Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033377 (prolapse)
 11,717 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prospective studies and recent intervention trials suggest that the risk of some cancers, including respiratory tract cancers, may be inversely related to selenium (SE) intake, and this is supported by strong experimental evidence with chemical-induced animal cancer models. How this cancer-protective effect is mediated is unclear, but interference with the balance of growth/apoptosis during tumor outgrowth is one plausible hypothesis. In general, there is a correlation between the effectiveness of SE compounds as chemopreventive agents in vivo and their ability to inhibit cell growth and induce apoptosis in vitro. This study has investigated the signal transduction pathways affected by SE compounds in biopsies of normal human oral mucosa cells and human oral squamous carcinoma cells (SCCs), using a primary culture system. Two SE compounds were tested: selenodiglutathione (SDG), the primary metabolite of selenite and the most commonly used cancer-protective SE compound in animal models, and the synthetic SE compound, 1,4-phenylenebis(methylene)selenocyanate (p-XSC), one of the most potent chemopreventive pharmacological SE compounds. Three novel findings are reported: (a) SCCs were found to be significantly more sensitive to induction of apo ptosis by SDG than normal human oral mucosa cells, though the differences were marginal with p-XSC; (b) both SE compounds induced the expression of Fas ligand (Fas-L) in oral cells to a degree that correlated with the extent of apoptosis induction; and (c) both SDG and p-XSC induced the stress pathway kinases, Jun NH2-terminal kinase (JNK) and p38 kinase, at concentrations causing apoptosis; p-XSC, and to a lesser extent SDG, also activated extracellular regulated kinases 1&2 (ERKs 1&2) and protein kinase-B or Akt. To test their functional involvement, the effect of inhibiting each of these pathways on induction of apoptosis by SDG and p-XSC was determined in SCCs. Inhibiting the ERKs 1&2 or Akt pathways with specific chemical inhibitors (PD98059 or LY294002, respectively) did not affect the extent of apoptosis induced by SDG or p-XSC (with the exception of LY294002, which actually enhanced the level of induction of apoptosis by SDG). The JNK pathway appeared to be most important for induction of Fas-L and apoptosis because concentrations of SB202190 that inhibited activation of both the JNK and p38 kinase (but not ERKs 1&2) in SCC reduced the extent of induction of Fas-L and apoptosis by SDG and p-XSC, whereas lower concentrations that inhibited activation only of p38 kinase did not. This was confirmed by the fact that exogenous expression of a dominant negative deletion mutant of c-Jun (TAM67) reduced the induction of both apoptosis and Fas-L by SDG.
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PMID:Enhanced sensitivity of human oral carcinomas to induction of apoptosis by selenium compounds: involvement of mitogen-activated protein kinase and Fas pathways. 1160 83

Nasal natural killer (NK)/T-cell lymphoma (NL) frequently co-expresses Fas (Apo-1/CD95) and Fas ligand (FasL), but the tumor cells seldom undergo apoptosis. To determine the reason for failure of apoptosis, we examined Fas mRNA expression in 23 NL cases by reverse transcriptase-polymerase chain reaction and sequenced the entire coding region of the Fas gene in 15 of these cases for which the full-length Fas cDNA could be amplified. The reverse transcriptase-polymerase chain reaction analysis revealed that all of the 23 cases expressed Fas mRNA and the sequencing results showed that in addition to the commonly expressed wild-type Fas mRNA and four alternative splice variants detected in 7 cases, mutant Fas transcripts were present in 9 of the 15 (60%) cases sequenced. With confirmation of some Fas mutations at the gene level, 12 deletions in nine cases and one insertion in one case were eventually identified. To rule out any potential polymerase chain reaction artifacts, the same protocol was used to examine 10 reactive tonsils as a control. No aberrant transcripts associated with deletions were detected in these tonsils except for three alternative splice variants. All of the deletion variants detected in NL contained N-terminal preligand assembly domain but not C-terminal death domain and/or transmembrane domain. Co-detection of the wild-type allele and the mutated Fas alleles without the death domain suggested that a dominant-negative mechanism could block the apoptosis signaling. Moreover, loss of the transmembrane domain could protect the tumor cells from apo-ptosis by producing a soluble form of the Fas receptor. The actuarial 3-year survivals leveled off at 15% for patients carrying the Fas mutations and/or splice variants in the lesions and 49% for those carrying the wild type only, but the difference did not reach statistical significance on the univariate analysis (P = 0.396). Taken together, the findings in this study suggest that frequent Fas gene mutations in NL can result in resistance to apoptosis and may contribute to the pathogenesis of NL by adding to the tumor immune privilege.
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PMID:Frequent deletion of Fas gene sequences encoding death and transmembrane domains in nasal natural killer/T-cell lymphoma. 1246 28