Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 endogenous expression of p53 and p53-regulated genes has been examined in a thymidylate synthase-deficient colon carcinoma cell line (TS-) and a derived mutant clone (Thy4) that exhibit acute or delayed apoptotic responses, respectively, when released from G0 synchrony under conditions of dThd starvation. These cell clones demonstrate heterozygosity in p53, thereby expressing one wt allele and one with an A-->C point mutation at codon 240. Following release from G0, upregulated expression of both alleles occurred. During apoptosis in TS-, a wtp53 phenotype was expressed and in Thy4 during cytostasis, a mp53 phenotype was manifested, as determined from the ratios of wtp53/mp53 proteins, transactivation of p50-2 (a wtp53-responsive CAT reporter construct) and the endogenous expression of MDM2. Neither cytotoxicity nor cytostasis correlated with expression of p21Waf1/Cip1 Thy4 cells sustained accumulation of high levels of Bax in a wtp53-independent and dThd-independent manner and survival was associated with upregulated expression of Bcl-2. In contrast, Bax expression decreased in TS- during apoptosis, except in a highly resistant subpopulation that retained high levels of Bax. Data suggest that resistant cells (Thy4) can sustain high Bax expression and that Bcl-2 is upregulated in response to an apoptotic stimulus due to the absence of negative regulation by wtp53.
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PMID:Acute and delayed apoptosis induced by thymidine deprivation correlates with expression of p53 and p53-regulated genes in colon carcinoma cells. 866 31

Fas is expressed constitutively in colonic epithelial cells and is also expressed in colon carcinomas and in cultured colon carcinoma cell lines. However, the potential role of Fas signaling in mediating apoptosis in cells of this type remains unknown. We have developed human colon carcinoma cell models deficient in thymidylate synthase that demonstrate acute (TS- cells) or delayed (Thy4 cells) apoptosis following DNA damage induced by thymineless stress. Complete protection of cells from acute apoptosis and prolongation of delayed apoptosis was obtained following exposure to the NOK-1 monoclonal antibody (inhibitory to Fas signaling) during the period of dThd deprivation. These results suggested that apoptosis induced by thymineless stress was regulated by autocrine signaling via Fas-FasL interactions. Fas expression was high in both TS- and Thy4 cells. However, FasL, undetectable in synchronous cultures, was up-regulated in TS- cells at 48 hr, when cells were undergoing acute apoptosis, and in Thy4 cells at 96 hr, correlating with the delayed onset of thymineless death. FasL expression also correlated with acute apoptosis induced in parental GC3/cl cells, commencing at 48 hr, following thymidylate synthase inhibition by 5-fluorouracil/leucovorin exposure. Fas-mediated apoptosis induced by the cytotoxic anti-Fas monoclonal antibody CH-11 was inhibited following adenoviral delivery of a Bcl-2 cDNA, and Bcl-2 also protected cells from acute apoptosis induced by dThd deprivation. Taken together, these data demonstrate a functional Fas system in these cultured colon carcinoma cell models, and they demonstrate that Fas-FasL interactions can link DNA damage induced by thymineless stress to the apoptotic machinery of colon carcinoma cells.
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PMID:Thymineless death in colon carcinoma cells is mediated via fas signaling. 922 29

Ras functions as a molecular switch for several downstream targets and may promote either apoptosis or survival dependent upon the cell system and stimulus. The functional significance of a transfected K-Ras oncogene in influencing apoptosis induced by thymineless stress was examined in a thymidylate synthase (TS)-deficient (TS-) colon carcinoma cell line derived from GC3/c1 after thymidine deprivation. Oncogenic K-Ras conferred survival in TS- K-Ras clones compared with TS- (untransfected) and TS- pCIneo (vector control). Previously, we had demonstrated that thymineless death involved signaling via Fas/FasL interactions. However, in the presence of oncogenic K-Ras, survival did not involve down-regulation of Fas or FasL expression but did involve members of the Bcl-2 family. Bcl-2 and Bax expression remained relatively constant during thymineless stress in all cell lines. Apoptosis in the presence of wild-type Ras correlated with up-regulated expression of Bak that did not occur in TS- K-Ras clones, whereas survival in these clones correlated with elevated expression of Bcl-xL. Thus, the Bak:Bcl-xL ratio was high in TS- and TS- pCIneo cells undergoing apoptosis, whereas the Bcl-xL:Bak ratio was high in TS- K-Ras clones exhibiting a survival response.
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PMID:Inhibition of apoptosis after thymineless stress is conferred by oncogenic K-Ras in colon carcinoma cells. 982 51

