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PubMed1985

The effect of cycloheximide on the expression of cell cycle dependent genes.

We have investigated the inducibility of several cell cycle-dependent genes (plus control sequences, not expressed in a cell cycle-dependent manner) in the presence of cycloheximide, an inhibitor of protein synthesis. The genes studied include: 1) five cDNA clones that are preferentially expressed in the G1 phase of the cell cycle: KC-1, JE-3, 2F1, 4F1 and 2A9; 2) one gene preferentially expressed in late G1/S phase: histone H3; and 3) the cell cycle-dependent oncogene p53. All the genes studied are induced by serum even in the presence of cycloheximide. Previous results in the literature have shown that 2 other oncogenes, c-myc and c-fos, can be induced by growth factors in the presence of cycloheximide. Together with our results, these findings indicate that protein synthesis is not required for the induction of at least nine cell cycle genes by growth factors.

Animals↗
PubMed1986

Hexose transport after glucose refeeding of glucose-starved human fibroblasts: 1. The effects of tunicamycin and cycloheximide. 2. Insulin binding and action.

Hexose transport in glucose-starved human fibroblasts was readily reversed by glucose refeeding. This hexose transport reversal was not inhibited by tunicamycin (1.5 microgram/ml) but was blocked by cycloheximide (20 micrograms/ml). The ability of insulin (100 mU/ml) to stimulate hexose transport was returned by glucose refeeding and this was not affected by tunicamycin. Cycloheximide which blocked the glucose refeeding effect on hexose transport, decreased the ability of insulin to stimulate hexose transport. Specific 125I-insulin binding was increased by glucose refeeding of glucose-starved cells and this change in binding was inhibited by tunicamycin and cycloheximide. Thus, it appears that under the conditions employed in human fibroblasts, the ability of insulin to stimulate hexose transport is differentially regulated more by factors affecting basal hexose transport than by those affecting changes in insulin binding.

Biological Transport↗
PubMed1991

Cycloheximide increases the thermostability of proteins in Chinese hamster ovary cells.

Protein denaturation resulting from temperatures between 42.0 degrees C and 50 degrees C has been observed and implicated as the lethal lesion for hyperthermic cell killing. A logical corollary is that protection against hyperthermic killing requires stabilization of cellular proteins against thermal denaturation. To test this, Chinese hamster ovary cells were treated with the heat protector cycloheximide and then subjected to differential scanning calorimetry to measure protein denaturation. Cycloheximide stabilized proteins that denatured between 42 degrees C and 52 degrees C in control cells by increasing their transition (denaturation) temperature by an average of 1.3 degrees C. In addition, cycloheximide reduced the cytotoxicity of actinomycin D and adriamycin, suggesting that protein stabilization protects cells against stresses other than hyperthermia.

Animals↗
PubMed1992

Cycloheximide treatment of mouse mast cells inhibits serotonin release. Evidence of a requirement for newly synthesized protein in the exocytotic response.

Treatment of mouse peritoneal mast cells and mouse bone marrow-derived cloned mast cells with the protein synthesis inhibitor cycloheximide led to a marked abrogation of serotonin (5-hydroxytryptamine; 5-HT) release induced by a range of activators including antigen, anti-immunoglobulin E (anti-IgE) antibody, calcium ionophore A23187, and the polycation polylysine. Significant inhibition (28%) of IgE-mediated secretion was attained after incubation of peritoneal cells for only 2 hr, and inhibition progressed over a 24 hr period, reaching greater than 80% after 15 hr. When peritoneal mast cells were exposed to cycloheximide and then washed and returned to culture conditions, a substantial recovery of responsiveness to anti-IgE was seen after 5 hr. Under the same conditions to those used in functional studies, cycloheximide inhibited protein synthesis, measured as incorporation of [35S]-methionine, by purified peritoneal mast cells and cloned mast cells to 18.5% and 7.9% of control levels, respectively. These results show that synthesis of new protein over a period of a few hours is required to render mast cells fully responsive to stimuli that act via the IgE receptor, and to certain other stimuli that are receptor-independent.

