UNIPROT:P10415 - FACTA Search

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Query: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gadd45 genes have been implicated in stress signaling in response to physiological or environmental stressors, which results in either cell cycle arrest, DNA repair, cell survival and senescence, or apoptosis. Evidence accumulated implies that Gadd45 proteins function as stress sensors is mediated by a complex interplay of physical interactions with other cellular proteins that are implicated in cell cycle regulation and the response of cells to stress. These include PCNA, p21, cdc2/cyclinB1, and the p38 and JNK stress response kinases. Recently we have taken advantage of gadd45a and gadd45b deficient mice to determine the role gadd45a and gadd45b play in the response of bone marrow (BM) cells to genotoxic stress. Myeloid enriched BM cells from gadd45a and gadd45b deficient mice were observed to be more sensitive to ultraviolet radiation (UVC), VP-16, and daunorubicin (DNR)-induced apoptosis compared to wild-type (wt) cells. The increased apoptosis in gadd45a and gadd45b deficient cells was evident also by enhanced activation of caspase-3 and PARP cleavage and decreased expression of cIAP-1, Bcl-2, and Bcl-xL compared to wt cells. Reintroduction of gadd45 into gadd45 deficient BM cells restored the wt apoptotic phenotype. Both gadd45a and gadd45b deficient BM cells also displayed defective G2/M arrest following exposure to UVC and VP-16, but not to DNR, indicating the existence of different G2/M checkpoints that are either dependent or independent of gadd45. Additional work conducted in this laboratory has shown that in hematopoietic cells exposed to UV radiation gaddd45a and gadd45b cooperate to promote cell survival via two distinct signaling pathways involving activation of the Gadd45a-p38-NF-kB-mediated survival pathway and Gadd45b-mediated inhibition of the stress response MKK4-JNK pathway [O. Kovalsky, F.D. Lung, P.P. Roller, A.J. Fornace, Jr. Oligomerization of human Gadd45a protein. J Biol Chem. 276 (42) (2001) 39330-39339]. These data reveal novel mechanisms that mediate the pro-survival functions of gadd45a and gadd45b in hematopoietic cells following UV irradiation. Taken together, these findings identify gadd45a and gadd45b as anti-apoptotic genes that increase the survival of hematopoietic cells following exposure to UV radiation and certain anticancer drugs. This knowledge should contribute to a greater understanding of the genetic events involved in the pathogenesis of different leukemias and response of normal and malignant hematopoietic cells to chemo and radiation therapy. These observations set the stage to evaluate, in clinically relevant settings, the impact that the status of gadd45a and gadd45b might have on the efficacy of DNR or VP-16 in killing leukemic cells.
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PMID:Gadd45 in the response of hematopoietic cells to genotoxic stress. 1765 13

We have established several glioma-relevant oncogene-engineered cancer cells to reevaluate the oncogene-selective cytotoxicity of previously well-characterized anticancer drugs, such as etoposide, doxorubicin, staurosporine, and carmustine. Among several glioma-relevant oncogenes (activated epidermal growth factor receptor, Ras, and Akt, as well as Bcl-2 and p53DD used in the present study), the activated epidermal growth factor receptor, Ras, and Akt exerted oncogenic transformation of Ink4a/Arf(-/-) murine astrocyte cells. We identified that etoposide, a topoisomerase II inhibitor, caused selective killing of myristylated Akt (Akt-myr)-transduced Ink4a/Arf(-/-) astrocytes and U87MG cells in a dose- and time-dependent manner. Etoposide-selective cytotoxicity in the Akt-myr-transduced cells was shown to be caused by nonapoptotic cell death and occurred in a p53-independent manner. Etoposide caused severe reactive oxygen species (ROS) accumulation preferentially in the Akt-myr-transduced cells, and elevated ROS rendered these cells highly sensitive to cell death. The etoposide-selective cell death of Akt-myr-transduced cells was attenuated by pepstatin A, a lysosomal protease inhibitor. In the present study, we show that etoposide might possess a novel therapeutic activity for oncogenic Akt-transduced cancer cells to kill preferentially through ROS-mediated damage.
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PMID:Selective cell death of oncogenic Akt-transduced brain cancer cells by etoposide through reactive oxygen species mediated damage. 1769 15