The effects of 24-hr exposures to 5-fluorouracil (FUra) and paclitaxel in various sequences were studied in MCF-7 breast cancer cells to determine an optimal schedule for possible clinical use. In clonogenic assays, pre-exposure to FUra followed by paclitaxel resulted in marked antagonism, while sequential paclitaxel followed by FUra was optimal. Concurrent or pre-exposure to paclitaxel did not affect [3H]FUra metabolism, [3H]FUra-RNA incorporation, or the extent of FUra-mediated thymidylate synthase inhibition. Paclitaxel led to G2/M phase accumulation that persisted for up to 24 hr after drug exposure, while a 24-hr FUra exposure produced S-phase accumulation. FUra pre-exposure diminished paclitaxel-associated G2/M phase block, whereas subsequent exposure to FUra after paclitaxel did not. FUra exposure resulted in transient induction of p53 and p21, which returned to basal levels 24 hr after drug removal. p53 and p21 protein content also increased markedly during paclitaxel exposure, accompanied by phosphorylation of Bcl-2. Double-stranded DNA fragmentation (approximately 50 kb) was seen at 48 hr when cells were exposed to paclitaxel for an initial 24-hr period. Paclitaxel-associated DNA fragmentation was not prevented by concurrent or subsequent exposure to FUra. Thus, paclitaxel-mediated G2/M phase arrest appeared to be a crucial step in induction of DNA fragmentation. Since an initial 24-hr paclitaxel exposure did not interfere with subsequent FUra metabolism or thymidylate synthase inhibition, and delayed exposure to FUra did not impede either paclitaxel-mediated induction of mitotic blockade or DNA fragmentation, the sequence of paclitaxel followed by FUra is recommended for clinical trials.
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PMID:Sequence-dependent antagonism between fluorouracil and paclitaxel in human breast cancer cells. 1042 68

Inhibition of the key enzyme in DNA synthesis, thymidylate synthase (TS), by 5-fluorouracil (5-FU) and the novel antifolate raltitrexed (Tomudex; ZD1694), induces dTTP depletion, resulting in DNA strand breaks, which can initiate pathways leading to an apoptotic mode of cell death. We studied 5-FU- and ZD1694-induced TS inhibition in relation to the expression of p53, p21, Bcl-2 and Bax in six colon carcinoma cell lines, two with a wild-type (wt) p53 (Lovo, LS174T) and four with a mutant (mt) p53 (WiDr, WiDr/F, HT29 and SW948) phenotype. In untreated cells, a reciprocal correlation between p53 and Bcl-2 was found: in cells with a low wt p53, Bcl-2 expression was present; whilst in cells with mt p53, Bcl-2 expression was not detectable. Exposure to 5-FU (50 and 100 microM) and ZD1694 (50 and 100 nM) for 24 and 48 h induced p53 and p21 expression in wt p53 cells, but not in mt p53 cells. TS was induced approximately 2-10-fold in all cell lines. TS induction was highest after ZD1694 exposure in the mt p53 cells HT29 and WiDr/F (6-10-fold). After 5-FU treatment, TS was present both as the free enzyme and in the ternary complex; however, predominantly as the ternary complex between TS, FdUMP and 5,10-methylenetetrahydrofolate. In wt p53 cells, both drugs increased Bax expression up to 5-fold, whereas in mt p53 cells, only a very slight induction was found. In wt p53 cells, Bcl-2 expression hardly changed after drug treatment. These results indicate a p53-independent induction of TS but a regulatory role of wt p53 in the synthesis of Bax in the colon carcinoma cell lines after TS inhibition.
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PMID:Molecular downstream events and induction of thymidylate synthase in mutant and wild-type p53 colon cancer cell lines after treatment with 5-fluorouracil and the thymidylate synthase inhibitor raltitrexed. 1078 98

