Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) serves as an extracellular signal that triggers apoptosis in tumor cells. To characterize the molecular events involved in TRAIL-induced apoptotic signaling, we investigated the role of extracellular signal-regulated kinase 1/2 (ERK1/2) in HeLa cell death. Here we show that TRAIL-activated ERK1/2 through a tyrosine kinase-dependent pathway, subsequently elevated anti-apoptotic Bcl-2 protein levels. ERK1/2 inhibition with PD98059 promoted apoptotic cell death through the downregulation of ERK1/2 activity and Bcl-2 protein levels. Moreover, tyrosine kinase inhibition with Genistein in TRAIL-induced apoptosis effectively attenuated ERK1/2 activity and enhanced apoptotic cell death. Taken together, our results indicate that ERK1/2 activation via tyrosine kinase pathway plays a protective role as the cellular defense mechanism through the upregulation of Bcl-2 protein levels in TRAIL-induced apoptosis.
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PMID:The activation of ERK1/2 via a tyrosine kinase pathway attenuates trail-induced apoptosis in HeLa cells. 1630 93

Among activating Flt3 mutations that have been shown in 25-30% of acute myeloid leukaemia (AML) Flt3-internal tandem duplication (ITD) mutations are predominant. We investigated the influence of all-trans-retinoic acid (ATRA) and granulocyte colony stimulating factor (G-CSF) for their effects on differentiation and apoptosis in human cell lines with different Flt3 variants (THP-1 versus MV4-11 and MOLM13) dependent on the inhibition of Flt3 tyrosine kinase by the bis(lH-2-indolyl)methanone D-65476. While myeloid differentiation was not observed in both Flt3-ITD cell lines (MV4-11 and MOLM13), we demonstrate an enhanced proapoptotic effect of D-65476 in the presence of ATRA that was restricted to the Flt3-ITD expressing cells. The combined treatment with ATRA and D-65476 also led to a pronounced down-regulation of surviv in on mRNA and protein level in Flt3-ITD but not in Flt3 wildtype expressing cells (THP-1). Surprisingly, there was no differential expression of important proteins like Bcl-X(L), Bcl-2 or Bax that might explain enhanced apoptosis. Furthermore, Akt phosphorylation after stimulation with Flt3 ligand dependent on D-65476 was not affected by pretreatment with ATRA. We suggest that regulation of inhibitors of apoptosis might play a crucial role how ATRA can increase the proapoptotic effect of Flt3 inhibitors in myeloid leukemia cells expressing Flt3-ITD. This effect can potentially be exploited for the treatment of Flt3-ITD positive acute myeloid leukemia.
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PMID:ATRA can enhance apoptosis that is induced by Flt3 tyrosine kinase inhibition in Flt3-ITD positive cells. 1647 6

Vav1 is an hematopoietic-specific Rho guanine nucleotide exchange factor coupling tyrosine kinase receptors and Rac GTPases, and has been implicated in transformation of fibroblasts and pancreas. To determine the biologic effect and oncogenic potential of Vav1 in hematopoietic lineages, we stably express oncogenic mutant of Vav1 in primary bone marrow cells using retrovirus-mediated gene transfer. Contrary to the growth stimulatory effects observed in fibroblasts, oncogenic Vav1 inhibits hematopoietic stem cell/progenitor engraftment in vivo and progenitor cell expansion in vitro via inducing apoptosis. The oncogenic Vav1-induced apoptosis is associated with reduced expression of Bcl-2 and Bcl-xL proteins and effectively suppressed by transgenic overexpression of Bcl-2, suggesting Vav1-mediated signaling via Bcl-2 in apoptosis. Also, oncogenic Vav1 stimulates sustained activation of Rac GTPases and the biologic effects of oncogenic Vav1 are Rac-dependent. Further, when expressed in the p53-deficient cells, which express elevated Bcl-2 and Bcl-xL and are resistant to the apoptosis, oncogenic Vav1 enhances both proliferation and self-renewal of hematopoietic progenitor cells. These results demonstrate clear phenotypic differences between wild-type and p53(-/-) hematopoietic cells expressing oncogenic Vav1, and suggest oncogenic potential of Vav1-mediated pathways in primary hematopoietic cell when they collaborate with additional genetic hits that affect the p53 pathway.
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PMID:Oncogenic Vav1 induces Rac-dependent apoptosis via inhibition of Bcl-2 family proteins and collaborates with p53 deficiency to promote hematopoietic progenitor cell proliferation. 1647 42