Animals↗
PubMed1978

Inhibition of 5,7-dihydroxytryptamine-induced supersensitivity to 5-hydroxytryptophan in mice by treatment with cycloheximide.

Intracisternal injection of 5,7-dihydroxytryptamine (5,7-DHT) following treatment with desmethylimipramine induced development of behavioral supersensitivity to the intraperitoneally administered serotonin precursor 5-hydroxytryptophan (5-HTP) in the mouse. This behavioral syndrome, characterized by tremor and muscle twitches (myoclonus), showed a clear dose-response relationship with 5,7-DHT as well as with 5-HTP. Mice lesioned with a low dose of 5,7-DHT (20 micrograms) or a placebo were treated repeatedly with a protein synthesis inhibitor, sycloheximide (45 mg/kg, s.c., every 12 h for up to 10 days). This treatment resulted in a reversible decrease of cerebral protein synthesis varying between 70 and 20% with time between treatments. The myoclonic response to 5-HTP in animals pretreated with 5,7-DHT and by cycloheximide showed a decrease in intensity within 24 h when evaluated quantitatively by an electronic activity monitor, the results of which were confirmed by direct observation. Cycloheximide also exerted a similar, though smaller, effect following full development of sensitivity to 5-HTP over 10 days. These effects may de mediated by inhibition of rapidly turning over serotonin receptor proteins, although their interpretation is somewhat obscured by possible toxic effects of cycloheximide.

5,7-Dihydroxytryptamine↗
PubMed1986

Source of increased serum aspartate and alanine aminotransferase: cycloheximide effect on carbon tetrachloride hepatotoxicity.

Repeated doses of the protein synthesis inhibitor cycloheximide prevented the increases in rat liver mitochondrial and cytosolic aspartate aminotransferase, in alanine aminotransferase and in protein content observed 24 h after a single carbon tetrachloride injection. Serum aminotransferase activity increases induced by carbon tetrachloride were also decreased as much as 75.7% with cycloheximide. Increased synthesis is, therefore, suggested as an important and sometimes major source of increased serum aminotransferases in hepatocellular injury. This effect of cycloheximide lends support to the hypothesis that the liver enzyme increases after CCl4 are probably due to increased synthesis, in addition to the classically held mechanisms of leakage from necrotic or damaged hepatocytes. This explanation of the mechanisms of release of aminotransferases in rat liver injury would clarify many clinical observations if the same phenomenon were to occur in humans in response to hepatic injury. These data suggest that increased serum aminotransferase activities represent a healing, in addition to a degenerative, process.

Alanine Transaminase↗
PubMed1976

Suppression of renin secretion in the isolated rat kidney by cycloheximide.

The effect of cycloheximide, an inhibitor of protein synthesis, on basal and stimulated renin secretion was examined in the isolated perfused rat kidney. Cycloheximide (0.05 mmol) was administered one hour before preparing the kidneys for perfusion. Both basal renin secretion and the response to intrarenal infusion of isoprenaline (0.06 nmol/min/g) or glucagon (0.1 nmol/min/g) were consistently reduced in the cycloheximide-treated group, suggesting dependence of these processes on protein synthesis.

Animals↗
PubMed1992

Toxin-induced cell lysis: protection by 3-methyladenine and cycloheximide.

The protein toxins ricin, abrin, Shiga toxin, and diphtheria toxin were found to induce lysis of several cell lines in a manner characteristic for programmed cell death or apoptosis. The toxins induced DNA degradation, and light and electron microscopical studies revealed that lysis was preceded by reorganization of intracellular vacuoles, cell blebbing, and chromatin condensation both in Vero and in MDCK cells. Cell lysis was efficiently inhibited by cycloheximide and 3-methyladenine (3MA), a specific inhibitor of autophagy. Cycloheximide, which like 3MA inhibits autophagy, protected even when added at a time when the protein synthesis had been blocked by ricin, suggesting that the effect of cycloheximide on cell lysis is independent of its ability to inhibit protein synthesis. Also theophylline and dibutyryl-cGMP had some protective effect, whereas a number of compounds reported to protect against apoptosis in other systems were without protective effects. The data suggest that autophagy is important for the toxin-induced cell lysis.

