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)

Many tumor cells are inherently resistant to curative treatment due to an altered pattern of gene expression. It is an attractive and logical proposition to use this difference within the lymphoma cell to eradicate the malignant process. One such new therapeutic approach based on the "silencing" of genes involved in the prevention of apoptosis is Bcl-2 antisense oligonucleotide (AO) therapy. In the field of lymphoma, obvious targets included follicular lymphoma with the t(15;18) translocation, which results in deregulated expression of the Bcl-2 gene, chemoresistance, and subsequent protection against lymphoma cell death. Targeting the initiating codon of the Bcl-2 gene decreases both cell viability and Bcl-2 protein expression in lymphoma and leukemia cell lines that overexpress Bcl-2. Preclinical toxicity studies using a Bcl-2 AO G3139 (Genta, San Diego, CA) show good tolerance at a dose of 10 mg/kg, which is considerably higher than the dose required for good antilymphoma efficacy. In a phase I clinical study, G3139 was well tolerated with minimal toxicity in a dose escalation up to 147.2 mg/m2/d. Evidence of efficacy includes a responder with stage IVB follicular lymphoma who achieved complete clinical and radiologic response that has lasted more than 2 years. The main dose-limiting toxicity has been reversible thrombocytopenia related to the thioate backbone. Other antisense reagents are also in development to combat non-Hodgkin's lymphoma (NHL). These include oligonucleotides that target the messages of the Bcl-X(L) and protein kinase-Calpha (PKCalpha) genes. AOs may also have an application in tumors expressing mutant p53. AOs against MDM2 genes have shown the ability to restore wild-type p53 expression, suggesting that as oncogenic pathways are unraveled, normal cell growth and death patterns may be restored by molecular manipulation. Downregulation of antiapoptosis by AOs in the human setting has low toxicity and antilymphoma activity in cases in which conventional chemotherapy has failed. In the future, antisense therapy followed by chemotherapy may overcome chemoresistance to provide effective therapy for a range of malignancies.
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PMID:Antisense therapy of hematologic malignancies. 1053 Jul 11

The MDM2 oncoprotein has been shown to inhibit p53-mediated growth arrest and apoptosis. It also confers growth advantage to different cell lines in the absence of p53. Recently, the ability of MDM2 to arrest the cell cycle of normal human fibroblasts has also been described. We report a novel function for this protein, showing that overexpression of MDM2 promotes apoptosis in p53-deficient, human medullary thyroid carcinoma cells. These cells, devoid of endogenous MDM2 protein, exhibited a significant growth retardation after stable transfection with mdm2. Cell cycle distribution of MDM2 transfectants [medullary thyroid tumor (MTT)-mdm2] revealed a fraction of the cell population in a hypodiploid status, suggesting that MDM2 is sufficient to promote apoptosis. This circumstance is further demonstrated by annexin V labeling. MDM2-induced apoptosis is partially reverted by transient transfection with p53 and p19ARF. Both MTT and MTT-mdm2 cells were tumorigenic when injected into nude mice. However, the percentage ofapoptotic nuclei in tumor sections derived from MDM2-expressing cells was significantly higher relative to that in the parental cell line. MDM2-mediated programmed cell death is at least mediated by a down-regulation of the antiapoptotic protein Bcl-2. Protein levels of caspase-2, which are undetectable in the parental cell line, appear clearly elevated in MTT-mdm2 cells. Caspase-3 activation does not participate in MDM2-induced apoptosis, as determined by protein levels or poly(ADP-ribose) polymerase fragmentation. The results observed in this medullary carcinoma cell line show for the first time that the product of the mdm2 oncogene mediates cell death by apoptosis in p53-deficient tumor cells.
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PMID:The MDM2 oncoprotein promotes apoptosis in p53-deficient human medullary thyroid carcinoma cells. 1061 65