The Aurora-A/STK15 gene encodes a kinase that is frequently amplified in cancer. However, it is not clear what role this plays in the development of cancer since little is known about its biochemical targets. We have showed that Aurora-A induces phosphorylation of IkappaBa, thereby mediating its degradation. Loss of IkappaBa leads to activation of NF-kappaB target gene transcription. We analysed primary human breast cancers and 13.6% of samples showed Aurora-A gene amplification all of which exhibited nuclear localisation of NF-kappaB. We propose that this subgroup of breast cancer patients might benefit from inhibiting Aurora-A. Further analysis of different human tumour cell types for their NF-kappaB activity have showed that there is an association between cell resistance to chemotherapeutic agents and NF-kappaB activation. A549 human lung adenocarcinoma cells and SKOV3 human ovarian cancer cells have high levels of NF-kappaB and are resistant to cytotoxic agents such as adriamycin and VP-16 (etoposide). We also found that in A549 and SKOV3 cells treated with a small molecule inhibitor towards Aurora kinases, the NF-kappaB activity was downregulated and the efficacy of cytotoxic drugs was enhanced. In addition, the transcriptional targets Bcl-XL and Bcl-2 were downregulated. These findings have important implications for cancer chemotherapy. Aurora-A-inhibition enhances the efficacy of chemotherapeutic agents and reverses acquired resistance resulting from the activation of NF-kappaB. Consequently, preventing NF-kappaB activation by inhibition of Aurora-A, may provide a valuable enhancement to specific chemotherapeutic regimens.
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PMID:Aurora-A kinase regulates NF-kappaB activity: lessons from combination studies. 1793 80

Anti-apoptotic proteins Bcl-2 and Bcl-xL are overexpressed in 80% of non Hodgkin's lymphoma cells and are thought to play an important role in the resistance of lymphoma cells to current chemotherapeutic agents. Gossypol, an orally-active polyphenolic aldehyde derived from the cotton plant, has been known to have potential anti-neoplastic activity. Recently, gossypol was found to bind to the BH3 binding groove of Bcl-xL and with lesser affinity to Bcl-2. The present study was conducted to determine whether gossypol increases the sensitivity of non-Hodgkin's lymphoma cells to the actions of chemotherapeutic agents by potentiating treatment-induced apoptosis. The interactions observed between gossypol and chemotherapeutic drugs were analyzed using the median effect principle (CalcuSyn analysis). Our data showed that treatment of Ramos cells with gossypol not only induced cell arrest on the G(0)/G(1) phase, but also augmented apoptosis and growth inhibition induced by etoposide (VP-16), doxorubicin hydrochloride (ADM), vincristine (VCR), and paclitaxel (taxol). However, when gossypol was combined with cisplatin (DDP) an antagonistic effect was observed. Gossypol-induced cell cycle arrest was accompanied by decreased expression of cyclin D1 in Ramos cells. In addition, the peroxisome proliferator-activated receptor (PARP) pathway is, at least in part, involved in the gossypol-induced apoptosis when combined with VP-16. These data indicate that single-agent gossypol is effective in inhibiting growth of non-Hodgkin's lymphoma cells in vitro and combination studies with certain secondary chemotherapeutic agents further demonstrate it's synergistic cytotoxicity. These findings support future preclinical and clinical studies of gossypol in the treatment of non-Hodgkin's lymphoma.
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PMID:Synergistic cytotoxicity of Bcl-xL inhibitor, gossypol and chemotherapeutic agents in non-Hodgkin's lymphoma cells. 1834 25

Interferonalpha (IFNalpha) induces cell cycle arrest and triggers apoptosis and chemosensitivity. But the mechanism of IFNalpha in regulating chemosensitivity has not been fully understood. To study whether IFNalpha affected chemosensitivity of osteosarcoma cells, we treated p53-wild U2OS cells and p53-mutant MG63 cells with IFNalpha and etoposide, alone or in combination, and then examined growth inhibition, cell cycle arrest and apoptosis. IFNalpha enhanced etoposide-induced growth inhibition and apoptosis in p53-wild U2OS cells but not p53-mutant MG63 cells in a dose- and time-dependent manner. Etoposide-induced G2/M phase arrest was also enhanced by IFNalpha. The enhanced apoptosis was associated with the accumulation of transcriptionally active p53 accompanied with increased Bax and Mdm2, as well as decreased Bcl-2. IFNalpha also activated caspases-3, -8 and -9 protein kinases and PARP cleavage in response to etoposide in U2OS cells. Moreover, the combination-induced cytotoxicity and PARP cleavage were significantly reduced by caspase pan inhibitor and p53 siRNA. Thus we conclude that IFNalpha enhances etoposide-induced apoptosis in human osteosarcoma U2OS cells by a p53-dependent and caspase-activation pathway. The proper combination of IFNalpha and conventional chemotherapeutic agents may be a rational strategy for the treatment of human osteosarcoma with functional p53.
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PMID:Interferonalpha enhances etoposide-induced apoptosis in human osteosarcoma U2OS cells by a p53-dependent pathway. 1819 51

