Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metastatic testicular cancers are curable, whereas bladder cancers and most other solid tumors are not. Cell lines derived from human testicular (GH, GCT27, and 833K) and bladder (RT4, RT112, and HT1376) tumors retain this differential chemosensitivity in vitro. We have investigated the hypothesis that differential sensitivity to chemotherapy is related to differences in the threshold of susceptibility to undergoing apoptosis. Sensitivity to etoposide was not directly related to the frequency of DNA strand breaks. DNA damage was on average 2-fold greater in the testicular than the bladder tumor cell lines; in contrast, the testicular tumor lines were 15-fold more sensitive to etoposide cytotoxicity than the bladder tumor lines (IC90 values of 19 +/- 6 versus 293 +/- 180 microM, respectively). Using equidamaging (550 rad equivalents) etoposide treatments, the percentage of cells that underwent drug-induced apoptosis was on average higher in the testicular tumor cell lines than the bladder tumor cell lines. The testicular tumor lines have two characteristics that could confer sensitivity to drug-induced apoptosis. First, they have functional p53: the product of the p53-dependent gene waf-1 was increased after etoposide treatment. Second, the testicular tumor lines expressed relatively high levels of the apoptosis-promoting protein Bax, but there was no expression of the suppressor of apoptosis Bcl-2. In contrast, only one of the three bladder cell lines (RT4) had functional p53, and all of the bladder lines had readily detectable levels of Bcl-2 and low levels of Bax. In the testicular cell lines, increases in p53 and p53-transactivated genes were associated with apoptosis but not arrest in G1. In contrast, in the bladder cell line (RT4), increases in p53 and Waf-1 were associated with both arrest in G1 and apoptosis. The differences in the ratio of Bax:Bcl-2 could contribute to the differential sensitivity of the two tumor types. However, in contrast to earlier reports, the ratio of Bax and Bel-2 was not perturbed by DNA damage.
 ...
PMID:Hypersensitivity of human testicular tumors to etoposide-induced apoptosis is associated with functional p53 and a high Bax:Bcl-2 ratio. 862 May 1

The p53 tumor-suppressor gene is the most commonly mutated gene in cancer. However, p53 gene alterations are infrequent in renal-cell cancer (RCC). Bcl-2 has been shown to inhibit apoptosis triggered by wild-type p53 and an inverse correlation between Bcl-2 expression and p53 mutation has been observed in breast cancer and glioma. To characterize the expression of bcl-2 in RCC and its relationship to the p53 status, we analyzed 25 RCCs by immunohistochemistry for Bcl-2 and p53, Southern hybridization for bcl-2, and PCR-SSCP and sequencing for p53. Positive Bcl-2 staining was detected in 17 of 25 RCCs, whereas positive p53 staining was seen in only 1. Amplification of bcl-2 or p53 mutation was not detected in any of the tumors. Bcl-2 protein was expressed in all 7 RCC cell lines examined. Only one of the 7 lines had p53 mutation. These results suggest that overexpression of bcl-2, rather than p53 mutation, may prevent apoptosis during RCC development.
 ...
PMID:Frequent expression of Bcl-2 in renal-cell carcinomas carrying wild-type p53. 862 Dec 51

The BHRF1 protein of Epstein-Barr virus (EBV) is a structural and functional homolog of the Bcl-2 protein. Both BHRF1 and Bcl-2 proteins promote the survival of cells exposed to various apoptotic stimuli. This promotion of cell survival is associated with a block in proliferation. It is believed that the Bcl-2 family of anti-apoptosis proteins contribute to oncogenesis merely by promoting cell survival. We have discovered that mutations within a regulatory domain of the BHRF1 protein not only suppress apoptosis induced by the tumor suppressor protein p53, but also permit efficient proliferation of cells that would otherwise undergo total apoptosis. These gain-of-function mutants of BHRF1 cooperate more efficiently with the E1a oncogene in transformation of primary rat kidney cells where E1A expression results in apoptosis. Our results suggest that such mutational inactivation of a proliferation-restraining activity in the BHRF1 gene may play a direct role in oncogenesis.
 ...
PMID:Unmasking of a proliferation-restraining activity of the anti-apoptosis protein EBV BHRF1. 862 91