Although the pathogenesis of leukoplakia has been unclear, carcinogenic transformation is postulated to result from alterations of apoptotic signal transduction proteins in epithelial cells. The pathogenesis of oral lichen planus (OLP) has also been unclear, but apoptotic changes of the epithelial cells in OLP have been reported. In the present study, we used a histochemical approach to describe human keratinocyte-expression of several apoptotic signaling proteins in leukoplakia, in OLP, and in normal oral mucosa as a control. Mucosal biopsies from patients with leukoplakia (n=13), OLP (n=10), and normal oral mucosa (n=9) were frozen, sectioned and immunostained with monoclonal antibodies to wild-type (wt) tumor suppressive protein p53, cyclin-dependent kinase inhibitor p21WAF1/CIP1 and the oncoproteins MDM2, and Bcl-2. Apoptosis was assessed in all cases by the TUNEL method. MDM2 and Bcl-2 expression in keratinocytes were quantitatively greater in leukoplakia than in OLP. Wt-p53 and p21WAF1/CIP1 expression was quantitatively greater in keratinocytes in OLP than in leukoplakia. Keratinocyte maturation appeared histologically normal in OLP, even though wt-p53 and p21WAF1/CIP1 were expressed in these cells. Altered keratinocyte maturation was seen in leukoplakia lesions expressing MDM2 and Bcl-2. No significant difference for the number of apoptotic epithelial cells was observed between leukoplakia and OLP, in spite of the divergent outcomes of the apoptotic signaling proteins.
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PMID:Expression of apoptotic signaling proteins in leukoplakia and oral lichen planus: quantitative and topographical studies. 1097 47

The simian virus 40 (SV40) large tumor (T) antigen is sufficient to transform cells in cultures and induce tumors in experimental animals. Transformation of primary cells in cultures requires both overcoming growth arrest by stimulating the cell cycle and blocking cell death activities presumably activated by oncogene-mediated hyperproliferation signals. The study presented here examined the ability of specific regions and activities of T antigen to modulate apoptosis in cells treated with the genotoxic agent 5-fluorouracil (5-FU). The results showed that the expression of full-length T antigen rendered rat embryo fibroblasts (REF) sensitive to 5-FU-induced apoptosis. Thus, neither the p53-binding region nor the Bcl-2 homology region of T antigen was sufficient to prevent cell death induced by the DNA-damaging agent. T-antigen-mediated sensitization occurred independently of retinoblastoma protein or p53 and p300 binding. An N-terminal segment containing the first 127 T-antigen amino acids (T1-127) was sufficient to sensitize cells. A C-terminal segment consisting of T-antigen amino acids 251 to 708 (T251-708) also sensitized cells to 5-FU-induced apoptosis. This sensitization did not occur when T251-708 was targeted to the nucleus by inclusion of the SV40 nuclear localization signal. The introduction of mutations into the T-antigen J domain resulted in mutation-specific and variable inhibition of apoptosis. This result suggested that either the structural or the functional integrity of the J domain is required to sensitize cells to apoptosis. Treatment of REF or REF expressing full-length T antigen, an N-terminal segment, or T251-708 resulted in increased expression of the p53-responsive MDM2 gene; apoptosis occurred through a p53-dependent pathway, as p53-null cells expressing these T antigens were resistant to 5-FU-induced apoptosis. Possible mechanisms involved in sensitizing cells to a p53-dependent apoptosis pathway in spite of the ability of T antigen to bind and inactivate the transcriptional transactivating activity of p53 are discussed.
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PMID:Simian virus 40 large T antigen and two independent T-antigen segments sensitize cells to apoptosis following genotoxic damage. 1213 45

Advances in molecular and cell biology have led to further understanding of the mechanisms of malignant growth and metastasis in human breast cancer cells. Initiation and progression of breast cancer results from mutations and the abnormal expression of many genes that control cellular proliferation, differentiation, invasion, metastasis and sensitivity to therapy (chemotherapy and radiation therapy). Inhibition of host immunity also plays a role in breast cancer progression. Many genes have been selected as targets for antisense therapy, including HER-2/neu, PKA, TGF-alpha, EGFR, TGF-beta, IGFIR, P12, MDM2, BRCA, Bcl-2, ER, VEGF, MDR, ferritin, transferrin receptor, IRE, C-fos, HSP27, C-myc, C-raf and metallothionein genes. The strategy behind antisense therapy is the development of specific therapeutic agents that aim to correct the mutations and abnormal expression of cellular genes in breast tumour cells by decreasing gene expression, inducing degradation of target mRNA and causing premature termination of transcription. Many in vitro and in vivo studies have investigated the therapeutic efficacy of oligonucleotides and antisense RNAs. These studies have demonstrated specific inhibition of tumour cell growth by antisense therapy and have shown synergistic inhibitory effects between antisense oligonucleotides or antisense RNA and conventional chemotherapeutic drugs used in the treatment of breast cancer. Antisense oligonucleotides have been modified to improve their ability to penetrate cells, bind to gene sequences and downregulate target gene function. Many delivery systems for antisense RNA and antisense oligonucleotides have been developed, including virus vectors (retrovirus, adenovirus and adeno-associate virus) and liposomes, to carry the antisense RNA or oligonucleotides through the cell membrane into the cytoplasm and nucleus of the tumour cells. However, in order to determine their feasibility antisense therapies need to be further investigated to determine their antitumour activity, pharmacokinetics and toxicity in breast cancer patients.
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PMID:Gene targets of antisense therapies in breast cancer. 1222 74