Ornithine decarboxylase (ODC), the rate-limiting enzyme of the polyamine biosynthetic pathway, plays an important role in cell cycle, tumor promotion and anti-apoptosis. In our previous studies, overexpression of ODC prevented apoptosis induced by tumor necrosis factor-alpha and methotrexate. We further investigated the apoptotic mechanisms of the cancer chemotherapeutic drugs, including etoposide (VP-16), paclitaxel (TAX) and cisplatin (CDDP), and the influences of ODC on apoptosis and cell cycle. Our results showed that the investigated drugs induced caspase-dependent apoptosis, the generation of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (Deltapsi m) in HL-60 cells, all of which were reversed by putrescine, glutathione or N-acetyl-l-cysteine. Overexpression of ODC prevented the cancer chemotherapeutic drugs-induced apoptosis, ROS generation and the disruption of Deltapsi m. After drug administrations, the decline of Bcl-2, cytochrome c release and caspases' activation were inhibited by ODC overexpression. In cell cycle, ODC overexpressed cells seemed to overcome the G1 arrest and G2/M arrest, caused by VP-16 and TAX, respectively, and kept on the cell cycle rolling. Overexpression of ODC increased the expression of Cyclin A, D, E and Cdk4 and the enzyme activity of Cdk1 and Cdk2 after the treatment of VP-16 and TAX, respectively. In conclusions, the cancer chemotherapeutic drugs-induced apoptosis is through ROS-related, mitochondria-mediated and caspase-dependent pathways. With higher ODC activity, cells are resistant to the cancer chemotherapeutic drugs-induced apoptosis and keep on the cell cycle rolling with the significant interference in G1/S arrest caused by VP-16 and G2/M arrest by TAX.
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PMID:Ornithine decarboxylase attenuates leukemic chemotherapy drugs-induced cell apoptosis and arrest in human promyelocytic HL-60 cells. 1833 22

The overexpression of a new cytokine-induced apoptosis inhibitor 1 (CIAPIN1) gene has been shown previously to promote a multidrug resistant phenotype in gastric cancer cells through the upregulation of MDR1 and MRP1. In the present study, we constructed the siRNA eukaryotic expression vectors of CIAPIN1 and transfected them into SGC7901/VCR cells to examine whether the down regulation of CIAPIN1 increased cell sensitivity towards chemotherapeutic drugs. After transfection, the expression of CIAPIN1 was dramatically decreased in CIAPIN1 siRNA transfectants compared with that in parental cells and empty vector control cells. The down-regulation of CIAPIN1 significantly enhanced the sensitivity of SGC7901/VCR cells to vincristine (VCR), adriamycin (ADR) and etoposide (VP-16), but not to 5-fluorouracil (5-FU) and cisplatin (CDDP). Cell capacity to efflux adriamycin decreased markedly in CIAPIN1 siRNA transfectants, and correlation between CIAPIN1 down regulation and decreased MDR1 transcriptional activity were observed. CIAPIN1 siRNA could significantly down regulate the expression of Bcl-2, and up-regulate the expression of Bax, but not alter the expression of PTEN in gastric cancer cells. These observations suggested that the siRNA constructs of CIAPIN1 we obtained could effectively down-regulate the expression of CIAPIN1 and reverse the resistant phenotype of gastric cancer cells. The further study of the biological functions of CIAPIN1 may be helpful for understanding the mechanisms of multidrug resistance of gastric cancer and developing possible strategies to treat gastric cancer.
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PMID:[Reversal of multidrug resistance of gastric cancer cells by down-regulation of CIAPIN1 with CIAPIN1 siRNA]. 1838 26

