The effect of surfactin on the proliferation of LoVo cells, a human colon carcinoma cell line, was examined. Surfactin strongly blocked the proliferation of LoVo cells by inducing pro-apoptotic activity and arresting the cell cycle, according to several lines of evidence on DNA fragmentation, Annexin V staining, and altered levels of poly (ADP-ribose) polymerase, caspase-3, p21 WAF1/Cip1 , p53, CDK2 and cyclin E. The anti-proliferative activity of surfactin was mediated by inhibiting extracellular-related protein kinase and phosphoinositide 3-kinase/ Akt activation, as assessed by phosphorylation levels. Therefore, our data suggest that surfactin may have anti-cancer properties as a result of its ability to downregulate the cell cycle and suppress its survival.
FBI-1 (also called Pokemon/ZBTB7A) is a BTB/POZ-domainKrüppel-like zinc-finger transcription factor. Recently, FBI-1 was characterized as a proto-oncogenic protein, which represses tumor suppressor ARF gene transcription. The expression of FBI-1 is increased in many cancer tissues. We found that FBI-1 potently represses transcription of the Rb gene, a tumor suppressor gene important in cell cycle arrest. FBI-1 binds to four GC-rich promoter elements (FREs) located at bp ؊308 to ؊188 of the Rb promoter region. The Rb promoter also contains two Sp1 binding sites: GC-box 1 (bp ؊65 to ؊56) and GC-box 2 (bp ؊18 to ؊9), the latter of which is also bound by FBI-1. We found that FRE3 (bp ؊244 to ؊236) is also a Sp1 binding element. The importance of the tumor suppressor retinoblastoma (Rb) 3 protein in regulating key cellular events was first suggested by the identification of a tumor, retinoblastoma, in which the Rb locus was invariably deleted (1-3). Rb is implicated in the development of various cancers (4 and references therein). Rb suppresses tumorigenesis by inhibiting cell cycle progression at G 1 /S by preventing the transcription of several genes important in cell cycle control (5). Rb is phosphorylated in a cell cycle-dependent manner (6 and references therein). When Rb is hypophosphorylated, it forms complexes with E2F family proteins and inhibits transcription by recruiting proteins involved in transcriptional repression (7). Once phosphorylated, Rb can no longer form complexes with E2F proteins. E2F proteins, upon dimerization with their differentiation-regulated transcription factor partners, are capable of activating the expression of a number of genes that are likely to regulate or promote entry into S phase (6 and references therein). FBI-1 represses transcription of theInvestigations on how transcription of the Rb gene is regulated are important in elucidating the cellular regulatory mechanism of Rb gene expression (8 -12). For example, induction of Rb gene transcription by MyoD, via CREB, is a key event in muscle differentiation (9). Furthermore, transcriptional activation of the Rb gene by GABP and HCF-1 is also important in muscle differentiation (10, 11). In contrast, YY1 and MIZF repress transcription of Rb, and this repression is important for inhibiting myogenesis (10, 12). All these data suggest that multiple transcription factors act on the transcriptional regulation of Rb gene.We have been investigating the biological functions of FBI-1 (also called Pokemon/ZBTB7A), which contains a BTB/POZdomain at its N terminus and Krüppel-like zinc fingers at its C terminus (13,14). Recently, there have been several reports on the function of FBI-1. FBI-1 stimulates the Tat activity of human immunodeficiency virus, type 1 long terminal repeat and represses human ADH5/FDH gene expression by interacting with Sp1 zinc fingers (14, 15). The mouse counterpart of FBI-1, LRF, co-immunoprecipitates and co-localizes with Bcl-6, and is involved in chondrogenesis and adipogenesis (16 -18). The rat homolog of FBI-1...
As Th1 and Th2 cytokines, IFN-γ/α and IL-4 counterregulate diverse immune functions. In particular, IFN-γ and IFN-α have been reported to markedly suppress the IL-4-induced IgE production and type II IgE receptor (FcεRII/CD23) expression. Because modulation of IL-4R may be an important mechanism in the regulation of IL-4 response, we have investigated the effect of IFN-γ/α on IL-4R expression and signal transduction mechanisms involved in this process. In human mononuclear cells and B cells isolated from tonsil or peripheral blood, IL-4 up-regulates IL-4R(α) expression at surface protein and mRNA levels, and the IL-4-induced IL-4R(α) is significantly down-regulated by both IFN-γ and IFN-α to a similar extent. The inhibitory effects of IFN-γ/α on the IL-4R mRNA expression require a lag period of about 8 h, and are sensitive to cycloheximide treatment, which suggests that the suppressive effect of IFNs on IL-4R gene expression is a secondary response requiring de novo synthesis of IFN-induced factors. Under such conditions that the inhibitory effects of IFNs are observed, IFNs do not affect the IL-4-induced STAT6 activation and IL-4R transcription, as analyzed by EMSA and nuclear run-on assays, respectively. Subsequently, mRNA stability studies have indicated that the action of IFN-γ/α is primarily mediated by an accelerated decay of IL-4-induced IL-4R mRNA. Thus, it appears that, as already shown in the case of the IL-4-induced FcεRII regulation, posttranscriptional inhibition of IL-4-inducible genes by mRNA destabilization is a common mechanism by which type I and II IFNs antagonize the IL-4 response in human immune cells.
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