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PubMed1999

IkappaBalpha is essential for maintaining basal c-Jun N-terminal kinase (JNK) activation and regulating JNK-mediated resistance to tumor necrosis factor cytotoxicity in L929 cells.

Early activation of c-Jun N-terminal kinase (JNK) is believed to block apoptosis in response to death signals such as tumor necrosis factor (TNF). Brief exposure of murine L929 fibroblasts to anisomycin for 1 hr to activate JNK resulted in resistance to TNF killing. TNF rapidly induced cytoplasmic shrinkage in control cells, but not in the anisomycin-pretreated L929 cells. However, the induced TNF resistance was suppressed in the L929 cells which were engineered to stably inhibit IkappaBalpha protein expression by antisense mRNA ( approximately 80% reduction in protein expression). No constitutive NF-kappaB nuclear translocation and increased TNF resistance were found in these IkappaBalpha antisense cells. Notably, these cells had a significantly reduced basal level of JNK activation (50-70%), compared to vector control cells. Furthermore, brief exposure of L929 cells to wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-kinase), resulted in resistance to TNF killing, probably due to preconsumption of caspases by wortmannin. Nonetheless, wortmannin-induced TNF resistance was suppressed in the IkappaBalpha antisense cells. Thus, these observations indicate that IkappaBalpha is essential for maintaining the basal level of JNK activation and regulating the JNK-induced TNF resistance.

Animals↗
PubMed2000

Suppression of IkappaBalpha expression is necessary for c-Jun N-terminal kinase-mediated enhancement of Fas cytotoxicity.

The role of c-Jun N-terminal kinase (JNK) in the regulation of Fas-mediated cell death was investigated. Murine L929 fibroblasts were pretreated with anisomycin for 1 h to activate JNK, followed by exposure to anti-Fas antibodies/actinomycin D (ActD) for 16-24 h. Compared to untreated controls, the induction of JNK activation failed to raise cellular sensitivity to anti-Fas/ActD killing. Notably, a significant increase in anti-Fas/ActD killing as induced by JNK preactivation was observed in L929 cells which were engineered to suppress IkappaBalpha protein expression by antisense mRNA. Restoration of the IkappaBalpha protein level in these cells by ectopic expression of a cDNA construct abolished the JNK-increased anti-Fas/ActD killing. Despite the suppression of IkappaBalpha, no constitutive p65 (RelA) NF-kappaB nuclear translocation was observed in the IkappaBalpha-antisense cells. Also, inhibition of NF-kappaB by curcumin failed to inhibit the JNK-increased Fas cytotoxicity, suggesting that NF-kappaB is not involved in the observed effect. Most interestingly, culturing of L929 cells on extracellular protein matrices resulted in partial suppression of IkappaBalpha expression and constitutive JNK and p42/44 MAPK activation. Upon stimulation with anisomycin, these matrix protein-stimulated cells further exhibited reduced IkappaBalpha expression and p42/44 MAPK activation, as well as became sensitized to JNK-increased anti-Fas/ActD killing. Again, ectopic expression of IkappaBalpha in these cells abolished the enhanced anti-Fas/ActD killing effect. Together, these results indicate that suppression of IkappaBalpha expression is essential for JNK-mediated enhancement of Fas cytotoxicity.

Animals↗
PubMed2000

Signalling to translational activation of tumour necrosis factor-alpha expression in human THP-1 cells.

Monocytic THP-1 cells expressed tumour necrosis factor-alpha (TNF-alpha) mRNA, but hardly any detectable TNF-alpha protein and a partially activated MAP kinase ERK-2 in the unstimulated state. Stimulation with phorbol ester led to expression of TNF-alpha protein without significant changes in mRNA, a response that was sensitive to the MEK-1/2 inhibitors PD98059 and U0126. A calcium signal also led to expression of TNF-alpha protein, but now accompanied by a rapid increase in mRNA. A synergistic effect between phorbol ester and calcium ionophore was evident at the level of TNF-alpha protein, but not its mRNA. Stimulation with anisomycin led to a TNF-alpha expression that was sensitive to the p38 inhibitor SB203580. Actinomycin D lowered TNF-alpha mRNA in a similar way as PD98059 but was less inhibitory on PMA- or anisomycin-induced formation of TNF-alpha, thus confirming that these agents acted by causing translational derepression. Thus, in THP-1 cells MAP kinase pathways involving MEK-1/2 and possibly ERK-2 as well as the human p38 analogue were essential for basal TNF-alpha mRNA expression and translational activation.

