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 Epstein-Barr virus latent membrane protein 1 (LMP-1) is essential for virus-induced B cell immortalization and can protect B lymphoma cell lines from apoptosis signals in vitro via induction of cellular Bcl-2 expression. However, we have reported that high-level expression of LMP-1 in epithelial cells (RHEK-1 cells) itself induces apoptosis. This apoptotic event occurs in the absence of detectable Bcl-2 expression in the LMP-1-transfected epithelial cells. In this study, we transfected the bcl-2 gene into the LMP-1-containing cells and examined the effect of Bcl-2 upon LMP-1-mediated apoptosis, and upon the growth phenotype of the transfected cells. The results show that ectopic expression of Bcl-2 specifically blocks apoptotic death induced by LMP-1. This was observed from cell culture viability and from gel electrophoresis and flow cytometric assays of the degree of DNA fragmentation in cultured cells. Furthermore, co-expression of LMP-1 and Bcl-2 in RHEK-1 cells enabled the cells to grow under low-serum conditions and to form colonies in semi-soft agar medium. These results suggest, therefore, that these two proteins play important complementary roles in the process of EBV-associated epithelial cell transformation. It appears significant, therefore, that LMP-1 and Bcl-2 are frequently co-expressed in the malignant cells of an EBV-positive epithelial tumour, nasopharyngeal carcinoma.
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PMID:Cooperative interaction between Bcl-2 and Epstein-Barr virus latent membrane protein 1 in the growth transformation of human epithelial cells. 936 85

Bcl-xL, an antiapoptotic member of the Bcl-2 family, inhibits programmed cell death in a broad variety of cell types. Recent reports have demonstrated that cytochrome c is released from mitochondria during apoptosis and have suggested that this release may be a critical step in the activation of proapoptotic caspases and subsequent cell death. Furthermore, it has been demonstrated that Bcl-2 can prevent the release of cytochrome c from mitochondria in cells triggered to undergo apoptosis. This has led to the hypothesis that the antiapoptotic effects of Bcl-2 family members are due specifically to their ability to prevent cytochrome c release thus preventing subsequent cytochrome c-dependent caspase activation. In the present report, we use microinjection techniques to investigate the relationship between cytochrome c release, induction of apoptosis, and Bcl-xL activity in intact cells. We demonstrate that microinjection of cytochrome c into the cytosol of human kidney 293 cells results in a dose-dependent induction of apoptosis. In contrast, MCF7 breast carcinoma cells (stably transfected to express the Fas antigen CD95, and denoted MCF7F) that lack detectable levels of caspase 3 (CPP32), are totally resistant to microinjection of cytochrome c. However, transfection of MCF7F cells with an expression plasmid coding for pro-caspase 3, but not other pro-caspases, restores cytochrome c sensitivity. Although MCF7F cells are insensitive to cytochrome c microinjection, they rapidly undergo apoptosis in a caspase-dependent manner in response to either tumor necrosis factor or anti-Fas plus cycloheximide, and these deaths are strongly inhibited by Bcl-xL expression. Furthermore, microinjection of cytochrome c does not overcome these antiapoptotic effects of Bcl-xL. Our results support the concept that the release of cytochrome c into the cytoplasm can promote the apoptotic process in cells expressing pro-caspase 3 but that cytochrome c release is not sufficient to induce death in all cells. Importantly, the ability of Bcl-xL to inhibit cell death in the cytochrome c-insensitive MCF7F cells cannot be due solely to inhibition of cytochrome c release from mitochondria.
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PMID:Cell-specific induction of apoptosis by microinjection of cytochrome c. Bcl-xL has activity independent of cytochrome c release. 937 16

Several investigators have reported on the clinical effects of 5-fluorouracil (5-FU) or the combination of 5-FU plus interferon-gamma (IFN-gamma) on patients with advanced colorectal carcinoma. It has also been reported that apoptosis induced by 5-FU is due to the effects on DNA synthesis and functional RNA synthesis. In the present study, we examine the biological mechanisms underlying 5-FU or the combination of 5-FU plus IFN-gamma, using the colorectal carcinoma cell line, COLO 201, 5-FU and IFN-gamma independently or additively induced apoptosis in COLO 201 in a dose- and time-dependent manner, which was correlated with the down-regulation of Bcl-2 and the up-regulation of Bax. An interleukin-1 beta-converting enzyme (ICE)-like protease inhibitor (but not an ICE-inhibitor) blocked apoptosis induced by only 5-FU. These results suggest that 5-FU has the capacity to induce apoptosis in COLO 201, resulting from the up-regulation of Bax; the apoptosis-inducing signal of 5-FU seems to be different from that of IFN-gamma. Thereby, 5-FU and IFN-gamma have additional effects on the induction of apoptosis. This finding provides an experimental basis for clinical therapy using 5-FU and/or IFN-gamma for colorectal cancer.
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PMID:Mechanisms underlying apoptosis induced by combination of 5-fluorouracil and interferon-gamma. 938 85