The clinical course of prostate cancer is highly variable and cannot satisfactorily be predicted by histological criteria alone. To study the prognostic significance of Bcl-2 and p53 overexpression in prostate cancer, 137 consecutive radical prostatectomy specimens were examined by immunohistochemistry. Both Bcl-2 and p53 were associated with malignant phenotype. Bcl-2 expression was more frequent in pT3 tumors (31% positive) than in pT2 tumors (5% positive, P = 0.001). p53 overexpression (found in 8%) was associated with high Gleason score (P = 0.03) and increased tumor growth fraction (Ki67 labeling index (LI); P = 0.017). Survival analysis showed that Bcl-2 expression (P = 0.03), high Ki67 LI (P = 0.018), high grade (P = 0.0037), advanced local stage (P = 0.0005), and positive lymph nodes (P = 0.026) were predictors of progression. The combined analysis of Ki67 LI and Bcl-2 allowed the distinction of three groups with different clinical outcome. Prognosis was best in Bcl-2-negative tumors with low Ki67 LI, worst in Bcl-2-positive tumors with high Ki67 LI, and intermediate in the remaining tumors (P = 0.03). These data suggest that altered expression of both Bcl-2 and p53 play a role in prostate cancer progression. Combined analysis of factors regulating both apoptosis and cell proliferation may be relevant in prostate cancer.
 ...
PMID:Prognostic significance of Bcl-2 in clinically localized prostate cancer. 862 24

Chemotherapeutic agent-induced DNA cleavage gives rise to apoptosis in a subpopulation of SK-N-SH human neuroblastoma cells; the remaining cells undergo Schwann cell-like differentiation. Like other neural crest and primitive neurectodermal tumor-derived cell lines, SK-N-SH cultures contain cells of neural (N-type) and epithelial (substrate-adherent, or S-type) phenotypes. Using isolated N-type and S-type cells from neuroblastoma, medulloblastoma, melanoma and glioma cell lines, we demonstrate that the determinants of the response to DNA cleavage are intrinsic properties of the cell. Furthermore, using a series of analogues of enediyne deoxyribonucleic acid (DNA) cleaving agents, we show that the molecular target of these agents is likely to be the same in N- and S-type cells, implying that the difference in response characteristics is a function of different distal pathways that are triggered by DNA cleavage. We demonstrate that the concentration of the DNA damaging agent used, and not the specific characteristics of the damage it produces, is the trigger for production of the cellular response. Response type does not correlate with previously published values for expression of the apoptosis modulators Bcl-2, Bcl-XL, wildtype p53, or, in medulloblastoma lines, p75.
 ...
PMID:Determinants of the response of neuroblastoma cells to DNA damage: the roles of pre-treatment cell morphology and chemical nature of the damage. 862 28

As a first step towards elucidating the potential role(s) of bcl-2 and bcl-2-related genes in lung tumorigenesis and therapeutic responsiveness, the expression of these genes has been examined in a panel of lung cancer cell lines derived from untreated and treated patients, and in cell lines selected in vitro for multidrug resistance. Bcl-2 was hyperexpressed in 15 of 16 small-cell lung cancer (SCLC) cell lines and two of five non-small-cell lung cancer (NSCLC) lines compared with normal lung and brain, and hyperexpression was not chemotherapy related. Bcl-x was hyperexpressed in the majority of SCLC and NSCLC cell lines as compared with normal tissues, and all lung tumour lines preferentially expressed bcl-x1-mRNA, the splice variant form that inhibits apoptosis. Bax gene transcripts were hyperexpressed in most SCLC and NSCLC cell lines examined compared with normal adult tissues. Mutant p53 gene expression was detected in the majority of the cell lines and no relationship between p53 gene expression and the expression of either bcl-2, bcl-x or bax was observed. No changes in bcl-2, bcl-x and bax gene expression were observed in multidrug-resistant cell lines compared with their drug-sensitive counterparts.
 ...
PMID:Expression of apoptosis-regulatory genes in lung tumour cell lines: relationship to p53 expression and relevance to acquired drug resistance. 863 Feb 78

Baxalpha was isolated due to its interaction with Bcl-2. Baxalpha overexpression in an interleukin (IL)-3 dependent cell line accelerates apoptosis upon removal of the cytokine. The ratio of Baxalpha to Bcl-2 appears to be crucial for the effect. To study the action of the bax gene product in vivo, we have generated transgenic mice overexpressing Baxalpha specifically in T cells. Such T cells show accelerated apoptosis in response to gamma-radiation, dexamethasone and etoposide. By crossing baxalpha mice with bcl-2 transgenics we show that the critical nature of the Baxalpha:Bcl-2 ratio holds in primary T cells and that it can be manipulated to elicit a strong response to previously resisted stimuli. p53 has a role in the regulation of apoptosis in response to DNA-damaging agents. p53 directly activates transcription of the bax gene. The presence of the baxalpha transgene accelerated apoptosis in thymocytes from both p53-l- and p53+l- mice in response to dexamethasone. Thymocytes from p53-l- mice with the baxalpha transgene showed similar resistance to apoptosis by DNA-damaging agents as did p53-l- mice without the transgene. Baxalpha overexpression alone cannot restore the DNA damage apoptosis pathway, suggesting that p53 is required to induce or activate other factor(s) to reconstitute the response fully.
 ...
PMID:T cells from baxalpha transgenic mice show accelerated apoptosis in response to stimuli but do not show restored DNA damage-induced cell death in the absence of p53. 863 54

