Tumor necrosis factor alpha (TNF-␣) and gamma interferon (IFN-␥
Abstract. Chlamydomonas reinhardtii cells shed their flagella in response to environmental stress . Under favorable conditions, flagella are quickly regrown . To learn more about the signals that trigger flagellar excision and regrowth we have investigated inositol phospholipid metabolites, molecules implicated in signal transduction in several other systems . After deflagellation by low pH or mastoparan, a potent activator of G proteins, there was a rapid increase in levels of inositol 1,4,5-trisphosphate measured by use of receptor-binding assays and HPLC. This increase was concomitant with a decrease in levels of phosphatidylinositol 4,5-bisphosphate and was followed by an increase in phosphatidic acid, results consistent with activation of phospholipase C and diacylglycerol kinase. Additional experiments suggest that this activated phospho-HE unicellular green alga Chlamydomonas reinhardtii sheds its two flagella when confronted with environmental stresses such as pH shock or mechanical shear (38, 39) . Deflagellation is quickly followed by increased synthesis of flagellar mRNA (2, 27, 31) and protein (29) and regrowth offlagella, which reach full length -90 min after deflagellation . Little is known about the biochemical pathways that couple environmental stress to deflagellation and the subsequent synthesis and assembly of flagellar components. Initially, the environmental stress (e.g ., pH shock) is communicated to the molecular apparatus responsible for deflagellation, and subsequently the deflagellated condition of the cell is communicated to the elements controlling relevant gene expression and flagellar assembly.The involvement of Caz+ in control of deflagellation (14,40, 42), flagellar mRNA accumulation (12a), and flagellar assembly (29) led us to postulate that products of inositol phospholipid hydrolysis might be components of signal transduction in this system. During signal transduction via the ino- lipase C is not important for flagellar regrowth but plays a role in informing the excision apparatus of the environmental stress . Addition of neomycin (an inhibitor of phospholipase C) before exposure of cells to low pH or mastoparan prevented the increase in inositol 1,4,5-trisphosphate and also prevented deflagellation . Addition of neomycin after deflagellation blocked increases in inositol 1,4,5-trisphosphate that normally followed deflagellation, but did not block flagellar assembly. Furthermore, a flagellar excision-defective mutant, fa-1, did not shed its flagella in response to low pH or mastoparan, yet both of these agents activated phospholipase C in these cells. The results suggest that activation of phospholipase C, possibly via a G protein, is a proximal step in the signal transduction pathway inducing deflagellation in Chlamydomonas.sitol phospholipid pathway in other systems, signal-activated phospholipase C hydrolyzes phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P2)t yielding the "second messengers" inositol 1,4,5-trisphosphate (Ins[1,4,5]P3) and 1,2-sn-diacylglycerol (DAG) . Th...
The Epstein ± Barr Virus (EBV) LMP1 protein is frequently expressed in nasopharyngeal carcinoma and is essential for the transforming eects of EBV. Analysis of LMP1 genes isolated from tumor biopsies has revealed considerable sequence variation including deletion of amino acids 343 ± 352. Several studies have suggested that this sequence variation could enhance the transforming potential of LMP1. LMP1 has profound eects on cellular gene expression mediated in part through activation of the NF-kB transcription factor. In addition, LMP1 engages the TRAF signaling pathway resulting in the induction of EGFR expression. In this study, the LMP1 proteins derived from the laboratory strain B95-8 and the NPC strain C15 were analysed for their ability to activate NF-kB and also to induce expression of the EGFR. The data suggest that the C15-LMP1 protein activates NF-kB more eciently and induces higher levels of the EGFR. Analysis of chimeric LMP1 proteins indicates that the amino terminal 181 amino acids of C15-LMP1 confer this increased signaling capability, and that deletion of amino acids 343 ± 352 does not aect these properties. Finally, these data provide evidence that ®ve amino acid changes within the transmembrane domain in the C15-LMP1 protein lead to enhanced NF-kB activation and EGFR induction.
The Epstein-Barr virus latent membrane protein 1 (LMP1) oncoprotein causes multiple cellular changes, including induction of epidermal growth factor receptor (EGFR) expression and activation of the NF-B transcription factor. LMP1 and the cellular protein CD40, which also induces EGFR expression, interact with the tumor necrosis factor receptor-associated factor (TRAF) proteins. The LMP1 carboxy-terminal activation region 1 signaling domain interacts specifically with the TRAFs and is essential for EGFR induction through a mechanism independent of NF-B alone. LMP1 and CD40 share a common TRAF binding motif, PXQXT. In this study, the PXQXT motifs in both LMP1 and CD40 were altered and mutant proteins were analyzed for induction of EGFR expression. Replacement of the T residue with A in CD40 completely blocked induction of the EGFR, while the same mutation in LMP1 did not affect EGFR induction. Replacement of both P and Q residues with A's in LMP1 reduced EGFR induction by >75%, while deletion of PXQXT blocked EGFR induction. These results genetically link EGFR induction by LMP1 to the TRAF signaling pathway. Overexpression of TRAF2 potently activates NF-B, although TRAF2 did not induce expression of the EGFR either alone or in combination with TRAF1 and TRAF3. In vivo analyses of the interaction of the TRAFs with LMP1 variants mutated in the PXQXT domain indicate that high-level induction of EGFR expression requires interaction with TRAF1, -2, and -3. However, exogenous expression of TRAF3 decreased EGFR induction mediated by either LMP1 or CD40. These data suggest that TRAF-mediated activation of EGFR expression requires assembly of a complex containing the appropriate stoichiometry of TRAF proteins clustered at the cell membrane with LMP1.The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is essential for immortalization of B lymphocytes infected in vitro with EBV and is expressed in lymphomas which develop in immunocompromised individuals (32,47,66). LMP1 is also expressed in all cases of premalignant lesions related to the human malignancy nasopharyngeal carcinoma (NPC) and in a majority of NPC biopsies (12,46,67). LMP1 is the only EBV protein shown to have transforming properties in rodent fibroblasts, highlighting the importance of this viral oncoprotein in cellular transformation associated with EBV infection (1,43,60). The function of LMP1 and the involvement of LMP1 in the activation of cellular signal transduction pathways are just beginning to be understood. Expression of LMP1 in B lymphocytes induces the transcription of many genes, including those encoding activation antigens such as CD23 and CD40, adhesion molecules such as ICAM-1, LFA-1, and LFA-3, and molecules which inhibit programmed cell death such as Bcl-2, Mch-1, and A20 (16,22,33,35,36,(62)(63)(64). Expression of LMP1 in epithelial cells induces expression of the genes encoding the epidermal growth factor receptor (EGFR) and the A20 molecule (38-40). Induction of these genes is likely to play an important role in the transf...
Tumor necrosis factor-␣ (TNF-␣) and ␥-interferon
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