Abrin↗
PubMed1992

How is the flagellar length of mature sperm determined? III. Comparison of initial growth rate of flagella in spermatids from Cynops and Xenopus in the presence and absence of cycloheximide.

Previous studies on flagellar growth in round spermatids from Cynops and Xenopus in vitro have shown that the period and rate of flagellar growth are greater in Cynops than in Xenopus. The present study shows, however, that during the initial phase of flagellar growth (for the first 12 h following the second meiotic division), the growth rate is very similar in both Cynops and Xenopus (0.5-0.6 microns/h at 22 degrees C). The difference in the growth rate between Cynops and Xenopus was observed beyond 12 h following the second meiotic division. When round spermatids in both species were inoculated with 10 microM cycloheximide, flagella grew at the same rate as in the absence of cycloheximide for the first 12 h following the second meiotic division. Beyond 12 h, however, cycloheximide suppressed flagellar growth in round spermatids in both species. These results indicate that the initial flagellar growth in round spermatids is provided for by flagellar protein pools which were present just after the second meiotic division; the growth beyond 12 h in round spermatids is contributed by newly synthesized flagellar proteins.

Animals↗
PubMed1984

Cycloheximide challenge of mice bearing subcutaneous tumours, with observations on heparin treatment.

Mice bearing large subcutaneous transplants of ovarian teratocarcinoma succumb when given large doses of cycloheximide, whereas animals with equally large subcutaneous Ehrlich tumours are resistant to this treatment. Adequate dosage of heparin is life-saving in cycloheximide-treated, teratoma-bearing mice. The results are discussed in the context of previous work, and one tentative suggestion made is that cycloheximide interferes with the mechanism for release of endogenous heparin which is an essential component of the host response to a growing teratocarcinoma.

Animals↗
PubMed1984

A lethal syndrome in mice following administration of carbon tetrachloride and cycloheximide, and its prevention by heparin treatment.

When a hepatotoxic dose of CCl4 is followed in 6 h (but not in 18 h) by 30 micrograms per g body weight of cycloheximide, a lethal, shock-like state develops. This is prevented by heparin treatment. This lethal syndrome is compared with other, similar, induced lethal states in which cycloheximide plays an essential role, and in which heparin is lifesaving. It is postulated that, after CCl4, a phase of procoagulant activity occurs in the dying centrilobular zone hepatocytes, but that unimpaired protein synthesis permits responsive release of endogenous heparin and thereby prevents thrombosis in centrilobular sinusoids. Cycloheximide is thought to inhibit this heparin release and to allow a transient episode of occlusive centrilobular microthrombosis with consequent irreversible ischaemic damage to the mid-gut.

Animals↗
PubMed1984

Rat adrenal cycloheximide-sensitive factors and phospholipids in the control of acute steroidogenesis.

ACTH in vivo induces the formation of several steroidogenic factors in both cytosol and extramitochondrial particulate fractions of rat adrenal. Cycloheximide prevents the formation of these factors. Here we show the presence of a cytosolic steroidogenic component (C1) which is cycloheximide-sensitive and not ACTH-dependent. C1 is able to solubilize an ACTH-dependent steroidogenic factor (C2) from particulate fractions resulting in the release of the rat-limiting constraint of mitochondrial steroidogenesis. The thermolabile and trypsin-resistant factor C1 has an apparent mol.wt of 28,000 Daltons. In contrast, the cycloheximide-sensitive factor C2 from extra-mitochondrial fractions of ACTH-treated rats comigrates on Sephadex G-10 with phospholipids. Endogenous phospholipids isolated from particulate adrenal fractions of ACTH-treated rats or exogenous phospholipids will also stimulate steroidogenesis in vitro. Indeed, cytosolic solubilizing factor C1 enhances the exogenous phospholipid effect 3-4-fold. The results taken together suggest that C1 may be very similar to a well defined phospholipid exchange protein and C2 is itself a phospholipid. Both factors seem to be obligatory for the ACTH-induced steroidogenesis.