The E1A oncoproteins of adenovirus type 5 are potent inducers of apoptotic cell death. To manifest growth promoting and transforming properties, therefore, E1A requires the co-expression of a suppressor of apoptosis. During normal viral infection, this function is provided by the E1B 19 kDa protein. However, the cellular suppressor Bcl-2 can substitute for 19K during infection, and both proteins can effectively cooperate with E1A to facilitate transformation of primary cells in culture. How E1A induces apoptosis and at what point(s) on this pathway Bcl-2 and E1B 19K act are not presently known. Here, we demonstrate that E1A-induced apoptosis is accompanied by specific endo-proteolytic cleavage of poly(ADP-ribose) polymerase (PARP), an event that is linked to the Ced-3/ICE apoptotic pathway in other systems. PARP cleavage was also observed in p53-null cells infected with 19K- virus expressing 13S E1A. In addition to PARP cleavage, expression of E1A caused processing of the zymogen form of CPP32, a Ced-3/ICE protease that cleaves PARP and is required for apoptosis in mammalian cells. These events were prevented when E1A was co-expressed with E1B 19K or BCL-2, which places these suppressors of apoptosis either at or upstream of processing of pro-CPP32.
 ...
PMID:Bcl-2 and adenovirus E1B 19 kDA protein prevent E1A-induced processing of CPP32 and cleavage of poly(ADP-ribose) polymerase. 863 9

Stimulation of the Fas (APO-1, CD95) receptor, which is present on a variety of cells, usually triggers a process of programmed cell death. Systemic injection of anti-Fas antibody into mice leads to fulminant liver destruction resulting from massive hepatocyte apoptosis, and to rapid death. Hepatocytes bear Fas but do not express Bcl-2, a protein that plays, in a number of conditions, a protective role against apoptosis. We have generated mice whose liver expresses Bcl-2 as the result of bcl-2 transgene placed under the control of the hepatocyte-specific alpha1-anti-trypsin gene promoter, but is otherwise not distinguishable from that of normal mice. These mice display a marked to almost total resistance to liver damage induced by anti-Fas antibody injection. This protective effect of Bcl-2 occurs in the absence of significant variations, in the stimulated livers, in the level of expression of other proteins also involved in resistance or sensitivity to apoptosis, namely Bcl-x, Bax, Bad, Bak, and p53. Mice with protected livers, however, die almost as rapidly as normal mice, which indicates that acute lethality results from stimulation of Fas receptors present on other target organs or cells.
 ...
PMID:A bcl-2 transgene expressed in hepatocytes protects mice from fulminant liver destruction but not from rapid death induced by anti-Fas antibody injection. 864 44

In this study, we investigated the responses of the T cell leukaemia cell line, CCRF-CEM, and a vincristine-resistant subline, CEM/VCR R, to the induction of cell death by serum withdrawal. This treatment was used to overcome any contribution of P-glycoprotein-mediated drug resistance to the responses of the CEM/VCR R cells. Following serum withdrawal both cell lines exhibited typical apoptotic responses including morphological changes and nucleosomal cleavage of the DNA. However, using several different assays for cell death the CEM/VCR R cell line was shown to undergo apoptosis at a slower rate than the parental CCRF-CEM cell line. Expression of c-Myc, Bcl-2 and p53 was found to be similar in both cell lines, discounting involvement of these proteins in the observed difference in apoptotic response. Given our previous finding that reorganisation of tubulin is involved in apoptosis, we examined the expression of alpha-, beta- and acetylated alpha-tubulin in the parental and resistant lines. The CEM/VCR R cell line had altered tubulin expression when compared to that of the CCRF/CEM line. Transnuclear microtubule networks were observed in log phase CEM/VCR R cells. In addition, increased expression of the acetylated form of the alpha-tubulin isotype suggested that a more stable microtubule network was present in the CEM/VCR R cells. These findings imply that the drug-resistance phenotype in the CEM/VCR R cells may involve the suppression of apoptosis, and that the development of an altered microtubule network may contribute to this suppression.
 ...
PMID:Resistance to apoptotic cell death in a drug resistant T cell leukaemia cell line. 864 60


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>