Etoposide is widely used in the treatment of patients with testicular cancer. The mechanism underlying apoptosis induction in cancer cells has been studied in different cell types, but it is not known whether the same factors participate in viable germ cells undergoing programmed cell death. Since testicular cancer primarily affects young males, we used pubertal rats (21 days old) as a model to determine different apoptotic parameters after etoposide treatment in healthy testes. We found that one intratesticular injection of etoposide (1.2 microg/testis) induced a significant increase in spermatocytes undergoing apoptosis, along with activation of caspase-9, -8 and -3 after 24 h of treatment. Spermatocyte apoptosis was inhibited when a general caspase inhibitor was added along with etoposide. Etoposide induces a significant stabilization/activation of p53, resulting in an increase level of this protein. The mRNA of Bcl-2 antagonist of cell death (BAD), a pro-apoptotic gene and a transcriptional target of p53, was significantly increased after etoposide treatment. Thus, our results suggest a single injection of etoposide induces apoptosis in healthy pachytene spermatocytes mediated by p53 and caspase activation. These findings will assist the search for new therapies to prevent the deleterious effect of cancer drugs upon normal cells.
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PMID:A molecular evaluation of germ cell death induced by etoposide in pubertal rat testes. 1934 30

Glycogen synthase kinase-3beta (GSK3beta) controls the survival of osteoblasts during bone development through Wnt canonical signaling. GSK3beta is a key factor for osteoblastogenesis, but relatively less is known regarding its role in osteoblast apoptosis. Genotoxic stress induced by etoposide promoted apoptotic signaling by GSK3beta activation in C3H10T1/2 cells, a mouse mesenchymal cell line. Etoposide led to the time-dependent activation of GSK3beta and caspase-3, which resulted in PARP cleavage. LiCl (a specific inhibitor) and siRNA (gene knock-down) of GSK3beta prevented the effects of etoposide on apoptosis. Staurosporine also induced apoptosis in C3H10T1/2 cells, but LiCl could not rescue. Bcl-2 was decreased in the cells by exposure to etoposide. LiCl completely recovered Bcl-2 expression as shown by both the mRNA and the protein expression levels. In conclusion, etoposide-induced apoptosis in C3H10T1/2 cells is mediated by GSK3beta, which leads to caspase-3 activation via decrease in Bcl-2 expression.
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PMID:Glycogen synthase kinase-3beta regulates etoposide-induced apoptosis via Bcl-2 mediated caspase-3 activation in C3H10T1/2 cells. 1940 26

Diffuse large B-cell lymphoma is an aggressive type of lymphoma, potentially curable, with heterogeneous prognosis. The aim of this study was to determine prognostic significance of clinical, laboratory and immunohystochemical factors. The retrospective study was done in 50 patients with diffuse large B-cell lymphoma. The following parameters were investigated: demographic (age, sex), clinical (time to diagnosis, B symptoms, clinical stage), laboratory (erythrocyte sedimentarion rate, haemoglobin, lactate dehydrogenase, albumine), standard and revised international prognostic index, and immunohystochemical parameters, cluster designation 20, B-cell-2, and Ki67 expression. There were 20 females and 30 males, their average age being 54 (22-83) years. The majority of patients had advanced disease: B symptoms in 76%, III and IV stage in 78%, increased lactate dehydrogenase in 74%, high risk standard international prognostic index in 62% of patients. B-cell leukemia/lymphoma 2 expression was found in 57%, and high Ki67 in 62% of patients. Rituximab-Cyclophosphamnide, Hydroxydaunorubicin, Vincristine, Prednisolone and Rituximab-Cyclophosphamide, Hydroxydaunorubicin, Vincristine, Etoposide, Prednisolone were conducted in 72% (36), and Cyclophosphamide, Hydroxydaunorubicin, Vincristine, Prednisolone and Cyclophosphamide, Hydroxydaunorubicin, Vincristine, Prednisolone-like treatment in 28% (14) of patients. The complete remission rate was 74%, and the partial remission rate was 9%. A significant difference in survival was found between low intermediate and high intermediate S-IPI risk groups, good and bad risk R-IPI, and patients with complete remission and patients with other treatment responses. The other parameters, including Bcl-2 and Ki67 expression, and type of treatment did not show significant influence on survival. The expected five-year survival was 69%. Our results have shown that international prognostic index, and complete remission status have prognostic significance in diffuse large B-cell lymphomas.
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PMID:[Prognostic factors in patients with diffuse large B-cell lymphoma]. 1962 49

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