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)

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

Some mutations in FOXL2 result in premature ovarian failure accompanied by blepharophimosis, ptosis, epicanthus inversus syndrome type I disease, and FOXL2-null mice exhibit developmental defects in granulosa cells. Recently, FOXL2 c.402C>G, a new somatic mutation that leads to a p.C134W change, was found in the majority of adult-type ovarian granulosa cell tumors (GCTs). In this study, we investigated the possible mechanisms by which the C134W mutation contributes to the development of GCTs. Wild-type (WT) and mutant FOXL2 displayed differential apoptotic activities. Specifically, WT FOXL2 induced significant granulosa cell death, but the mutant exhibited minimal cell death. The FOXL2-induced apoptotic response was greatly dependent on caspase 8, BID and BAK because the depletion of any of these three proteins inhibited FOXL2 from eliciting the full apoptotic response. Activation of caspase 8 and subsequent increased production of truncated BID, and oligomerization of BAK, and release of cytochrome c were all associated with the apoptosis induced by WT FOXL2 expression. In contrast, the mutant FOXL2 was unable to elicit the full array of apoptotic signaling responses. In addition, we found differential TNF-R1 (tumor necrosis factor-receptor 1) and Fas (CD95/APO-1) upregulation between the WT and the mutant, and the silencing of TNF-R1 or Fas and the blockage of the death signaling mediated by TNF-R1 or Fas using TNF-Fc or Fas-Fc, respectively, resulted in significant attenuations of FOXL2-induced apoptosis. Moreover, granulosa cells that expressed either WT FOXL2 or mutant exhibited distinct cell death sensitivities on activation of death receptors and deprivation of serum. Thus, the differential activities of FOXL2 and its mutant may partially account for the pathophysiology of GCT development.
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PMID:Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W). 2111 1