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PubMed1987

Differential effects of cycloheximide on rat liver cytochrome P-450 gene transcription in the whole animal and hepatoma cell culture.

The induction of cytochrome P-450 (c+d) messenger RNAs in rat liver by 3-methyl cholanthrene follows a biphasic pattern. Administration of cycloheximide blocks the induction of cytochrome P-450 (c+d) messenger RNAs by 3-methylcholanthrene as well as cytochrome P-450 (b+e) messenger RNAs by Phenobarbitone. Transcription of these messenger RNAs in isolated nuclei is also blocked by cycloheximide administration. Thus cycloheximide not only fails to mimic the superinduction effects reported in hepatoma cell cultures, but actually blocks the specific transcription process. Exogenous hemin, while counteracting the effects of CoCl2 (heme biosynthetic inhibitor) on cytochrome (c+d) messenger RNA induction by the hydrocarbon, fails to counteract the effects of cycloheximide. It is suggested that a positive labile transcription factor is involved in the regulation of cytochrome P-450 gene expression in vivo.

Animals↗
PubMed1990

Hydrocortisone protects cycloheximide-challenged mice pretreated with Ehrlich ascites tumour cells or with cell-free Ehrlich ascites tumour fluid.

The invariably fatal outcome following cycloheximide challenge of mice pretreated 24 h earlier with either 1 x 10(7) washed Ehrlich ascites tumour cells i.v. or with 0.2 ml of cell-free Ehrlich ascites tumour fluid i.v. was prevented by hydrocortisone treatment. However, glucocorticosteroids failed to prevent the fatal outcome of cycloheximide challenge in mice bearing 5-day-old Ehrlich ascites tumours. The results are interpreted as indicating that there is a steroid demand which must be met to ensure survival of cycloheximide-challenged mice pretreated with tumour cells or with cell-free tumour ascites fluid and that an additional and essential requirement for uninterrupted protein synthesis exists in the case of mice with established ascites tumours and challenged with cycloheximide.

Animals↗
PubMed1997

Protection of rat spinal cord from ischemia with dextrorphan and cycloheximide: effects on necrosis and apoptosis.

OBJECTIVE: We examined the characteristics of neuronal cell death after transient spinal cord ischemia in the rat and the effects of an N-methyl-D-aspartate antagonist, dextrorphan, and a protein synthesis inhibitor, cycloheximide. METHODS: Spinal cord ischemia was induced for 15 minutes in Long-Evans rats with use of a 2F Fogarty catheter, which was passed through the left carotid artery and occluded the descending aorta, combined with a blood volume reduction distal to the occlusion. The rats were killed after 1, 2, and 7 days. Other groups of rats were pretreated with dextrorphan (30 mg/kg, intraperitoneally, n = 7), cycloheximide (30 mg, intrathecally, n = 7), or vehicle (saline solution, n = 12) and killed after 2 days. RESULTS: This model reliably produced paraplegia and histopathologically distinct morphologic changes consistent with necrosis or apoptosis by light and electron microscopic criteria in different neuronal populations in the lumbar cord. Scattered necrotic neurons were seen in the intermediate gray matter (laminae 3 to 7) after 1, 2, and 7 days, whereas apoptotic neurons were seen in the dorsal horn laminae 1 to 3 after 1 and 2 days. Deoxyribonucleic acid extracted from lumbar cord showed internucleosomal fragmentation (laddering) on gel electrophoresis indicative of apoptosis. The severity of paraplegia in the rats treated with dextrorphan and cycloheximide was attenuated 1 day and 2 days after ischemia. The numbers of both necrotic and apoptotic neurons were markedly reduced in both dextrorphan- and cycloheximide-treated rats. CONCLUSIONS: The results suggest that both N-methyl-D-aspartate receptor-mediated excitotoxicity and apoptosis contribute to spinal cord neuronal death after ischemia and that pharmacologic treatments directed at blocking both of these processes may have therapeutic utility in reducing spinal cord ischemic injury.

Animals↗
PubMed1977

Effect of the protein synthesis inhibitor cycloheximide on RNA synthesis in radish seedlings.

The effect of cycloheximide on rRNA and poly (A) (+) RNA synthesis is studied in radish seedlings. When used at a concentration of 50 microng/ml cycloheximide selectively blocks rRNA synthesis without altering poly (A) (+) RNA synthesis. Processing of the 2.3 X 10(6) dalton pre-rRNA is severely impaired. This observation should help in studies of mRNA metabolism in plants. When the concentration of cycloheximide is lowered, it is possible to completely block protein synthesis without preventing RNA synthesis. This implies that the effect of cycloheximide on RNA synthesis is probably more complex than usually assumed.

Cycloheximide↗
PubMed2000

GDP-fucose: beta-galactoside alpha1,2-fucosyltransferase, MFUT-II, and not MFUT-I or -III, is induced in a restricted region of the digestive tract of germ-free mice by host-microbe interactions and cycloheximide.