Adrenal Glands↗
PubMed1990

The influence of severity of bile flow reduction, cycloheximide, and methyl isobutyl ketone pretreatment on the kinetics of taurolithocholic acid disposition in the rat.

Pretreatment of rats with methyl isobutyl ketone (MIBK) potentiates the effect of taurolithocholic acid (TLCA) on bile flow, while cycloheximide pretreatment diminishes the cholestatic response. Experiments were performed to determine if the effects of the pretreatments were related to changes in the kinetic disposition of TLCA. Groups of rats were pretreated daily with either 7.5 mmol MIBK/kg po for 3 days or 3.55 mumol cycloheximide/kg ip for 2 days prior to an iv challenge of TLCA. Bile and blood samples were collected for 3 hr and the blood concentrations and biliary excretion of TLCA monitored. The severity of the bile flow reduction had a marked effect on the kinetic pattern of TLCA. The volume of distribution and bile disposition constant of TLCA decreased inversely with the severity of bile flow reduction, while the blood disposition constant increased. The total clearance of TLCA was not affected, but increasing the severity of the cholestasis altered the contribution of biliary and extrabiliary clearance to total clearance. The changes in the kinetics of TLCA observed in MIBK- and cycloheximide-pretreated rats were consistent with the effects the pretreatments exerted on TLCA-induced reduction in bile flow. They were interpreted to be the result of the effects of the pretreatments rather than their cause. Thus, pretreatment with MIBK and cycloheximide appears to exert a modulating effect on TLCA-induced cholestasis by mechanisms unrelated to an alteration of TLCA kinetic profile.

Animals↗
PubMed1976

Effects of frontal polar cortical ablation and cycloheximide on ethanol tolerance in rats.

Thirty adult male Wister rats were pretrained to criterion on the moving belt test, and then made tolerant to ethanol by daily administration of increasing doses over a period of 3 weeks. After a one-month recovery period, they were divided into 3 groups, subjected to bilateral frontal polar cortical ablations, sham-operation and no operation respectively. After postoperative recovery, the cycle of ethanol treatment and testing was repeated. Only the lesioned group failed to reacquire tolerance. A pilot experiment showed that occipital cortical ablations also prevented tolerance. In a second experiment 32 rats, which had similarly undergone and then recovered from an initial period of ethanol tolerance, were divided into 4 groups which received daily treatment with sucrose plus cycloheximide (0.3 mg/kg), sucrose plus saline, ethanol plus cycloheximide, and ethanol plus saline respectively. Only the ethanol plus saline group re-acquired tolerance. Tt is concluded that frontal polar cortical lesions and cycloheximide can both block the development of tolerance to ethanol in animals previously shown to be capable of developing such tolerance.

Animals↗
PubMed1985

Immunological effect of cycloheximide in mice.

We evaluated the effects of cycloheximide on two immune responses in the mouse. The data obtained in this series of experiments showed enhancement of the direct splenic plaque-forming cell response to sheep red blood cells when the drug was administered at doses of 25 and 50 mg/kg i.p. and of the delayed type hypersensitivity reaction to oxazolone when cycloheximide was injected at doses of 10, 25 and 50 mg/kg i.p. Depression of these responses was observed when the dose of drug injected was 75 or 100 mg/kg i.p. At a dose of 5 mg/kg cycloheximide had no effect on these immune responses.

Animals↗
PubMed1985

Effects of cycloheximide on inverse regulation of phenolic and nonphenolic ring deiodinases in monkey hepatocarcinoma cells.