Treatment of haematopoietic BA/F3 cells with the thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine (FUdR) activated apoptosis through a mechanism that required continuous protein synthesis and was inhibited by Bcl-2 over-expression. Analysis of p53 levels in cells treated with FUdR indicated a marked accumulation of this protein. Accumulation of p53 was also observed in cells over-expressing Bcl-2. In BA/F3 cells transfected with a cDNA coding for the human papilloma virus protein E6, p53 accumulation after FUdR treatment was inhibited markedly. However, apoptosis was induced in both control and E6 cells to a similar extent. The role of the CD95/CD95 ligand (CD95L) system in FUdR-induced apoptosis was also assessed. As determined by reverse transcriptase PCR, BA/F3 expressed a low constitutive level of CD95L mRNA, which decreased following FUdR treatment. Moreover, blocking CD95-CD95L interactions with antagonistic CD95 monoclonal antibody did not prevent drug-induced apoptosis. Furthermore, analysis of caspase involvement showed important differences in apoptosis induced by CD95-triggering or FUdR treatment. In summary, these results suggest that apoptosis induced by thymineless stress in haematopoietic BA/F3 cells occurs by a mechanism that does not require accumulation of p53 and which is independent of CD95-CD95L interactions.
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PMID:Apoptosis of haematopoietic cells upon thymidylate synthase inhibition is independent of p53 accumulation and CD95-CD95 ligand interaction. 1111 3

Preoperative chemotherapy and radiation (chemoradiation) are increasingly used in the treatment of advanced rectal carcinoma to downstage the tumor so that a sphincter sparing procedure is used. This treatment modality has also resulted in not only local disease control but also decreased metastasis and increased survival. It is well known that with standard chemoradiation some tumors show marked pathologic response, while others remain non-responsive. Identification of tumor markers that can predict responsiveness to chemoradiation is extremely useful to avoid unnecessary preoperative treatment. To understand the role of thymidylate synthase (TS), p53 and Bcl-2 proteins, if any, in tumor response/resistance to chemoradiation, we examined pretreatment biopsy material obtained from 12 responsive and 13 non-responsive patients by immunohistochemistry. TS was undetectable in 11 of 12 (92%) responsive tumors and overexpressed in only 1 tumor (8%); whereas, p53 or Bcl-2 was overexpressed in 8 tumors (66%). In the non-responsive group of 13 tumors, overexpression of TS, p53 and Bcl-2 was observed in 7, 5 and 6 tumors, respectively. In 6 non-responsive tumors in which TS was undetectable, 5 tumors contained high levels of p53 or Bcl-2. These results indicate that level of TS in tumors is the best predictor of sensitivity or resistance to chemoradiation. No such correlation between overexpression of p53 and Bcl-2 and response to chemoradiation is observed.
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PMID:Molecular markers and prediction of response to chemoradiation in rectal cancer. 1129 69

The molecular mode of cell killing by the antiviral drug (E)-5-(2-bromovinyl-2'-deoxyuridine (BVDU) was studied in Chinese hamster ovary (CHO) cells stably transfected with the thymidine kinase gene (tk) of varicella zoster virus (CHO-VZVtk). The colony-forming ability of the cells was reduced to <1% at a concentration of approximately 1 microM BVDU, whereas for nontransfected cells or cells transfected with tk gene of herpes simplex virus type 1 (CHO-HSVtk), a 1000-fold higher dose was required to achieve the same response. BVDU inhibited thymidylate synthase in CHO-VZVtk but not in CHO-HSVtk and control cells. On the other hand, the drug was incorporated into DNA of VZVtk- and HSVtk-expressing cells to nearly equal amounts. Because coexposure of CHO-VZVtk cells to exogenous thymidine protected them from BVDU-induced cell killing, the cells obviously die because of thymidine depletion. At highly cytotoxic BVDU doses (50 microM) and longer exposure times (24-48 h), VZVtk cells were blocked to some extent in S and G2/M phase and underwent apoptosis (48-72 h). Not only apoptosis but also necrosis was induced. The findings also show that the drug causes the induction of c-Jun and the activation of activator protein-1 resulting in increased level of Fas ligand (FasL) and caspase-8/-3 activation. Bid and poly(ADP-ribose) polymerase were cleaved by caspases. Expression of Bax increased, whereas Bcl-2/Bcl-x(L) remained unchanged. Transfection of dominant-negative Fas-associated death domain and inhibition of caspase-8 by N-benzyloxycarbonyl-IETD-fluoromethyl ketone strongly abrogated BVDU-induced apoptosis, indicating Fas/FasL to be crucially involved. Thus, BVDU-triggered apoptosis differs significantly from that induced by ganciclovir, which induces in the same cellular background the mitochondrial damage pathway.
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PMID:Apoptosis induced by (E)-5-(2-bromovinyl)-2'-deoxyuridine in varicella zoster virus thymidine kinase-expressing cells is driven by activation of c-Jun/activator protein-1 and Fas ligand/caspase-8. 1252 16

