treatment of adult Philadelphia chromosome-positive lymphocytic leukemia is rarely successful. We report here the effects of TZD18, a novel dual ligand specific for peroxisome proliferator-activated receptor alpha and gamma (PPARalpha/gamma) on Ph(+) lymphocytic leukemia cell lines BV173, SD1, and SupB-15. Exposure of these cells to TZD18 resulted in growth inhibition in a dose- and time-dependent manner that was associated with G(1) cell cycle arrest. This effect was much stronger than that mediated by the PPARgamma ligand pioglitazone (PGZ), which also belongs to the thiazolidinediones (TZD) class of ligands. However, it may not be mediated through PPARgamma or PPARalpha activation because antagonists of PPARgamma and PPARalpha cannot reverse it. Study of the key regulators of cell cycle progression by Western blot analysis showed that the expression of the cyclin-dependent kinase inhibitor (CDKI) p27(kip1), but not that of p21(cip1), was enhanced, whereas that of c-Myc, cyclin E, cyclin D2, and cyclin-dependent kinases 2 and 4 (CDK-2 and CDK-4) was decreased when these cells were treated with TZD18 (10 or 20 microM). Therefore, the up-regulation of p27(kip1) and the down-regulation of CDK-2 and CDK-4 may, at least in part, account for the G(1) cell cycle arrest. Furthermore, a remarkable induction of apoptosis was observed in the cells treated with this dual ligand. No obvious alteration of bcl-2 protein level occurred, but bax was up-regulated in these TZD18-treated cells. Activation of caspase 8 and caspase 9 by TZD18 was also observed. Importantly, NF-kappaB DNA-binding activity was markedly decreased by the TZD18 treatment. In addition, TZD18 enhanced the growth inhibitory effect of imatinib, a specific tyrosine kinase inhibitor therapeutically used in the treatment of Ph(+) leukemia. Overall, our findings strongly suggest that TZD18 may offer a new therapeutic approach to aid in the treatment of Ph(+) lymphocytic leukemia.
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PMID:Growth inhibition and apoptosis in human Philadelphia chromosome-positive lymphoblastic leukemia cell lines by treatment with the dual PPARalpha/gamma ligand TZD18. 1640 7

In non-small-cell lung cancer (NSCLC), stage of the disease is still the most important prognostic factor. Other than stage, many biological markers and many other prognostic factors are studied to define their effects on prognosis of lung cancer. In this study, we aimed to evaluate the expressions of Bax and bcl-2 genes which are important in apoptosis and c-kit, which is a tyrosine kinase transmembrane receptor, as well as searched their response to treatment modalities and effects on survival. Sixty-nine NSCLC cases' pathological samples were stained with specific Bax, bcl-2 and c-kit dyes by immunohistochemical (IHC) methods. IHC evaluation was done by the semichantitative method according to the distribution and intensity of the staining. Twelve of 69 cases (17.4%) were stage I, 28 (40.5%) were stage II, 17 were (24.6%) stage IIIA, nine cases were (13.1%) stage IIIB and three cases (4.4%) were stage IV patients. Their histological subtypes were as follows: of 69 cases, 36 (52.2%) were squamous cell carcinoma, 28 (40.6%) were adenocarcinoma, five (7.2%) were adenosquamous cell carcinoma (two patients) and large-cell carcinoma (three patients). The positive immunostaining rates for Bax and bcl-2 in whole group, squamous cell carcinoma and adenocarcinoma groups were 40.6%/36.2%, 55.6/69.4% and 25.0/0.0%, respectively. The positive immune staining rates for c-kit in whole group, squamous cell carcinoma and adenocarcinoma groups were 7.2, 5.6 and 7.1%, respectively. We didn't find any correlation with Bax, bcl-2 and c-kit expressions and clinicopathological parameters such as age, tumour size, lymph node involvement, smoking, stage of the disease, response to radiotherapy and chemotherapy. Results are interpreted according to survival; bax and bcl-2 expressions were not so effective both in whole group and histologically subgrouped patients. C-kit expression was also found not related with survival in whole group whereas found as a bad prognostic factor in patients with squamous cell carcinoma. These findings could indicate that the expression of apoptotic pathway markers and c-kit may have a role in the prognosis of early stage NSCLC, especially with squamous cell carcinoma subtype.
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PMID:Bax, bcl-2 and c-kit expression in non-small-cell lung cancer and their effects on prognosis. 1680 52

JSI-124 (cucurbitacin I) has been recently described as a specific inhibitor of signal transducer and activator of transcription-3 (STAT3). As STAT3 activation is pathogenetically important in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL), we investigated whether JSI-124 can mediate significant inhibitory effects in this cell type. In two ALK+ ALCL cell lines (Karpas 299 and SU-DHL-1), JSI-124 significantly reduced the number of viable cells to 50% of that of negative controls at a dose of 5-10 micromol/l at 24 h and 1-1.25 micromol/l at 48 h. This decrease in viability was associated with apoptosis, as confirmed by the increase in the subG(0/1) fraction, poly(ADP-ribose)polymerase cleavage and expression of active caspase 3. JSI-124 decreased the phosphorylated-STAT3 and -Janus kinase-3 (JAK3) levels in a dose-dependent fashion, and these changes were coupled with significant decreases in several STAT3 downstream targets, including mcl-1, bcl-2, bcl-xL and cyclin D3. Interestingly, JSI-124 also dramatically decreased the protein levels of JAK3 and nucleophosmin (NPM)-ALK, and these effects were reversible by MG132. Our data support that JSI-124 is a potentially useful therapeutic agent for ALK+ ALCL. In addition to its role as a tyrosine kinase inhibitor, JSI-124 appears to be involved in regulating proteosome degradation for proteins such as JAK3 and NPM-ALK.
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PMID:JSI-124 (cucurbitacin I) inhibits Janus kinase-3/signal transducer and activator of transcription-3 signalling, downregulates nucleophosmin-anaplastic lymphoma kinase (ALK), and induces apoptosis in ALK-positive anaplastic large cell lymphoma cells. 1693 98


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