Rhabdomyosarcoma (RMS) cell lines were transduced with an adenoviral vector containing the wild-type p53 (wtp53) cDNA (Ad-p53) and then exposed to four cytotoxic agents: actinomycin D, vincristine, 5-fluorouracil and bleomycin. Potentiation of cytotoxicity following wild-type p53 expression varied from 0- to 20-fold for different drugs and between cell lines. It appeared that alveolar RMS cells (n = 2) were more susceptible to p53-mediated chemosensitization than embryonal RMS cells (n = 3), although this was independent of pax3-FKHR expression. Overall, cells that were most chemosensitive prior to Ad-p53 exposure were those that were most susceptible to p53 potentiation of cytotoxicity. The different results obtained with these RMS cell lines does not appear to be related to expression of pax3-FKHR, p21, Bax or Bcl-2 but may in part be due to differential regulation of p53 target genes, such as MDM2. In conclusion, exogenous wild-type expression selectively chemosensitizes RMS cells to cytotoxic agents. However, expression of transcriptionally active wtp53 does not predict a chemosensitive phenotype.
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PMID:Selective chemosensitization of rhabdomyosarcoma cell lines following wild-type p53 adenoviral transduction. 1239 75

Previous research has suggested that repletion of cellular glutathione peroxidase (GPX1) activity by a single injection of Se was dissociated from the Se protection against the pro-oxidant-induced liver necrosis in Se-deficient rodents. Using the GPX1 knockout (GPX1-/-) mice, TUNEL assay, and apoptosis gene expression microarray, we have demonstrated strikingly different impacts of GPX1 knockout on hepatotoxicity and the related signaling induced by an intraperitoneal injection of 12.5 mg paraquat/kg body weight (b.wt.). In both Se-deficient GPX1-/- and wild-type (WT) mice, the paraquat did not induce typical liver necrosis, rather aponecrosis or necrapoptosis, a syncretic process of cell death sharing characteristics of both apoptosis and necrosis. The severity of liver aponecrosis and the associated mortality were reduced to a much greater extent by an injection of Se (ip, 50 microg/kg b.wt. as Na2SeO3) prior to paraquat stress in the WT mice, compared with the GPX1-/- mice. The induced liver aponecrosis seemed to be more apoptotic in the GPX1-/- mice but more necrotic in the WT mice. The paraquat-mediated gene or protein expression of proapoptotic Bax, Bcl-w, and Bcl-X(S), cell survival/death factors GADD45, MDM2, c-Myc, and caspase-3 was upregulated, but that of antiapoptotic Bcl-2 was downregulated in the GPX1-/- mice vs. the WT mice. Overall, these differences between the two groups of mice were related to a low level of liver GPX1 activity in the WT mice that represented < 4% of the normal physiological level. Therefore, the low level of GPX1 activity in the Se-deficient mice can exert a potent role in defending against liver aponecrosis induced by moderate oxidative stress.
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PMID:Impacts of glutathione peroxidase-1 knockout on the protection by injected selenium against the pro-oxidant-induced liver aponecrosis and signaling in selenium-deficient mice. 1265 81