Samples of normal esophageal squamous epithelium (n = 10), severe squamous cell dysplasia (n = 22), carcinoma in situ (n = 15), invasive squamous cell carcinoma (n = 172), lymph-node metastasis (n = 21) and 2 permanent esophageal squamous cell carcinoma cell lines were analyzed immunohistochemically for Bax expression using a polyclonal anti-Bax antibody. Immunostaining was evaluated according to a score system (0-8 points) based on the percentage of positive tumor cells and the relative immunostaining intensity. Cytoplasmatic staining for Bax protein was found uniformly in all cell layers of the normal esophageal squamous epithelium. In contrast, a gradual loss of immunoreactivity for Bax was found in a fraction of pre-neoplastic and neoplastic lesions. Upon comparison of the amount of Bax expression between the different types of lesion, however, no significant differences were found between severe squamous cell dysplasias, carcinomas in situ, invasive carcinomas and lymph-node metastases. In both esophageal carcinoma cell lines, immunoreactivity for Bax was found and confirmed by means of Northern blot analysis. In invasive carcinomas, Bax immunoreactivity was inversely correlated with Bcl-2 expression (p = 0.0243) and decreased continuously with decreasing tumor differentiation (p = 0.0011). No correlation was found between Bax expression and the following parameters: depth of invasion, nodal status and tumor size. Bax expression had no influence on the post-operative survival of esophageal cancer patients.
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PMID:Expression of Bax, a pro-apoptotic member of the Bcl-2 family, in esophageal squamous cell carcinoma. 938 64

Galectin-3, a beta-galactoside-binding protein, has been shown to be involved in tumor progression and metastasis. Here, we demonstrate that expression of galectin-3 in human breast carcinoma BT549 cells inhibits cis-diamminedichloroplatinum (cisplatin)-induced poly(ADP-ribose) polymerase degradation and apoptosis, without altering Bcl-2, Bcl-X(L), or Bax expressions. Galectin-3 contains the NWGR amino acid sequence highly conserved in the BH1 domain of the bcl-2 gene family, and a substitution of glycine to alanine in this motif abrogated its antiapoptotic activity. Our findings demonstrate that galectin-3 inhibits apoptosis through a cysteine protease pathway and highlight the functional significance of the NWGR motif in apoptosis resistance of a non-Bcl-2 protein.
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PMID:Galectin-3: a novel antiapoptotic molecule with a functional BH1 (NWGR) domain of Bcl-2 family. 939 48

Nip3 (nineteen kD interacting protein-3) is an E1B 19K and Bcl-2 binding protein of unknown function. Nip3 is detected as both a 60- and 30-kD protein in vivo and in vitro and exhibits strong homologous interaction in a yeast two-hybrid system indicating that it can homodimerize. Nip3 is expressed in mitochondria and a mutant (Nip3(163)) lacking the putative transmembrane domain and COOH terminus does not dimerize or localize to mitochondria. Transient transfection of epitope-tagged Nip3 in Rat-1 fibroblasts and MCF-7 breast carcinoma induces apoptosis within 12 h while cells transfected with the Nip3(163) mutant have a normal phenotype, suggesting that mitochondrial localization is necessary for induction of cell death. Nip3 overexpression increases the sensitivity to apoptosis induced by granzyme B and topoisomerase I and II inhibitors. After transfection, both Nip3 and Nip3(163) protein levels decrease steadily over 48 h indicating that the protein is rapidly degraded and this occurs in the absence of cell death. Bcl-2 overexpression initially delays the onset of apoptosis induced by Nip3 but the resistance is completely overcome in longer periods of incubation. Nip3 protein levels are much higher and persist longer in Bcl-2 expressing cells. In conclusion, Nip3 is an apoptosis-inducing dimeric mitochondrial protein that can overcome Bcl-2 suppression.
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PMID:The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis. 939 66

Flow cytometry and microscopy analyses have demonstrated that 9-nitrocamptothecin (9NC) induces apoptosis in prostate carcinoma LNCaP, DU-145 and PC-3 cells grown in culture or as xenografts. 9NC induces apoptosis regardless of the ability of the cells to induce tumors following xenografting into nude mice. Detection of apoptosis by flow cytometry was preceded or accompanied by increased cell size, loss of nuclear structure and vacuolization, as the tumor regressed, but no visible chromatin fragmentation. This is the first demonstration that 9NC is curative for human prostate carcinoma xenografts in the nude mouse model in the absence of detectable drug-induced toxicity during and after tumor regression. These findings indicate that 9NC may develop into a chemotherapeutic drug for the effective treatment of prostate cancer patients. Further, there was no apparent correlation of the steady-state level of the apoptosis-regulating proteins, Bcl-2, Bcl-XL, Bax and Ich-1, with tumorigenicity of the prostate cells xenografted in nude mice, aggressiveness of tumors grown in nude mice, and induction of apoptosis by 9NC. However, the TIAR protein was present at markedly high levels in all prostate carcinoma cell lines and this may correlate with their susceptibility to 9NC-induced apoptosis.
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PMID:Establishment of human prostate tumor xenografts in nude mice and response to 9-nitrocamptothecin in vivo and in vitro does not correlate with the expression of various apoptosis-regulating proteins. 941 21

