Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 tumor suppressor gene product is a transcriptional transactivator and a potent apoptotic inducer. The fact that many of the DNA tumor virus oncoproteins bind to p53 and affect these p53 functions indicates that this interaction is an important step in oncogenic transformation. We and others have recently demonstrated that the hepatitis B virus oncoprotein, HBx, can form a complex with p53 and inhibit its DNA consensus sequence binding and transcriptional transactivator activity. Using a microinjection technique, we report here that HBx efficiently blocks p53-mediated apoptosis and describe the results of studies exploring two possible mechanisms of HBx action. First, inhibition of apoptosis may be a consequence of the failure of p53, in the presence of HBx, to upregulate genes, such as p21WAF1, Bax, or Fas, that are involved in the apoptotic pathway. Data consistent with this hypothesis include HBx reduction of p53-mediated p21WAF1 expression. Alternatively, HBx could affect p53 binding to the TFIIH transcription-nucleotide excision repair complex as HBx binds to the COOH terminus of p53 and inhibits its binding to XPB or XPD. Binding of p53 to these constituents of the core TFIIH is a process that may be involved in apoptosis. Because the HBx gene is frequently integrated into the genome of hepatocellular carcinoma cells, inhibition of p53-mediated apoptosis by HBx may provide a clonal selective advantage for hepatocytes expressing this integrated viral gene during the early stages of human liver carcinogenesis.
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PMID:Abrogation of p53-induced apoptosis by the hepatitis B virus X gene. 852 83

Pim-1, a protooncogene product, induced tumor in the combination with MYC. So far, two reports were published concerning Pim-1 function to apoptosis. One was that Pim-1 inhibit apoptosis in Pim-1 introduced transgenic mouse with a background of lpr/lpr, in which Fas was abrogated. However, the other that Pim-1 induced apoptosis in a transient expression system was also reported. In this communication, we survey the possible functions of Pim-1 in terms of the factor related to apoptosis and carcinogenesis.
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PMID:[Apoptosis related gene, Pim-1]. 874 85

Recent study has demonstrated the development of pregnancy-dependent mammary tumors (PDMTs) in GR/A mice during pregnancy and their regression by apoptotic cell death after parturition. In the present study, we examined the molecular machinery of PDMTs before and after parturition and in progression. The death associated-cell surface molecule Fas was expressed only when apoptosis occurred, and no expression could be determined after progression. Interestingly, death suppressor Bcl-2 showed down-regulation when apoptosis occurred, and intense expression after progression. Examination of the possible involvement of PKC isozymes showed that only PKC-epsilon showed drastic changes in expression: expression was not detected in normal mammary gland cells and PDMTs, but was instead seen only when PDMTs progressed to malignant tumors. On the basis of these results, we suggest that PDMT-regression is due to Fas-mediated apoptosis, and that lack of Fas, persistent expression of Bcl-2, and new expression of PKC-epsilon are essential events for tumor progression.
Carcinogenesis 1997 May
PMID:Progression of PDMT is accompanied by lack of Fas and intense expression of Bcl-2 and PKC-epsilon. 916 71

The suppression of apoptosis may contribute to the carcinogenicity of the peroxisome proliferators (PPs), a class of non-genotoxic rodent hepatocarcinogens. Our previous work demonstrated that the PP nafenopin suppressed both spontaneous and transforming growth factor beta1 (TGFbeta1)-induced hepatocyte apoptosis both in vivo and in vitro. Here, we extend these observations by demonstrating the ability of nafenopin to suppress apoptosis induced by other major candidates for the signalling of cell death in the liver. Treatment of rat or mouse hepatocyte monolayers with TGFbeta1 or the DNA damaging drugs etoposide or hydroxyurea induced high levels of apoptosis. Western blot analysis did not support a role for either p53 or p21waf1 in etoposide-induced apoptosis in rat hepatocytes. Treatment of mouse hepatocytes with an agonistic anti-Fas antibody also resulted in an induction of high levels of apoptosis. Pre-addition and continued exposure to nafenopin suppressed apoptosis induced by all three stimuli. Overall, our studies demonstrate that the ability of nafenopin to protect hepatocytes from apoptosis is not restricted to species or apoptotic stimulus. It is possible, therefore, that the PPs may suppress apoptosis by acting on diverse signalling pathways. However, it seems more likely that nafenopin suppresses hepatocyte apoptosis elicited by each death stimulus by impinging on a core apoptotic mechanism.
Carcinogenesis 1998 Feb
PMID:The non-genotoxic hepatocarcinogen nafenopin suppresses rodent hepatocyte apoptosis induced by TGFbeta1, DNA damage and Fas. 949 80