Anisomycin↗
PubMed1998

Protein tyrosine kinase is downstream of protein kinase C for ischemic preconditioning's anti-infarct effect in the rabbit heart.

The present study tested the hypothesis that one or more tyrosine kinase(s) are downstream of protein kinase C (PKC) in the signal transduction pathway responsible for the cardioprotective effect of ischemic preconditioning (PC). Isolated rabbit hearts were subjected to 30 min of regional ischemia followed by 2 h of reperfusion. Infarct size was measured by triphenyltetrazolium staining and expressed as a percentage of the area at risk. Infarction in control hearts was 32.9+/-1.8%. Ischemic PC with 5-min ischemia/10-min reperfusion reduced infarct size to 11.5+/-1.5% (P<0.05). Infusion of the tyrosine kinase inhibitors, genistein (50 microM) or lavendustin A (0.5 microM), alone did not affect the level of infarction. When infused around the 5-min PC ischemia genistein failed to block protection (13.7+/-1.0%). However, when present at the onset of the 30-min ischemia both genistein and lavendustin A completely aborted protection (31.4+/-2.0 and 28.1+/-1.5%, respectively). Activation of PKC by phorbol 12-myristate 13-acetate (PMA, 0.05 nmol) was as protective is ischemic PC (14.9+/-3.0%; P<0. 05). Similar to PC, PMA-induced protection was completely prevented by both genistein and lavendustin A. Conversely, anisomycin (50 ng/ml), an activator of MAP kinase kinases (dual tyrosine and threonine kinases), was very protective (7.5+/-1.6%; P<0.05) and this protection was still present when PKC was inhibited by 5 microM chelerythrine (12.1+/-1.6%; P<0.05). In conclusion, activation of a tyrosine kinase during the long ischemia appears to be required for cardioprotection in the rabbit heart. Furthermore, the ability of tyrosine kinase inhibitors to block PMA-induced protection in conjunction with the failure of PKC inhibition to prevent anisomycin-induced protection suggests that the tyrosine kinase is downstream of PKC and that the tyrosine kinase may be a MAP kinase kinase.

Alkaloids↗
PubMed1999

Chloramphenicol-induced amnesia for passive avoidance training in the day-old chick.

The antibiotic chloramphenicol, an inhibitor of mitochondrial protein synthesis, was used to investigate the time-related changes in protein synthesis following passive avoidance training in the day-old chick (white leghorn-black Australorp). Retention of memory for this simple learning task is known to be prevented by an inhibitor of cytosolic protein synthesis, anisomycin, in a biphasic manner, with the first phase of sensitivity occurring up to 90 min post-training and the second phase between 4 and 5 h post-training (Freeman, Rose, & Scholey, 1995). Birds received bilateral intracranial injections of chloramphenicol (10 microl/hemisphere of a 7.4 mM solution) at various times relative to training and were tested 24 h later. This report shows that at the second phase of anisomycin susceptibility there was a chloramphenicol-sensitive period (5 h post-training) which had an onset time less than 1 h after injection. The effect of chloramphenicol appears not to be due to the mitochondria being energetically compromised since intracranial injections of an uncoupler of mitochondrial oxidative phosphorylation, 2,4-dinitrophenol (0.1 mM), did not disrupt memory formation when injected 5 h after training, even though it did cause amnesia when injected at the earlier time point of 20 min post-training. These results are discussed in the context of what is already known about memory formation in the day-old chick.

Animals↗
PubMed1978

Characterisation of ribosomes from drug resistant strains of Schizosaccharomyces pombe in a poly U directed cell free protein synthesising system.