The heterogeneity of acute myeloid leukemia (AML) has been established by many new insights into the diagnosis, pathogenesis, clinical manifestations, treatment, and prognosis of patients with AML. Morphology remains the foundation for the diagnosis. However, additional diagnostic studies, including immunophenotyping, cytogenetic evaluation, and molecular genetic studies, are necessary to develop treatments because specific subtypes of AML can now be approached with targeted therapy. Acute promyelocytic leukemia (APL), defined by a single molecular abnormality, is now treated with specific targeted therapy, all-trans retinoic acid (ATRA), and this subtype of AML is now highly curable. Currently, a number of agents have been explored in AML, including anti-CD33 antibodies and immunoconjugate drugs, inhibitors of multidrug resistance proteins, farnesyl transferase inhibitors, tyrosine kinase inhibitors, anti-Bcl-2 transcription agents, and inhibitors of mammalian target of rapamycin (mTOR). New alkylating agents, and purine analogs such as Cloretazine and clofarabine, affect DNA and ribonucleoside reductases, respectively. These agents have shown promise in small studies. Large phase III studies will address whether these are effective in inducing complete responses. Combining targeted agents with chemotherapy may improve the response rates. The plan for the future is to find therapeutic strategies that are specific for patients based on the specific biology of the disease. Future studies will investigate combinations of targeted therapies with each other and with chemotherapies to maximize the inhibition of multiple pathways present in AML. Additionally, evaluation of the identified prognostic factors and gene mutations will enable further pathologic classification of patients with AML.
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PMID:New agents for the treatment of acute myeloid leukemia. 1651 28

Gastrointestinal neuroendocrine tumours (NET) represent a heterogeneous tumour entity. The anti-neoplastic therapy of advanced NET disease is still unsatisfactory and innovative therapeutic approaches are needed. As NET frequently express insulin-like growth factors (IGFs) and their receptors (IGFR), known to promote survival, oncogenic transformation, tumour growth and spreading, the inhibition of the IGF/IGF-receptor system may offer possibilities for novel targeted treatment strategies of NET. Here, we studied the anti-neoplastic effects of an inhibition of the IGF-I receptor (IGF-1R) signalling in NET cells by the novel IGF-1R tyrosine kinase (TK) inhibitor NVP-AEW541, whose anti-neoplastic potency has not yet been tested in NET disease. Using two human NET cell lines with different growth characteristics, we demonstrated that NVP-AEW541 dose-dependently inhibited the proliferation of NET cells by inducing apoptosis and cell cycle arrest. Anti-neoplastic effects of NVP-AEW541 were also detected in primary cultures of human neuroendocrine gastrointestinal tumours. Apoptosis was characterized by activation of the apoptotic key enzyme, caspase-3, as well as by detection of changes in the expression of the pro- and anti-apoptotic proteins, BAX and Bcl-2, after NVP-AEW541 treatment. Cell cycle was arrested at the G1/S checkpoint. The anti-neoplastic effects of NVP-AEW541 involved the inactivation of ERK1/2. Induction of immediate cytotoxicity did not account for the anti-neoplastic effects of NVP-AEW541, as shown by measurement of lactate dehydrogenase release. Moreover, additive anti-neoplastic effects were observed when NVP-AEW541 was combined with cytostatics such as doxorubicin or the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, fluvastatin. This is the first report on the induction of apoptosis and cell cycle arrest by the IGF-1R-TK inhibitor, NVP-AEW541, in NET cells. The inhibition of the IGF/IGFR system appears to be a promising novel approach for future treatment strategies of NET disease.
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PMID:The insulin-like growth factor receptor 1 is a promising target for novel treatment approaches in neuroendocrine gastrointestinal tumours. 1660 Dec 84