The nonsteroidal antiinflammatory drugs (NSAIDs) indomethacin and salicylic acid and the short chain fatty acid butyrate are effective colon cancer chemopreventive agents that increase reactive oxygen species (ROS) generation in colon cancer cells. Here we demonstrate that these agents sensitize the normally resistant human HT-29 colon cancer cell line to apoptosis induced by TNF-alpha or a Fas ligating antibody. The role of ROS in this sensitization is supported by the finding that direct exposure of the cells to H2O2 is sufficient for sensitization. Neither TNF-alpha nor Fas ligation alter basal or chemopreventive agent-activated ROS generation, suggesting that the death ligands and chemopreventive agents act in a complementary fashion. The dual chemopreventive agent/death ligand treatments do not increase Fas, TNF receptor 1, Bak or c-myc expression (although salicylic acid moderately induces of Fas expression). Cell death does correlate with alterations in NF-kappa B activity: the NSAIDs, butyrate and H2O2 enhance c-Rel complex formation by TNF-alpha and provide an overall enhancement of NF-kappa B activation by Fas. The antioxidant N-acetylcysteine (NAC) blocks cell death and NF-kappa B activation induced by Fas ligation, suggesting a potential role for NF-kappa B in Fas-induced apoptosis in these cells. The effects of NAC on TNF-alpha-induced cell death are more complex, with NAC being marginally protective and itself enhancing the formation of c-Rel containing complexes at higher concentrations (25 mM). The influence of NSAIDs and butyrate on ROS generation and death ligand sensitivity may be relevant to their ability to suppress colon carcinogenesis.
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PMID:NSAIDs and butyrate sensitize a human colorectal cancer cell line to TNF-alpha and Fas ligation: the role of reactive oxygen species. 999 Feb 95

The death receptor Fas transduces apoptotic death signaling upon stimulation by Fas ligand and plays a key role in viral hepatitis. When hepatitis-B virus (HBV) infects hepatocytes, the Fas ligand/Fas system responds as the triggering machinery of hepatitis. However, some HBV-infected cells may circumvent Fas-mediated apoptosis and transform to hepatoma cells, as do PLC/PRF/5 hepatoma cells. Therefore, in the present study, we used PLC/PRF/5 hepatoma cells to investigate this ability to avoid Fas-mediated apoptosis. When the cells were treated with an agonistic Fas antibody, they showed resistance to Fas-mediated apoptosis. In contrast, HepG2 cells of the same hepatoma line succumbed. Caspase 3 and 8, which are essential regulators for Fas-mediated cell death, were expressed in both hepatoma cell lines, but only HepG2 cells showed activation of the caspases. A comparison study of expression of other death-associated factors between PLC/PRF/5 and HepG2 cells revealed no apparent differences. However, Far-Western blotting analysis using the Fas death domain (FDD) showed a significant difference. Molecular weight comparison and immunoblotting analysis revealed that PLC/PRF/5 cells lack the FDD-associated protein FADD. In addition, FDD-injected HepG2 cells showed a resistance to Fas-mediated apoptosis, and PLC/PRF/5 cells acquired Fas-sensitivity by FADD injection. Here, we propose that a functional absence of FADD is one of the pathways for the carcinogenesis of HBV-infected hepatocytes.
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PMID:Functional absence of FADD in PLC/PRF/5 hepatoma cells: possible involvement in the transformation to hepatoma in HBV-infected hepatocytes. 1032 Jun 34

Normal human mesothelial cells from individual donors were studied for susceptibility to asbestos-induction of apoptosis and generation of an extended lifespan population. Such populations were generated after death of the majority of cells and arose from a subset of mesothelial cultures (4/16) whereas fibroblastic cells (5/5) did not develop extended lifespan populations after asbestos exposure. All mesothelial cultures were examined for the presence of SV40 T antigen to obtain information on (i) the presence of SV40 T antigen expression in normal human mesothelial cells and (ii) the relationship between generation of an extended lifespan population and expression of SV40 T antigen. Immunostaining for SV40 T antigen was positive in 2/38 normal human mesothelial cultures. These cultures also had elevated p53 expression. However, the two isolates expressing SV40 T antigen did not exhibit enhanced proliferative potential or develop an extended lifespan population. Asbestos-generated extended lifespan populations were specifically resistant to asbestos-mediated but not to alpha-Fas-induced apoptosis. Deletion of p16Ink4a was shown in 70% of tumor samples. All mesothelioma cell lines examined showed homozygous deletion of this locus which extended to exon 1beta. Extended lifespan cultures were examined for expression of p16Ink4a to establish whether deletion was an early response to asbestos exposure. During their rapid growth phase, extended lifespan cultures showed decreased expression of p16Ink4a relative to untreated cultures, but methylation was not observed, and p16Ink4a expression became elevated when cells entered culture crisis. These data extend the earlier observation that asbestos can generate extended lifespan populations, providing data on frequency and cell type specificity. In addition, this report shows that generation of such populations does not require expression of SV40 T antigen. Extended lifespan cells could represent a population expressing early changes critical for mesothelioma development. Further study of these populations could identify such changes.
Carcinogenesis 1999 May
PMID:Asbestos induction of extended lifespan in normal human mesothelial cells: interindividual susceptibility and SV40 T antigen. 1033 93