Mutants of Schizosaccharomyces pombe were isolated as resistant either to trichodermin or to anisomycin. Growth tests showed that the majority of mutants isolated were cross resistant to both drugs and also to cycloheximide. A limited genetic analysis showed that mutants at least four loci, tri3, tri4, ani1 and ani2, had this phenotype as was also the case for mutants at three cycloheximide resistant loci, cyh2, cyh3 and cyh4 reported previously (Ibrahim and Coddington, 1976). Allelism tests showed that the tri3, ani2 and cyh4 strains were allelic. A mutant at another trichodermin resistant locus, tri5, was cross resistant to anisomycin but sensitive to cycloheximide. Ribosomes from wild type and selected strains were analysed in a poly U directed cell free protein synthesising system. Three strains, cyh1-C7, ani1-F1 and tri-N15 (probably a tri5 allele) possessed ribosomes which were more resistant than the wild type to the drugs used in their isolation. In each case the site of the resistance was in the 60S subunit. Ribosomes from the cyh2, cyh3 and cyh4 strains were as sensitive to cycloheximide as those from wild type.

Anisomycin↗
PubMed1977

The effects of various protein synthesis inhibitors on the sleep-wake cycle of rats.

The present investigation sought to determine the effects of Anisomycin (A), Chloramphenicol (ChA), Vincristine (V), and Penicilline G on the sleep-wake cycle of rats. It was found that both high and low doses of anisomycin decreased rapid eye movement (REM) sleep, while only high doses of ChA and V produced such a decrease. Slow wave sleep (SWS) was unaffected by these drugs. Penicilline G, on the other hand, had no effect on the sleep-wake cycle. It was further shown that the reduction of REM sleep was the result of a decrease in the number of REM periods rather than in the duration of each individual period. These results suggest that protein synthesis may participate in the mechanisms that trigger REM sleep.

Animals↗
PubMed1983

Effects of synthesis inhibition and nervous activity on concentrations of neuronal substance P.

1. When dorsal root ganglia were incubated in vitro with a range of concentrations of anisomycin, incorporation of [ 3H ]lysine into protein and synthesis of substance P(SP) were inhibited to a similar extent confirming that SP is synthesised by a conventional ribosomal mechanism. 2. Doses of anisomycin sufficient to inhibit protein synthesis in mouse CNS in vivo by greater than 95% did not cause a significant fall in the SP content of any of five brain areas, spinal cord, dorsal root ganglia or cornea over an 8 h period. 3. Electrical stimulation of the hind limbs however, produced a 25% fall in the SP content of the dorsal spinal cord of these animals. 4. These findings suggest that the turnover-time of neuronal SP is much longer than that of non-peptide neurotransmitters.

Animals↗
PubMed2005

PKCdelta and mTOR interact to regulate stress and IGF-I induced IRS-1 Ser312 phosphorylation in breast cancer cells.

IRS-1 (Insulin Receptor Substrate-1) is an adaptor protein important for insulin and IGF-I receptor (Insulin-like Growth Factor-IR) transduction to downstream targets. One mechanism recently identified to downregulate IGF-I or insulin receptor signaling in diabetic models is IRS-1 Ser(312) phosphorylation. To date, the importance of this residue in cancer is unknown. This paper identifies mechanisms leading to Ser(312) regulation in MCF-7 breast cancer cells. Whereas IGF-I phosphorylation of IRS(312) is PI (phosphatidylinositol) 3-kinase dependent, anisomycin stress treatment requires JNK activation to induce phosphorylation of IRS(312). We show that both IGF-I and anisomycin stress treatment converge downstream onto mTOR (Mammalian Target of Rapamycin) and PKCdelta (Protein Kinase C-delta) to induce IRS-1 Ser(312) phosphorylation. mTOR associates with IRS-1 and is primarily required for Ser(312) phosphorylation in response to stress or IGF-I treatment. PKCdelta binds to mTOR and its activity is also important for stress or IGF-I mediated Ser(312) phosphorylation. Thus, mTOR and PKCdelta convey diverse signals to regulate IRS-1 function.