Both phenolic and nonphenolic ring deiodinase activities in monkey hepatocarcinoma cells (NCLP-6E) were increased by addition of serum in a concentration-dependent manner: the stimulatory effect of serum was evident at a concentration as low as 1.5%, and was maximal at 5%. Lineweaver-Burk analysis showed that the increases in the deiodinase activities are due to the increase in Vmax, but not in Km. The addition of cycloheximide at concentrations ranging from 0.1 to 50 micrograms/ml inhibited the stimulatory effect of serum on phenolic ring deiodinase activity progressively. On the other hand, nonphenolic ring deiodinase activity was increased as much as 4-fold by the addition of 0.5-5 micrograms/ml cycloheximide together with 0.5% serum; a high concentration of the drug, 50 micrograms/ml, however, did not elicit such an increase. Actinomycin D at 5 micrograms/ml completely abolished the increase in nonphenolic ring deiodinase activity by serum or cycloheximide. In addition, actinomycin D inhibited the increase in phenolic ring deiodinase activity by serum in a dose-dependent manner at concentrations ranging from 0.05 to 5 micrograms/ml. It is concluded that phenolic and nonphenolic ring deiodinases are regulated by different mechanisms in monkey hepatocarcinoma cells (NCLP-6E).

Animals↗
PubMed1986

MHV nucleocapsid synthesis in the presence of cycloheximide and accumulation of negative strand MHV RNA.

We have found that genomic RNA synthesis is inhibited by cycloheximide in cells infected with mouse hepatitis virus, strain A59 (MHV-A59), in agreement with previously published results (Sawicki, S.G. and Sawicki, D.L. (1986) J. Virol, 57, 328-334). In the present study, the fate of the residual genomic RNA synthesized in the presence of cycloheximide was determined. Nearly all of the genomic RNA synthesized in the presence of drug was incorporated into nucleocapsid structures, suggesting that even in the absence of protein synthesis, genomic RNA synthesis and encapsidation are coupled in MHV-infected cells. Sufficient free nucleocapsid N protein was available for this purpose, since the pool of soluble N protein was determined to decay with a half-life of approximately one hour. Negative strand RNA is the template for the synthesis of both genomic and subgenomic positive strand RNA, and would be predicted to accumulate primarily during the early phases of the lytic cycle. In agreement with this prediction, negative strand RNA accumulated during the first 5-6 h of infection, with little additional accumulation occurring over the next 2.5 h. In marked contrast, positive strand RNA increased 5-6-fold over the same 2.5 h period. These results, taken in conjunction with published data, suggest that negative strand RNA is synthesized during the early period of the infectious cycle and is stable in infected cells and also suggest that treatment with cycloheximide at late times does not inhibit positive strand RNA synthesis indirectly by blocking the formation of negative strand templates.

Capsid↗
PubMed1988

Replicon initiation in normal human cells and in ataxia telangiectasia cells: its differential inhibition by cycloheximide and bleomycin.

Treatment of normal human fibroblasts (NHFs) with cycloheximide, which inhibits protein synthesis, resulted in partial inhibition of their DNA synthesis, as determined by incorporation of radioactive thymidine and resistance of the cells to subsequent treatment with bleomycin. The effects of treatments of ataxia telangiectasia fibroblasts (ATFs) with cycloheximide and then bleomycin on their DNA synthesis were very similar to those on DNA synthesis of NHFs. The fact that treatment with bleomycin only caused transient inhibition of DNA synthesis within an hour in NHFs but not ATFs was confirmed. Studies by alkali-density gradient centrifugation showed that the cycloheximide mainly inhibited formation of short fragments of DNA in both NHFs and ATFs, as bleomycin does in NHFs. These findings suggest that these two chemicals both inhibit replicon initiation, and thus provide evidence that the genetic defect in ATFs is related to replicon initiation.

Ataxia Telangiectasia↗