Tumors of the central nervous system account for approximately 9% of all primary neoplasm in humans, while tumors of covering elements, the meninges, account for 13-19% and constitute the second largest group of brain tumors. These are known to exhibit a variety of chromosomal abnormalities besides change in the expression level of certain oncogenes. Among oncogenes, bcl2, an anti-apoptotic factor and ROS1 that encodes a protein with a structure similar to the epidermal growth factor (EGF) and insulin receptor and has a tyrosine kinase activity, have been shown to be associated with many malignant tumors. In the present study we have analysed the expression of bcl2 using immuno-histochemistry and ROS1 expression by reverse-transcription coupled with polymerase chain reaction (RT-PCR) of the transcript using primers specific for the intra-cellular domain and then tried to correlate the findings with the subtype of the meningioma defined on the basis of histology. Out of the six bcl2 positive cases in our study, there were three transitional tumors, two fibroblastic and one recurrent meningioma subtype. bcl2 seemed to be more consistently expressed in the cytoplasm of spindle cell component of meningiomas. Thirteen meningiothelial meningiomas did not show any staining for bcl2. ROS1 gene expression could be detected in 4 tumors all of those were Grade-I meningothelial meningiomas. One of the malignant meningioma included in the study was clearly negative for bcl2 as well as ROS1. Thus bcl2 and ROS1 oncogene expression in meningiomas are not concurrent and neither can be ascribed to any histologic subtype or grade of tumor.
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PMID:Bcl2 and ROS1 expression in human meningiomas: an analysis with respect to histological subtype. 1676 43

We show here that donepezil, galanathamine and tacrine, therapeutic acetylcholinesterase inhibitors currently being used for treatment of Alzheimer's disease, protect neuronal cells in a time- and concentration-dependent manner from glutamate neurotoxicity that involves apoptosis. The neuroprotective effects were antagonized by mecamylamine, an inhibitor of nicotinic acetylcholine receptors (nAChRs). Dihydro-beta-erythroidine and methyllycaconitine, antagonists for alpha4-nAChR and alpha7-nAChR, respectively, antagonized the protective effect of donepezil and galanthamine, but not that of tacrine. Previous reports suggest the involvement of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway in the nicotine-induced neuroprotection. Inhibitors for a non-receptor type tyrosine kinase, Fyn, and janus-activated kinase 2, suppressed the neuroprotective effect of donepezil and galanthamine, but not that of tacrine. Furthermore, LY294002, a PI3K inhibitor, also suppressed the neuroprotective effect of donepezil and galanthamine, but not that of tacrine. The phosphorylation of Akt, an effector of PI3K, and the expression level of Bcl-2, an anti-apoptotic protein, increased with donepezil and galanthamine treatment, but not with tacrine treatment. These results suggest that donepezil and galanthamine prevent glutamate neurotoxicity through alpha4- and alpha7-nAChRs, followed by the PI3K-Akt pathway, and that tacrine protects neuronal cells through a different pathway.
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PMID:Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. 1676 77

Hypereosinophilic syndrome (HES) has recently been recognized as a clonal leukemic lesion, which is due to a specific oncogenic event that generates hyperactive platelet-derived growth factor receptor-alpha-derived tyrosine kinase fusion proteins. In the present work, the effect of retinoids on the leukemic hypereosinophilia-derived EoL-1 cell line and on primary HES-derived cells has been investigated. We show that all-trans-retinoic acid (ATRA) inhibits eosinophil colony formation of HES-derived bone marrow cells and is a powerful inducer of apoptosis of the EoL-1 cell line. Apoptosis was shown in the nanomolar concentration range by phosphatidylserine externalization, proapoptotic shift of the Bcl-2/Bak ratio, drop in mitochondrial membrane potential, activation of caspases, and cellular morphology. Unlike in other ATRA-sensitive myeloid leukemia models, apoptosis was rapid and was not preceded by terminal cell differentiation. Use of isoform-selective synthetic retinoids indicated that retinoic acid receptor-alpha-dependent signaling is sufficient to induce apoptosis of EoL-1 cells. Our work shows that the scope of ATRA-induced apoptosis of malignancies may be wider within the myeloid lineage than thought previously, that the EoL-1 cell line constitutes a new and unique model for the study of ATRA-induced cell death, and that ATRA may have potential for the management of clonal HES.
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PMID:Apoptosis induction by retinoids in eosinophilic leukemia cells: implication of retinoic acid receptor-alpha signaling in all-trans-retinoic acid hypersensitivity. 1677 11