Anisomycin↗
PubMed2006

Protein synthesis-dependent reactivation of a contextual conditioned reflex in the common snail.

We report here a study of the effects of blockade of protein synthesis with anisomycin during reactivation of a contextual conditioned reflex in the common snail. The amplitudes of the defensive reactions of snails to standard tactile stimulation before training were identical in two conditions: 1) testing of responses of snails fixed by the shell to a plastic ball floating in water and 2) on the surface of the terrarium glass. After applying electric shocks to the snails' skin for 5 days, a significant difference in responses reflecting the formation of a contextual conditioned reflex was seen in only one of the contexts. Placing trained snails in the same context (reminding) two days after training with simultaneous injection of anisomycin led to significant weakening of training, while control injections of physiological saline produced no such changes. These data suggest that the mechanisms of memory consolidation after training and reminding are not identical.

Animals↗
PubMed1981

Distribution of membrane glycoproteins among the organelles of a single identified neuron of Aplysia. II. Isolation and characterization of a glycoprotein associated with vesicles.

Glycoprotein-I (mol.wt. 180,000) is associated with a vesicle fraction from the cytoplasm of R2, the giant cholinergic neuron in the abdominal ganglion. Electron microscopy has shown that R2 contains both lucent and compound vesicles. We have used anisomycin, an inhibitor of protein synthesis, to provide evidence that Component-I is a constituent of somatic compound vesicles. In the presence of the drug, [3H]N-acetylgalactosamine injected into R2 is incorporated almost exclusively into Component-I. Quantitative electron microscopic radioautography of treated cells shows a marked increase in the proportion of silver grains over compound vesicles and a decrease in labeling of other organelles compared with untreated cells. Analysis of Component-I, isolated using the chaotropic agent lithium diiodosalicylate, shows it to contain fucose, N-acetylgalactosamine, and N-acetylglucosamine. Proteolytic digestion with pronase yields a complex pattern of glycopeptides. The proportion of [3H]N-acetyl-galactosamine in these glycopeptides is altered in the presence of anisomycin. These results together with radioautographic analyses suggest that large carbohydrate chains are elaborated within the endoplasmic reticulum and that smaller chains are added in the Golgi region or on the membrane of the compound vesicle.

Acetylgalactosamine↗
PubMed1984

Nerve growth-promoting factor produced in culture media conditioned by specific CNS tissues of the snail Helisoma.

Medium conditioned by tissue from the CNS of the snail, Helisoma, is capable of promoting neurite outgrowth in isolated neurons from adult central ganglia. The conditioning factor(s) (CF), contained in conditioned medium (CM), is produced only by central ganglionic rings and buccal ganglia and not by other tissues, including hemolymph. CF requires a minimum of 24 h to be produced or released into the medium. At 12 h growth-promoting activity was not detectable. CF binds tightly to the polylysine substratum and its activity is not mimicked by addition of various sera, NGF or fibronectin. CF activity is abolished by chymotrypsin, trypsin or heating to 100 degrees C, but is stable to DNase and RNase treatment. The percentage of cells exhibiting neurite outgrowth is approximately linear with the amount of neural tissue used to condition the medium up to 2 ganglionic rings/ml. Addition of more ganglia fails to stimulate a greater response. This apparent plateau of CM activity appears to be a function of production and/or release of CF, rather than a saturation effect on plated cells, since dose-response curves for dilutions of CM are approximately linear regardless of the number of ganglia used for conditioning. In addition, anisomycin inhibits 35% of CF appearance under conditions of over 90% protein synthesis inhibition in the ganglia used to produce the CM. Under these conditions anisomycin has no apparent effect on the maintenance of electrical excitability. The inhibitor data suggest that 65% of CF is derived from a pre-existing storage pool and that the remainder is synthesized during the 72 h conditioning period.

Amino Acids↗
PubMed1988

Single or repeated mild stress increases synthesis and release of hypothalamic corticotropin-releasing factor.

