We investigated the effect of oral feeding of heat-killed Lactobacillus casei strain Shirota on immunoglobulin E (IgE) production in mice. The strain was orally administered to BALB/c mice that had been preinjected intraperitoneally with ovalbumin, and the level of IgE in serum was determined. Results indicated that the oral feeding of L. casei strain Shirota was effective in inhibiting IgE production in serum, and the IgE production in response to ovalbumin was significantly inhibited in the mice. The in vitro production of IgE by the spleen cells from mice fed L. casei strain Shirota in response to restimulation with ovalbumin was inhibited in contrast to that of spleen cells from the control group. We also examined the pattern of cytokine production by spleen cells from mice fed L. casei strain Shirota followed by restimulation with ovalbumin in vitro. In the mice fed L. casei strain Shirota, the production by the spleen cells of Th1 cell-associated cytokines, such as interferon-gamma and interleukin-2, was higher than that by the spleen cells from the control group. In contrast, the production of Th2 cell-associated cytokines, such as interleukin-4, interleukin-5, interleukin-6, and interleukin-10, by spleen cells in the group fed L. casei strain Shirota was lower than that by the cells from the control group. Furthermore, the interleukin-12 production of the spleen cells from mice fed L. casei strain Shirota was also higher than that of the control group.
Expression of an interferon inducible gene 6-16, G1P3, increases not only in type I interferon-treated cells but also in human senescent fibroblasts. However, the function of 6-16 protein is unknown. Here we report that 6-16 is 34 kDa glycosylated protein and localized at mitochondria. Interestingly, 6-16 is expressed at high levels in gastric cancer cell lines and tissues. One of exceptional gastric cancer cell line, TMK-1, which do not express detectable 6-16, is sensitive to apoptosis induced by cycloheximide (CHX), 5-fluorouracil (5-FU) and serum-deprivation. Ectopic expression of 6-16 gene restored the induction of apoptosis and inhibited caspase-3 activity in TMK-1 cells. Thus 6-16 protein has anti-apoptotic function through inhibiting caspas-3. This anti-apoptotic function is expressed through inhibition of the depolarization of mitochondrial membrane potential and release of cytochrome c. By two-hybrid screening, we found that 6-16 protein interacts with calcium and integrin binding protein, CIB/KIP/Calmyrin (CIB), which interacts with presenilin 2, a protein involved in Alzheimer's disease. These protein interactions possibly play a pivotal role in the regulation of apoptosis, for which further detailed analyses are need. These results overall indicate that 6-16 protein may have function as a cell survival protein by inhibiting mitochondrial-mediated apoptosis.
Although the in£uence of selective cyclooxygenase (COX)-2 inhibitors on the proliferation of colon adenocarcinoma cells have been the subject of much investigation, relatively little research has compared the e¡ects of di¡erent COX-2 inhibitors. Celecoxib strongly suppressed the proliferation of COX-2 expressing HT-29 cells at 10^40 W WM. NS-398 and nimesulide also inhibited cell proliferation, whereas rofecoxib, meloxicam, and etodolac did not. Only celecoxib induced apoptosis of HT-29 cells, as detected on the basis of DNA fragmentation, TUNEL positivity, and caspase-3/7 activation. DNA fragmentation was also increasd in COX-2 non-expressing cell lines (SW-480 and HCT-116) by exposure to celecoxib for 6^24 h. All six COX-2 inhibitors suppressed the production of prostaglandin E 2 by HT-29 cells, suggesting that the pro-apoptotic e¡ect of celecoxib was unrelated to inhibition of COX-2. Inactivation of Akt might explain the di¡erential pro-apoptotic effect of these selective COX-2 inhibitors on colon adenocarcinoma cells.
The cell cycle is strictly regulated by numerous mechanisms to ensure cell division. The transcriptional regulation of cell-cyclerelated genes is poorly understood, with the exception of the E2F family that governs the cell cycle. Here, we show that a transcription factor, zinc finger protein 143 (ZNF143), positively regulates many cell-cycle-associated genes and is highly expressed in multiple solid tumors. RNA-interference (RNAi)-mediated knockdown of ZNF143 showed that expression of 152 genes was downregulated in human prostate cancer PC3 cells. Among these ZNF143 targets, 41 genes (27%) were associated with cell cycle and DNA replication including cell division cycle 6 homolog (CDC6), polo-like kinase 1 (PLK1) and minichromosome maintenance complex component (MCM) DNA replication proteins. Furthermore, RNAi of ZNF143 induced apoptosis following G2 ⁄ M cell cycle arrest. Cell growth of 10 lung cancer cell lines was significantly correlated with cellular expression of ZNF143. Our data suggest that ZNF143 might be a master regulator of the cell cycle. Our findings also indicate that ZNF143 is a member of the growing list of non-oncogenes that are promising cancer drug targets. (Cancer Sci 2010; 101: 2538-2545 T ranscriptional regulation of gene expression requires the orchestrated recruitment of transcription factors by sequence-specific DNA binding regulators. Staf was initially identified as the transcriptional activator of the RNA polymerase III-dependent Xenopus tRNA gene.(1) It has recently been shown that its human ortholog zinc finger protein 143 (ZNF143; formerly known as hStaf) is also involved in RNA-polymerase-IIdependent gene transcription.(2,3) The DNA binding domain of ZNF143 is located in the central part of the protein and consists of seven zinc finger domains.(1,4) The ZNF143 DNA binding site is thought to be at least 18 bp long because the protein has seven zinc fingers; by analogy, the well-known zinc finger transcription factor Sp family and members of the KLF family contain three zinc fingers and recognize DNA sequences approximately 6 bp long.(5) Recently, it has been shown by a bioinformatics approach that ZNF143 binding sites are widely distributed in the CpG island-type promoters of the human genome.(6) Functional classification of ZNF143 target genes has revealed that many of the identified genes are important for cell growth: 27% of the genes are categorized as cell cycle ⁄ DNA replication ⁄ DNA repair proteins.We have previously reported that expression of ZNF143 is induced by DNA-damaging agents and is enhanced in cisplatinresistant cell lines.(7) ZNF143 binds preferentially to cisplatinmodified DNA. We also found that ZNF143 binding sites are frequently found in the promoter region of DNA repair genes. Here, we investigated the ZNF143 target genes by RNA interference (RNAi). One hundred and fifty-two genes were downregulated by ZNF143-specific small interfering RNA (siRNA) transfection. Among them, 41 genes are categorized as concerned with cell cycle and DNA replication. ZNF143 wa...
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