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)

The myeloid leukemic cell line HL-60 was studied by using DNA gel electrophoresis, flow cytomery, McAb C-myc, McAb Bcl-2 and CFU-L. From zero to 36 h, the apoptosis rates of 8 different phases and other indexes were observed. The results showed that with the prolonged time of drug incubation, apoptosis of HL-60 cells increased progressively. This effect can be enhanced obviously by rh-IL-3 and rh-GM-CSF. At the same time, the killed rate of leukemic cells by Ara-C induction was increased. C-myc expression was decreased and Bcl-2 expression did not display apparent change. Interestingly, the normal hemopoietic cells were not affected by these two kinds of cytokine. The theoretical basis was provided for concurrent use of rh-IL-3, rh-GM-CSF and cytotoxic drugs whose purpose is to elevate remission rate during the phase of induced remission of leukemia.
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PMID:Effect of concurrent use of rh-IL-3 and rh-GM-CSF on apoptosis of HL-60 cells induced by Ara-C. 963 77

Scatter factor (SF) (hepatocyte growth factor) is a cytokine that may play a role in human breast cancer invasiveness and angiogenesis. We now report that SF can block the induction of apoptosis by various DNA damaging-agents, including cytotoxic agents used in breast cancer therapy. SF protected MDA-MB-453 human breast cancer cells, EMT6 mouse mammary tumor cells and MDCK renal epithelial cells against apoptosis induced by adriamycin (ADR), X-rays, ultraviolet radiation, and other agents. Protection was observed in assays of DNA fragmentation, cell viability (MTT), and clonogenic survival. Protection of MDA-MB-453 cells against ADR was dose- and time-dependent; maximal protection required pre-incubation with 75-100 ng/ml of SF for 48 h or more. Protection required functional SF receptor (c-Met), but was not dependent on p53. Western blotting analysis revealed that pre-treatment of MDA-MB-453 cells with SF inhibited the ADR-induced decreases in the levels of Bcl-XL, an anti-apoptotic protein related to Bcl-2; and the dose-response and time course characteristics for SF-mediated increases in the Bcl-XL protein levels of ADR-treated cells were consistent with the degrees of protection against apoptosis observed under the same conditions. Furthermore, Bcl-XL levels were not down-regulated by ADR in MDA-MB-231 breast cancer cells, consistent with the finding that SF failed to protect these cells against ADR, despite the fact that they contain functional c-Met receptor. In contrast to Bcl-XL, SF blocked ADR-induced increases in c-Myc and inhibited the expression of p21WAF1/CIP1 and of the BRCA1 protein in MDA-MB-453 cells. However, SF did not cause significant changes in the cell cycle distribution of ADR-treated cells. These findings suggest that SF-mediated protection of human breast cancer cells may involve inhibition of one or more pathways required for the activation of apoptosis and may particularly target the anti-apoptotic mitochondrial membrane pore-forming protein Bcl-XL as a component of the protective mechanism. By implication, the accumulation of SF within human breast cancers may contribute to the development of a radio- or chemoresistant phenotype.
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PMID:Scatter factor protects epithelial and carcinoma cells against apoptosis induced by DNA-damaging agents. 967 97

Eosinophils are potent inflammatory cells involved in allergic reactions. Inhibition of apoptosis of purified eosinophils by certain cytokines has been previously shown to be an important mechanism causing tissue eosinophilia. To elucidate the role of Bcl-2 family members in the inhibition of eosinophil apoptosis, we examined the expression of the known anti-apoptotic genes Bcl-2, Bcl-xL, and A1, as well as Bax and Bcl-xS, which promote apoptosis in other systems. We show herein that freshly isolated human eosinophils express significant amounts of Bcl-xL and Bax, but only little or no Bcl-2, Bcl-xS, or A1. As assessed by reverse transcription-polymerase chain reaction, immunoblotting, flow cytometry, and immunocytochemistry, we show that spontaneous eosinophil apoptosis is associated with a decrease in Bcl-xL mRNA and protein levels. In contrast, stimulation of the cells with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-5 (IL-5) results in maintenance or upregulation of Bcl-xL mRNA and protein levels. Moreover, Bcl-2 protein is not induced by GM-CSF or IL-5 in purified eosinophils. Bcl-2 protein is also not expressed in tissue eosinophils as assessed by immunohistochemistry using two different eosinophilic tissue models. Furthermore, Bcl-xL antisense but not scrambled phosphorothioate oligodeoxynucleotides can partially block the cytokine-mediated rescue of apoptotic death in these cells. These data suggest that Bcl-xL acts as an anti-apoptotic molecule in eosinophils.
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PMID:Role for Bcl-xL in delayed eosinophil apoptosis mediated by granulocyte-macrophage colony-stimulating factor and interleukin-5. 968 Mar 44