The p53 mutant 143Ala is a human temperature-sensitive mutant with two conformational states. To definitively determine whether the Fas signal transduction pathway and the function of the pathway are dependent on p53 status, we have established stable transfectants of p53 mutant 143Ala in two human cancer cell lines: H1299 (lung cancer line) and PC-3 (prostate cancer line), the native state of which contains null p53 status and can grow at 37 degrees C and 32.5 degrees C. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell cycle analysis showed inhibition of the growth of cells overexpressing p53 mutant 143Ala in the wild-type p53 form at 32.5 degrees C because of induction of G0/G1 arrest. Transfected cells had increased protein expression of p21, Fas, and MDM2 at the wild-type p53 conformation at 32.5 degrees C, but not in the mutant p53 form at 37 degrees C. However, there was no change in protein expression of FADD, FAP-1, Bcl-2, or Bax at 32.5 or 37 degrees C. Assays for apoptosis demonstrated that anti-Fas antibody CH-11 and FasL induced apoptosis only in cells that overexpress p53 mutant 143Ala at 32.5 degrees C with the wild-type p53 form. Both caspase-3 and caspase-8 activities were increased by anti-Fas antibody CH-11 only in cells at 32.5 degrees C with wild-type p53. Our results demonstrated that Fas-mediated apoptosis in H1299 and PC-3 cells expressing p53 mutant 143Ala occurred only with the wild-type p53 phenotype. These results support the hypothesis that Fas-mediated apoptosis is dependent, at least partially, on the presence of a functional wild-type p53 state. This model may be a useful tool for dissecting the specific interactions between wild-type p53 and the Fas signal transduction pathway in human cancer cells.
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PMID:Fas-mediated apoptosis is dependent on wild-type p53 status in human cancer cells expressing a temperature-sensitive p53 mutant alanine-143. 1267 Sep

We have recently shown that staurosporine (ST) can trigger apoptosis of CaSki and HeLa cervical tumor cells from G2/M checkpoint, though the mechanism remains elusive. In this study, we reported that ST induced the inhibition of E6 and E7 viral oncogene and MDM2 expression, while it led to increased levels of p53, which was transiently located to mitochondria. Additionally, the proteins of the p53-regulated genes, p21(WAF1) and Bax, were increased with a similar time, while Bcl-2 and Bcl-X(L) expression was lowered. Upon ST treatment, the cytochrome c was released into the cytosol and, then, activation of caspases-9 and -3 led to Poly(ADP)RibosePolymerase (PARP) cleavage. Finally, characteristic morphological signs confirmed the apoptosis execution. Thus, taken together, all these observations suggest that apoptosis can be reactivated in HPV-positive human carcinoma cells and highlight that ST could be used as a potently chemotherapy agent to enhance the sensitivity of tumor cells to apoptosis.
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PMID:Human papillomaviruses type 16+ and 18+ cervical carcinoma cells are sensitive to staurosporine-mediated apoptosis. 1275 50

We have recently shown that oral consumption of green tea polyphenols inhibits prostate carcinogenesis in transgenic mouse model of prostate cancer and suggested that induction of apoptosis in prostate cancer cells is responsible for these effects. Much of the chemopreventive effects of green tea are attributed to its major polyphenolic constituent (-) epigallocatechin-3-gallate (EGCG). In the present study, we report that EGCG-induced apoptosis in human prostate carcinoma LNCaP cells is mediated via modulation of two related pathways: (a) stabilization of p53 by phosphorylation on critical serine residues and p14ARF-mediated downregulation of murine double minute 2(MDM2) protein, and (b) negative regulation of NF-kappaB activity, thereby decreasing the expression of the proapoptotic protein Bcl-2. EGCG-induced stabilization of p53 caused an upregulation in its transcriptional activity, thereby resulting in activation of its downstream targets p21/WAF1 and Bax. Thus, EGCG had a concurrent effect on two important transcription factors p53 and NF-kappaB, causing a change in the ratio of Bax/Bcl-2 in a manner that favors apoptosis. This altered expression of Bcl-2 family members triggered the activation of initiator capsases 9 and 8 followed by activation of effector caspase 3. Activation of the caspases was followed by poly (ADP-ribose) polymerase cleavage and induction of apoptosis. Taken together, the data indicate that EGCG induces apoptosis in human prostate carcinoma cells by shifting the balance between pro- and antiapoptotic proteins in favor of apoptosis.
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PMID:Role of p53 and NF-kappaB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells. 1289 26


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