The benefit of postoperative adjuvant chemotherapy in patients with Dukes' B colorectal cancer is still uncertain and its routine use is not recommended. Prognostic biomarkers may be useful for identifying high-risk patients with resected, node-negative disease, and this stratification may represent an innovative strategy for designing adjuvant chemotherapy trials. Featured prognostic molecular markers can be divided into the following categories: cell proliferation indices (Ki-67, Mib-1, proliferating cell nuclear antigen); oncogenes/tumor suppressor genes [p53, K-ras, Deleted in Colorectal Cancer (DCC), Bcl-2, c-erbB2]; DNA repair (microsatellite instability); markers of angiogenesis (vascular count, vascular endothelial growth factor); markers of invasion/metastasis (plasminogen-related molecules, matrix metalloproteinases); and biochemical markers (thymidylate synthase). Studies that have investigated their prognostic role in Dukes' B colorectal cancer patients are reviewed here. Current data do not provide sufficient evidence for the incorporation of available prognostic biomarkers into clinical practice. However, a biomarker-based approach could be an effective strategy for improving results of postoperative adjuvant treatments in high-risk Dukes' B colorectal cancer patients. Markers of altered DCC function have shown promising prognostic role and sufficient prevalence in retrospective investigations and they deserve further assessment in prospective studies.
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PMID:Prognostic molecular markers for planning adjuvant chemotherapy trials in Dukes' B colorectal cancer patients: how much evidence is enough? 1285 43

Few studies have investigated the biological factors associated with sensitivity to bolus infusions of 5-fluorouracil (5FU), including sequential methotrexate (MTX)/5FU therapy. We investigated the relationship between the expression of thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), E2F-1, Bcl-2, Bak, and Bcl-X, and the chemotherapeutic effects of sequential MTX/5FU. We studied 38 patients with unresectable or recurrent gastric cancer, treated weekly with sequential MTX/5FU (MTX 100 mg/m2, 5FU 600 mg/m2, by bolus infusions, with a three-hour interval). Expression of the above proteins was examined in initial biopsy samples with immunohistochemical methods. Immunohistochemical reactivity was defined as positive when over 25% of cancer cells showed strong staining in the cytoplasm for TS, TP, DPD, Bak, Bcl-2, and Bcl-X, and in the nucleus for E2F-1. The overall response rate was 28% in the 29 patients who had measurable lesions. Bak-negative patients showed a higher response rate than Bak-positive patients (39% versus 9%, respectively; p=0.1096), although expression of the other proteins was not associated with chemosensitivity. The median survival time (MST) of all patients was 256 days. Bak-negative patients survived significantly longer than Bak-positive patients (MST, 302 days versus 134 days, respectively; p=0.0044). Bcl-X-negative patients survived significantly longer than Bcl-X-positive patients (MST, 302 days versus 215 days, respectively; p=0.0080). Furthermore, patients negative for both Bak and Bcl-X had significantly better prognoses than other patients (MST, 373 days; p<0.0001). Within the limits of the small patient population, multivariate analysis using the Cox proportional hazards model showed that Bak, Bcl-X, and histological type were independent variables predicting survival (p=0.0008, 0.0081, and 0.0082, respectively). Although previously described predictive markers for protracted infusion of 5FU, including TS, TP, and DPD, might not be associated with clinical outcome in patients treated with sequential MTX/5FU, Bak may be a useful marker for chemoresponse and survival. Furthermore, both Bcl-X expression and the coupled expression of Bak and Bcl-X, as well as histological type, may be useful predictive markers for survival.
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PMID:Expression of thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, E2F-1, Bak, Bcl-X, and Bcl-2, and clinical outcomes for gastric cancer patients treated with bolus 5-fluorouracil. 1465 96


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