The effect of a specific mild stress on the levels of corticotropin-releasing factor immunoreactivity (CRF-ir) in the hypothalamus of adult male rats was determined using a radioimmunoassay specific for rat CRF. A single 5 min restraint significantly increased CRF-ir in the median eminence 24 h later compared to appropriate controls (P less than 0.025), with no change detected earlier. Plasma ACTH, an indirect index of CRF release, was significantly elevated within 15 min (P less than 0.025). Repetition of a mild stress daily for 9 days (P less than 0.01), or a single episode of handling (P less than 0.05), both resulted in significantly increased CRF-ir in the whole hypothalamus 24 h later. Blockade of axonal transport by intracisternal colchicine decreased CRF-ir in the median eminence 24 h later (P less than 0.005). Inhibition of protein synthesis by anisomycin during a single 5 minute restraint resulted in significantly decreased CRF-ir in the median eminence 24 h later compared to vehicle-injected stressed rats (P less than 0.005) or to anisomycin-injected unstressed controls (P less than 0.025). These data show that mild stress increased net hypothalamic CRF content as a result of the balance between augmented synthesis and augmented release.

Adrenocorticotropic Hormone↗
PubMed1995

Inhibitor of protein synthesis phase-shifts the circadian oscillator and inhibits the light induced-phase shift of the melatonin rhythm in pigeon pineal cells.

Our recent study showed that dissociated pigeon pineal cells expressed a circadian oscillation of melatonin release which entrained to light-dark cycle and persisted under constant darkness in vitro, suggesting that pigeon pineal cells contain the circadian oscillator and photoreceptors. Six-hour pulses of anisomycin, an inhibitor of protein synthesis that acts at hte 80S ribosomal subunit, induced steady state and phase depended phase shifts of the circadian oscillation of melatonin release. The phase advances and delays were produced at CT 7.9 h and between CT 18.6 h and CT 4.5 h, respectively. The magnitudes of phase shifts were dose dependent and correlated with the magnitudes of inhibition of protein synthesis determined at CT 4.5 h. Furthermore, anisomycin blocked the light-induced phase advance. Two dimensional electrophoresis revealed that synthesis of two proteins with Mr of 17,600 and less than 5000 are stimulated by a 3-h light pulse at CT 18.6 h which corresponds to the light-induced phase advance region. These results suggest that 80S ribosomal protein synthesis is involved in normal or light-entrainment functions of the circadian oscillator in pigeon pineal cells.

Animals↗
PubMed1996

Expression of urokinase-type plasminogen activator, its receptor and type-1 plasminogen activator inhibitor is differently regulated by inhibitors of protein synthesis in human cancer cell lines.

Expression of the various components of the plasminogen activation system is under tight regulation by hormones, cytokines, and growth factors under physiologic conditions. Like early-response genes, these components are modulated by inhibitors of protein synthesis in some cell lines. To clarify the specific expression and regulation of mRNAs for urokinase (uPA), its receptor (uPAR), and type-1 plasminogen activator inhibitor (PAI-1), I analyzed RNA from four human cancer cell lines by RNA blotting after treatment with cycloheximide, anisomycin, emetine or puromycin. These inhibitors, all of which induced translational arrest, induced a very diverse response in the various transcripts, suggesting that the inhibitors mediate their effects through different molecular mechanisms. Dose-response analysis showed that, in A549 cells, anisomycin strongly induced uPAR and PAI-1 mRNA at concentrations that did not cause complete inhibition of protein synthesis, whereas cycloheximide induced these transcripts in a dose-dependent manner only at concentrations sufficient to inhibit total protein synthesis by >90%. Puromycin induced the 3.4-kb transcript of PAI-1 mRNA in A549 and RD cells, whereas it decreased the expression of both the 3.4-kb and 2.4-kb PAI-1 transcripts in HT-1080 cells. Different time patterns of induction for uPA, uPAR and PAI-1 mRNA suggest that even in the same cell type, inhibitors of protein synthesis mediate their effects on various genes through different mechanisms. Thus, induction of uPA, uPAR, and PAI-1 transcripts by inhibitors of protein synthesis was dependent on the gene, the cell line, and the type of inhibitor, and inhibition of protein synthesis per se was not sufficient for induction of these transcripts.