The c-myc oncoprotein accelerates programmed cell death (apoptosis) after growth factor deprivation or pharmacological insult in many cell lines. We have shown that max, the obligate c-myc heterodimeric partner protein, also promotes apoptosis after serum withdrawal in NIH3T3 fibroblasts or cytokine deprivation in interleukin-3 (IL-3)-dependent 32D murine myeloid cells. We now show that c-myc- and max-overexpressing 32D cells differ in the nature of their apoptotic responses after IL-3 removal or treatment with chemotherapeutic compounds. In the presence of IL-3, c-myc overexpression enhances the sensitivity of 32D cells to Etoposide (Sigma, St Louis, MO), Adriamycin (Pharmacia, Columbus, OH), and Camptothecin (Sigma), whereas max overexpression increases sensitivity only to Camptothecin. Drug treatment of c-myc-overexpressing cells in the absence of IL-3 did not alter the spectrum of drug sensitivity other than to additively accelerate cell death. In contrast, enhanced sensitivity to Adriamycin, Etoposide, and Taxol (Bristol-Meyers Squibb, Princeton, NJ) was revealed in max-overexpressing cells concurrently deprived of IL-3. Differential rates of apoptosis were not strictly correlated with the ability of the drugs to promote G1 or G2/M arrest. Ectopic expression of Bcl-2 or Bcl-XL blocked drug-induced apoptosis in both cell lines. In contrast, whereas Bcl-2 blocked apoptosis in both cell lines in response to IL-3 withdrawal, Bcl-XL blocked apoptosis in max-overexpressing cells but not in c-myc-overexpressing cells. These results provide mechanistic underpinnings for the idea that c-myc and max modulate distinct apoptotic pathways.
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PMID:Distinct apoptotic responses imparted by c-myc and max. 968 Mar 70

To elucidate the mechanisms by which glucocorticoids promote Th2-type responses, we investigated the influence of dexamethasone (DEX) on both cytokine production and viability of NK1.1+ T cells. The in vivo administration of DEX enhanced the IL-4 production of spleen cells and liver mononuclear cells in wild-type mice, but not in beta2m-deficient mice. DEX reduced the cellularity of conventional T cells, but not that of NK1.1+ T cells, in both spleen and liver, suggesting an increased proportion of NK1.1+ T cells. Moreover, the proportion of IL-4-producing NK.1 + T cells increased in the DEX-injected mice. These results suggest that DEX induced IL-4 production through the preferential survival of IL-4-producing NKI.1+ T cells. In investigating the reason for the preferential survival of NK1.1+ T cells, we found that NK1.1+ T cells were resistant to DEX-induced apoptosis and expressed a higher level of intracellular Bcl-2 compared with conventional NKI.1- T cells. In addition, splenic and hepatic NK1.1+ T cells were resistant to radiation-induced apoptosis. Collectively, our findings revealed an important role for NK1.1+ T cells in the regulation of Th1/Th2 balance by glucocorticoids and their possible functions under various apoptotic stimuli.
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PMID:IL-4-producing NK1.1+ T cells are resistant to glucocorticoid-induced apoptosis: implications for the Th1/Th2 balance. 968 84

Kaposi's sarcoma (KS) is a vascular tumor predominantly found in the immunosuppressed. Epidemiologic studies suggest that an infective agent is the etiologic culprit. Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus-8 (HHV-8), is a gamma human herpesvirus present in all epidemiologic forms of KS and also in a rare type of a B cell lymphoma, primary effusion lymphoma (PEL). In addition, this virus is present in most biopsies from human immunodeficiency virus (HIV)-associated multicentric Castleman's disease (MCD). MCD is a lymphoproliferative disorder with, like KS, a prominent microvasculature. The genome of KSHV contains the expected open reading frames (ORFs) encoding for enzymes and viral structural proteins found in other herpesviruses, but it also contains an unprecedented number of ORFs pirated during viral evolution from cellular genes. These include proteins that may alter cellular growth (e.g., Bcl-2 and cyclin homologs), induce angiogenesis (e.g., chemokine, chemokine receptor, and cytokine homologs), and regulate antiviral immunity (e.g., CD21 and interferon regulatory factor homologs). No ORF with sequence similarity to the Epstein-Barr nuclear antigens (EBNAs) and latent membrane proteins (LMPs) of Epstein-Barr virus (EBV) is present, but proteins analogous to these in structure and in latent expression are found [e.g., ORF 73 encoding for KSHV latent nuclear antigen (LNA-1) and K12 encoding for a possible latent membrane protein]. Current serologic assays confirm the strong association of infection with KSHV and risk of KS development. The mechanism of how this new virus may trigger the precipitation of KS is still unclear.
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PMID:Kaposi's sarcoma-associated herpesvirus. 970 7