Cell proliferation and papillogenesis are growth factor-sensitive events in the ovarian mesothelium, the tissue source of ovarian epithelial cancer. To further investigate the regulation of cell proliferation in this tissue, rabbit ovarian mesothelial cells (OMC) were transfected in vitro with a CVN expression vector carrying the human gene for insulin-like growth factor 1 receptor (IGF-1R). The growth characteristics of IGF-1R transfectants (OMIR) and their response to IGF-1 were then compared with those of OMC in serumless HL-1 cultures. OMIR cells formed epithelial-like colonies and, even when nonconfluent, produced tridimensional structures reminiscent of papillae seen in ovarian serous epithelial tumors. After 3 and 7 days of exposure to IGF-1, OMIR cells grew approximately 20-fold (P < 0.05), and papillogenesis was 15- to 25-fold over similar events in OMC, respectively. Exposure to treatment with antisense oligonucleotides against IGF-1R mRNA inhibited OMIR growth rate by 70%. Western immunoblotting and flow cytometry revealed higher expression of IGF-1R in OMIR cells than in OMC. The reverse was true when Fas-receptor expression was evaluated. OMIR cells were clonogenic in 15% serum-rich soft agar assay (OMIR:OMC colony-forming ratio 150-200:1), and tumorigenic in nude mice in which high-grade carcinomas with occasional lung metastases were observed. These data suggest that IGF-1R plays a role in ovarian epithelial carcinogenesis. The overexpression of this receptor induces transformation and morphogenesis of OMCs via an autocrine mechanism. IGF-1R may down-regulate the Fas expression rendering transformed ovarian mesothelial cells resistant to apoptosis.
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PMID:The insulin-like growth factor 1 receptor induces transformation and tumorigenicity of ovarian mesothelial cells and down-regulates their Fas-receptor expression. 1039 75

Recent studies have suggested that MAP kinase phosphatase 1 (MKP-1) is overexpressed in prostate cancer. To evaluate the role of MKP-1 in regulating cell death and tumor growth in prostate cancer, MKP-1 was conditionally overexpressed in the human prostate cancer cell line DU145. Overexpression of MKP-1 in DU145 cells blocked activation of stress-activated protein kinase (SAPK/JNK). MKP-1 overexpression in DU-145 cells was also found to inhibit Fas ligand (FasL)-induced apoptosis, as well as block the activation of caspases by Fas engagement. In addition, MKP-1 blocked the activation of apoptosis by transfected MEKK-1 and ASK-1, presumably through its inhibition of the SAPK/JNK family of enzymes. MKP-1 blocked the ability of FasL to induce loss of mitochondrial transmembrane potential (delta Psi(m)), suggesting that MKP-1 acts upstream of mitochondrial pro-apoptotic events induced by FasL and that the SAPK/JNK pathway may form the signaling link between Fas receptor and mitochondrial dysfunction. Thus, MKP-1 overexpression in prostate cancer may play a role in promoting prostate carcinogenesis by inhibiting FasL-induced cell death.
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PMID:Human DU145 prostate cancer cells overexpressing mitogen-activated protein kinase phosphatase-1 are resistant to Fas ligand-induced mitochondrial perturbations and cellular apoptosis. 1054 65

Programmed cell death or apoptosis is a widespread biological phenomenon. Apoptosis is characterized by typical cell features such as membrane blebbing, chromatin condensation, and DNA fragmentation. It involves a number of membrane receptors (e.g., Fas, TNFR) and a cascade of signal transduction steps resulting in the activation of a number of cysteine proteases known as caspases. Disordered apoptosis may lead to carcinogenesis and participates in the pathogenesis of Alzheimer disease, Parkinson disease, or AIDS. Programmed cell death plays an important role in the processes of gamete maturation as well as in embryo development, contributing to the appropriate formation of various organs and structures. Apoptosis is one of the mechanisms of action of various cytotoxic agents and teratogens. Teratogen-induced excessive death of embryonic cells is undoubtedly one of the most important events preceding the occurrence of structural abnormalities, regardless of their nature. Therefore understanding the mechanisms involved in physiological as well as in disturbed or dysregulated apoptosis may lead to the development of new methods of preventive treatment of various developmental abnormalities. The present review summarizes data on the mechanisms of programmed cell death and concentrates on apoptosis involved in normal or disturbed gametogenesis and in normal and abnormal embryonic development.
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PMID:The role of apoptosis in normal and abnormal embryonic development. 1057 78


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