Anisomycin↗
PubMed1976

Effects of ACTH peptide fragments on memory formation.

The effects of peptides derived from ACTH on the formation of long-term memory have been investigated in male mice. Post-training administration of ACTH 4-10-L-Phe-7 (ACTH-L) improved retention for both passive and active avoidance tasks. Administration of ACTH 4-10-D-Phe-7 (ACTH-D) impaired retention for both tasks. The optimum dose for ACTH-L was about 0.3 mg/kg; the optimum dose for ACTH-D was in the range of 1.0-3.0 mg/kg. Using the passive avoidance task, it was shown that either drug had to be administered within 60 min of training to be highly effective. Amnesia produced by anisomycin (Ani), an inhibitor of protein synthesis, was lessened by ACTH-L and increased by ACTH-D, ACTH-D opposed the memory facilitating effects of ACTH-L. Using intact mice, ACTH-L or ACTH-D did not significantly change the incorporation of valine into protein, nor did these peptides influence the inhibition of protein synthesis caused by anisomycin. The results show that ACTH may play a major role in memory processing, perhaps by facilitating essential protein synthesis at sites specific for the memory being established.

Adrenocorticotropic Hormone↗
PubMed1977

Protein synthesis and amnesia: studies with emetine and pactamycin.

Two antibiotic inhibitors of protein synthesis, emetine and pactamycin, have been tested for their effects on cerebral and peripheral protein synthesis and amnesia. Peripherally administered emetine but not pactamycin inhibited cerebral protein synthesis, although this inhibition was lower than that observed with cycloheximide or anisomycin. Pactamycin had a lesser effect on adrenal protein synthesis than emetine. This was reflected in the ability of emetine but not pactamycin to block ACTH-induced corticosteroidogenesis. Anisomycin and cycloheximide caused amnesia in a passive avoidance task, whereas pactamycin and emetine did not. These results are inconsistent with the amnesia being due to inhibition of protein synthesis in a peripheral organ. They are also inconsistent with the amnesia being due to the suppression of an adrenocortical response as previously suggested. No obvious correlation between amnesia and the mechanism of protein synthesis was observed. The most parsimonious explanation is that inhibition of cerebral protein synthesis is necessary for amnesia.

Adrenal Glands↗
PubMed1984

Investigation of the reported protective effect of cycloheximide on memory.

Many findings support the hypothesis that formation of long-term memory requires synthesis of proteins in the nervous system close to the time of learning. This hypothesis has been challenged recently by reports that the protein synthesis inhibitor cycloheximide (CYC) injected 2 hr prior to passive avoidance training in mice or rats attenuated the memory impairment induced by a usually amnestic dose of CYC administered 30 min pretraining. To investigate the reports of a "protective" effect of the prior injection, we attempted to replicate them and test their generality. For replication we administered either paired injections of CYC--120 mg/kg 2 hr prior to training and 30 mg/kg 30 min prior to training--or single injections of CYC (either 120 mg/kg or 30 mg/kg) 30 min pretraining and tested for retention of the passive avoidance habit either 1 or 7 days later. No attenuation of amnesia was observed at 1 day tests. Attenuation of amnesia following the double injection of CYC was observed at 7 day tests. When another protein synthesis inhibitor, anisomycin, was used in the same experimental design, there was no "protective" effect; two injections of anisomycin produced greater memory impairment for the passive avoidance habit than did the single low dose. Also, for active avoidance training, two successive injections of CYC caused significantly greater amnesia than did a single dose; this is the opposite of a "protective" effect. We suggest that the reported "protective" effect of CYC on memory is an as yet unexplained phenomenon that does not generalize to other antibiotic drugs and is specific to the passive avoidance task.

Animals↗