Some cytokines can prolong cell survival in hematolymphoid cells and thus may be crucial for regulation of hematolymphoid cell numbers. It has been shown that mitogenic cytokines can induce not only cellular proliferation but also cellular survival by inhibiting apoptosis in hematolymphoid cells. The signals transduced by these cytokines eventually go to the nucleus and induce expression of their specific target genes. In this context, the induction of anti-apoptotic molecules such as Bcl-2 oncoprotein and BAG-1 protein seems to be a key event for the anti-apoptotic function of cytokines. In T lymphocytes, the interaction of interleukin-2 (IL-2) with its receptor (IL-2R) induces both cellular proliferation and cellular survival. The IL-2R consists of three subunits, i.e., IL-2Ralpha, IL-2R(beta)c, and IL-2R(gamma)c chains. Structure-function analysis of the IL-2R(beta)c chain has revealed that there are at least two functional domains within the subunit. The serine-rich (S) region but not the acidic (A) region within the (beta)c chain is responsible for the mitogenic signaling of IL-2R. The S region is also crucial for the cellular survival signaling, which include the induction of anti-apoptotic gene expressions bcl-2 and bag-l. However, the cellular survival signaling is segregated from the mitogenic signaling in independence from the Jak-family protein kinase activation and rapamycin sensitivity. Segregation of the two signaling pathways of a cytokine receptor has also been shown in receptors of the other mitogenic cytokines. Current topics regarding signal transductions of cytokine receptors responsible for the suppression of apoptosis are discussed in this review.
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PMID:BAG-1 and Bcl-2 in IL-2 signaling. 971 11

We have investigated cutaneous purified protein derivative-induced delayed-type hypersensitivity (DTH) responses in healthy volunteers to determine features associated with both the generation and resolution of the reaction. The clinical peak of the response occurred at day 3; however, T cell numbers were maximal on day 7. There was a preferential increase of CD4+ CD45RO+ T cells on day 7, which was largely due to proliferation, since a mean of 19% was in cycle. The proliferation of this subset was associated with the presence of IL-15, which was expressed as early as 12 h, and IL-2, which showed peak expression at 7 days. By day 14, there was a significant decrease in both the mean T cell number/unit area and IL-2 and IL-15 expression in perivascular infiltrates. Maximal CD95 (Fas/Apo-1) ligand and TNF-alpha expression were observed at 7 days and were associated with the presence of 1.83% (range 0.81-2.48%) apoptotic T cells. At 14 days, CD95 ligand and TNF-alpha expression were reduced significantly, and the presence of 2.5% (range 1.5-3.75%) of apoptotic T cells at this time was probably due to cytokine deprivation, associated with decreased Bcl-2 relative to Bax expression. The induction and resolution of the Mantoux reaction may depend on the expression of cytokines, such as IL-2 and IL-15, which regulate both proliferation and apoptosis in T cells. Failure to control either of these phases of the Mantoux reaction may contribute to the chronicity of inflammatory responses in certain cutaneous diseases.
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PMID:The role of apoptosis in the resolution of T cell-mediated cutaneous inflammation. 971 23

Bcl-2 family proteins are key regulators of apoptosis and function as cell death antagonists (e.g., Bcl-2, Bcl-XL, and Mcl-1) or agonists (e.g., Bax, Bad, and Bak). Here we report that among the Bcl-2 family of proteins tested (Bcl-2, Bcl-XL, Mcl-1, Bax, Bad, and Bak), Bcl-XL was unique in that its protein levels were tightly regulated by hemopoietins in both immortal and primary myeloid progenitors. Investigating signaling pathways utilized by cytokine receptors established that the regulation of Bcl-XL protein levels is mediated by the Jak kinase pathway and is independent of other signaling effectors including STATs, PI-3' kinase, and Ras. Moreover, we provide the first direct evidence that Bcl-X is altered in cancer, because bcl-X expression was activated selectively by retroviral insertions in murine myeloid and T-cell hemopoietic malignancies. Tumors harboring bcl-X insertions had altered bcl-X RNAs, expressed elevated levels of Bcl-XL protein, and lacked the requirements for cytokines normally essential for cell survival. Finally, overexpression of Bcl-XL effectively protected IL-3-dependent myeloid cells from apoptosis following removal of trophic factors. Therefore, Bcl-XL functions as a key cytokine regulated anti-apoptotic protein in myelopoiesis and contributes to leukemia cell survival.
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PMID:Selective regulation of Bcl-XL by a Jak kinase-dependent pathway is bypassed in murine hematopoietic malignancies. 971 1

Human neutrophils possess a very short half-life because they constitutively undergo apoptosis. Cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), and other agents can rescue neutrophils from apoptosis but the molecular mechanisms involved in this rescue are undefined. Here, we show by Western blotting that human neutrophils do not express Bcl-2 or Bcl-X but constitutively express Bax. However, cellular levels of these proteins are unaffected by agents which either accelerate or delay neutrophil apoptosis. In contrast, neutrophils express the antiapoptotic protein Mcl-1 and levels of this protein correlate with neutrophil survival. Thus, cellular levels of Mcl-1 decline as neutrophils undergo apoptosis and are enhanced by agents (eg, GM-CSF, interleukin-1beta, sodium butyrate, and lipopolysaccharide) that promote neutrophil survival. Neutrophils only possess few, small mitochondria, and much of the Mcl-1 protein seems to be located in nuclear fractions. These observations provide the first evidence implicating a Bcl-2 family member in the regulation of neutrophil survival. Moreover, this work also provides a potential mechanism whereby cytokine-regulated gene expression regulates the functional lifespan of neutrophils and hence their ability to function for extended time periods during acute inflammation.
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PMID:Mcl-1 expression in human neutrophils: regulation by cytokines and correlation with cell survival. 974 90


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