p27KiP1, a member of the Cip/Kip family of cyclin-dependent kinase (cdk) inhibitors, has been implicated in mediating G1 arrest in response to a variety of growth inhibitory signals. Its importance in regulating cell growth is emphasized by the fact that mice lacking p27Kip1 are abnormally large and display hyperplasia of multiple tissues. However, these mice retain the ability to undergo G1 arrest in response to growth inhibitory signals, suggesting that p27KiP1 may serve other functions important for controlling tissue growth. In the present study, we utilized an adenoviral vector-based expression system to examine the consequences of p27Kip1 overexpression in the human carcinoma cell lines A549, HeLa and RKO, in human melanoma SK-MEL-110 cells, in human lung fibroblasts IMR90 and in the rat fibroblast line Rat1. We demonstrate that overexpression of p27Kip1 leads to apoptotic cell death in all cell types, and further show that ectopic expression of Bcl-2 can protect HeLa cells from apoptosis mediated by p27Kip1 overexpression. To our knowledge, this is the first study demonstrating that p27Kip1 can induce apoptosis. Our findings provide new insight into the possible functions of this growth regulatory protein, and support the potential utility of gene therapeutic approaches aimed at elevating p27Kip1 expression for treatment of human cancers.
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PMID:p27Kip1 overexpression causes apoptotic death of mammalian cells. 941 43

Despite the insights genetics and molecular biology have given to a better understanding of the mechanisms which lead to the onset and development of bladder carcinoma, the factors that influence its unpredictable and, at times, particularly aggressive outcome are still largely unknown. Also in bladder carcinoma the study of cellular differentiation markers has been replaced by that of genotypic alterations, and, mainly with the help of immunohistochemistry, of the expression of genes involved in cell proliferation and death, such as MTS1, TP53, Rb, c-myc, Bcl-2, c-erb-B2. So far, anyway, no independent and reliable indicator able to predict the outcome of the single tumour has been identified, and this issue seems to be best addressed by studies of the altered expression of more than one oncoprotein simultaneously. Fairly identical is the question arised by TP53 mutations, which, while worsening the evolution of advanced muscle-infiltrating tumours, hold a still unclear and debated meaning in superficial tumours. It is anyway clear that molecular analysis only may enable to reliably detect the presence of any TP53 mutations. As a matter of fact, the multiplicity of genetic mutations, the frequent transcript variations and the intrinsic limits of immunohistochemistry may explain the discrepancy between immunohistochemical and molecular analysis results, with specificity and sensitivity levels clinically not acceptable. To date, anyway, the biological and clinical meaning of this discrepancy has still to be clarified, as well as the clinical meaning, if any, of p53 overexpression in the absence of gene mutations.
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PMID:[Molecular biology in bladder carcinoma: contributions of immunohistochemistry]. 941 98

Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany), is a potent inhibitor of cyclin dependent kinases (CDKs) 1, 2, and 4. It has potent antiproliferative effects in vitro and is active in tumor models in vivo. While surveying the effect of flavopiridol on cell cycle progression in different cell types, we discovered that hematopoietic cell lines, including SUDHL4, SUDHL6 (B-cell lines), Jurkat, and MOLT4 (T-cell lines), and HL60 (myeloid), displayed notable sensitivity to flavopiridol-induced apoptosis. For example, after 100 nmol/L for 12 hours, SUDHL4 cells displayed a similar degree of DNA fragmentation to that shown by the apoptosis-resistant PC3 prostate carcinoma cells only after 3,000 nmol/L for 48 hours. After exposure to 1,000 nmol/L flavopiridol for 12 hours, typical apoptotic morphology was observed in SUDHL4 cells, but not in PC3 prostate carcinoma cells despite comparable potency (SUDHL4: 120 nmol/L; PC3: 203 nmol/L) in causing growth inhibition by 50% (IC50). Flavopiridol did not induce topoisomerase I or II cleavable complex activity. A relation of p53, bcl2, or bax protein levels to apoptosis in SUDHL4 was not appreciated. While flavopiridol caused cell cycle arrest with decline in CDK1 activity in PC3 cells, apoptosis of SUDHL4 cells occurred without evidence of cell cycle arrest. These results suggest that antiproliferative activity of flavopiridol (manifest by cell cycle arrest) may be separated in different cell types from a capacity to induce apoptosis. Cells from hematopoietic neoplasms appear in this limited sample to be very susceptible to flavopiridol-induced apoptosis and therefore clinical trials in hematopoietic neoplasms should be of high priority.
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PMID:Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. 942 98


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