Chemotherapy has produced unsatisfactory results in pancreas cancer and novel approaches, including treatment tailoring by pharmacogenetic analysis and new molecular-targeted drugs, are required. The scarcity of effective therapies may reflect the lack of knowledge about the influence of tumor-related molecular abnormalities on responsiveness to drugs. Advances in the understanding of pancreas cancer biology have been made over the past decade, including the discovery of critical mutations in oncogenes (i.e., K-Ras) as well as the loss of tumor suppressor genes, such as TP53 and p16(INK4). Other studies showed the dysregulation of the expression of proteins involved in the control of cell cycle, proliferation, apoptosis, and invasiveness, such as Bcl-2, Akt, mdm2, and epidermal growth factor receptor. These characteristics might contribute to the aggressive behavior of pancreatic cancer and influence response to treatment. Indeed, the inactivation of p53 may explain the relative resistance to 5-fluorouracil, whereas Bcl-2 overexpression is associated with reduced sensitivity to gemcitabine. However, the future challenge of pancreas cancer chemotherapy relies on the identification of molecular markers that help in the selection of drugs best suited to the individual patient. Recent pharmacogenetic studies focused on genes encoding proteins directly involved in drug activity, showing the role of thymidylate synthase and human equilibrative nucleoside transporter-1 as prognostic factor in 5-fluorouracil- and gemcitabine-treated patients, respectively. Finally, inhibitors of signal transduction and angiogenesis are under extensive investigation, and several prospective trials have been devoted to this area. Pharmacogenetics is likely to play a central role in the personalization of treatment, to stratify patients based on their likelihood of response to both standard agents (i.e., gemcitabine/nucleoside transporters) and targeted treatments (i.e., epidermal growth factor receptor gene mutations and/or amplification and tyrosine kinase inhibitors), Thus, molecular analysis should be implemented in the optimal management of the patient affected by pancreatic adenocarcinoma.
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PMID:Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer. 1681 96

We have identified mitochondrial adenine nucleotide translocase (ANT)3 as a novel target up-regulated by IL-4 in human T cells. The IL-4-induced ANT3 expression is dependent on tyrosine kinase, NF-kappaB, PI3K/Akt, and Erk pathways. In fact, IL-4 induced specific activation of NF-kappaB, Akt, and Erk in Jurkat T cells and partially rescued these cells from dexamethasone-induced apoptosis. The IL-4-mediated T cell survival was blocked by inhibitors of tyrosine kinase, NF-kappaB, PI3K/Akt, and Erk. During the IL-4-induced T cell rescue, there was a concomitant increase in ANT3, nuclear NF-kappaB, and Bcl-2 and a decrease in ANT1, I-kappaB, and mitochondrial Bax-alpha levels. Importantly, overexpression of ANT3 effectively protected T cells from dexamethasone-induced apoptosis, while forced expression of ANT1 caused apoptosis. In contrast, siRNA knock-out of ANT3 expression induced T cell apoptosis and blocked the IL-4-mediated cell survival. Together these results suggest that ANT3 has a potential role in Th cell survival and immune cell homeostasis.
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PMID:IL-4-induced upregulation of adenine nucleotide translocase 3 and its role in Th cell survival from apoptosis. 1693 May 76


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