A shift from sialylation to fucosylation of mucosal glycoconjugates occurred in the mammalian digestive tract in the weaning period, but mice under germ-free conditions were found to express both fucosyl GM1 (FGM1) and fucosyl asialo GM1 (FGA1) in the stomach, cecum and colon, but not in the small intestine. By host-microbe interactions and administration of cycloheximide, FGA1 was quickly induced in the small intestine, but the concentrations of fucosylated glycolipids in the other regions were not altered significantly. Their expression coincided with the activity of GDP-fucose:GA1 alpha(1, 2)-fucosyltransferase (alpha1,2-FT), and we isolated a cDNA with an open reading frame encoding the murine alpha1,2-FT (MFUT-II) of 347 amino acids with a predicted molecular mass of 39.21 kDa. The intraperitoneal injection of cycloheximide induced the mRNA and activity of alpha1,2-FT (MFUT-II) in the small intestine of germ-free mice, whereas no change in the mRNA or activity was observed in the stomach, cecum and colon, indicating that expression of FGA1 in response to microbial colonization or cycloheximide is transcriptionally regulated in a restricted region of the murine digestive tract. At 24 h after the administration of cycloheximide, FGA1 was preferentially produced in the upper half of the duodenal microvilli.

Amino Acid Sequence↗
PubMed1976

Control of ribonucleic acid synthesis in eukaryotes. 3. The effect of cycloheximide and edeine on rna synthesis in yeast.

The addition of cycloheximide to a thermosensitive conditional yeast mutant (ts-187) before and after transfer to the nonpermissive temperature (36 degrees C) for initiation of protein synthesis produces the uncoupling of the RNA and protein synthetic machineries. Since the drug can produce this relaxation in the presence and absence of protein synthesis, it is concluded that the coupling of protein and RNA synthesis, which a temperature shift produces, is not exclusively related to the inhibition of protein synthesis. Support for this assumption has been obtained using the parental (A364A) strain. Transferring this strain to 36 degrees C produces inhibition of RNA synthesis in the presence of stimulation of protein synthesis. Furthermore, cycloheximide and edeine prevent this inhibtion of RNA synthesis that temperature shift produces. It is, therefore, postulated that this inhibition of RNA synthesis results from the synthesis or activation of a factor(s) elicited by the increase in temperature whose function is to repress the transcriptional apparatus. Cycloheximide or edeine can prevent the function of this repressor-like factor by binding to the factor or by preventing its synthesis. The fact that inhibition of protein synthesis either by cycloheximide action or temperature shift in ts-187 produces inhibition of RNA synthesis in isolated nuclei indicates that, in addition to the aforementioned repressor, other factor(s) having a promoter function may exist. Since a slight inhibition of protein synthesis produces nuclear template restrictions, it is postulated that the promoter-like factor(s) is a polypeptide different from the RNA polymerase and, at least in yeast, has a high turnover.

Amanitins↗
PubMed2002

Different effects of p58PITSLRE on the apoptosis induced by etoposide, cycloheximide and serum-withdrawal in human hepatocarcinoma cells.

Minimal overexpression of the p58PITSLRE protein kinase in Chinese hamster ovary cells induces telephase delay, abnormal cytokinesis, retarded cell growth and apoptosis. Fas mediated T cell death is correlated with p58PITSLRE proteolysis and an increase in its histone H1 kinase activity. In this study, it was found that p58PITSLRE had different effects on the apoptosis induced by etoposide, cycloheximide and serum-withdrawal in human hepatocarcinoma cells. The ectopic expression of p58PITSLRE in human hepatocarcinoma cells suppressed apoptosis induced by etoposide, while enhancing the apoptosis induced by cycloheximide and serum-withdrawal respectively. Elevated expression of p58PITSLRE was found during the apoptosis induced by etoposide, whereas most of p58PITSLRE was proteolytically processed during apoptosis induced by cycloheximide and serum-withdrawal. Furthermore, transient transfection of p50PITSLRE resembling the proteolytic form of p58PITSLRE enhanced the 7,721 cells susceptibility to apoptosis induced by all the three stimuli. These findings suggest that the full-length p58PITSLRE might protect the cells from the apoptosis induced by etoposide and its proteolysis might contribute to and enhance the apoptosis induced by cycloheximide and serum-withdrawal respectively.

Apoptosis↗
PubMed1975

Amnesic effect of cycloheximide in the mouse mediated by adrenocortical hormones.

The involvement of adrenocortical hormones in the amnesic effect of cycloheximide was examined in mice. Subcutaneous injection of cycloheximide shortly before a training trial of a passive avoidance task resulted in an amnesia of the avoidance response. However, amnesia was absent in the adrenalectomized animals in which cerebral protein synthesis was suppressed by cycloheximide. Injection of corticosteroids antagonized the amnesic effect, most effecively if the steroids were given immediately after training. The influence of the hormonal treatments upon the amnesic effect was not ascribable to a change in general activity level. The amnesic effect of subcutaneously injected cycloheximide appears to be mediated by hormonal deficiency, and not related to suppression of the cerebral protein synthesis.

Adrenal Glands↗
PubMed1976

Genetic studies on cycloheximide-resistant strains of Schizosaccharomyces pombe.

Cycloheximide-resistant mutants of Schizosaccharomyces pombe were isolated either as spontaneous mutants or after mutagenic treatment with nitrous acid, UV and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Twenty-three spontaneous mutants and 64 induced mutants were analysed genetically. Crosses revealed that at least four loci, designated cyh1, cyh2, cyh3 and cyh4 are responsible for resistance. Alleles of cyh1 show good growth on either high (100 mug/ml) or low (40 mug/ml) concentrations of cycloheximide whereas alleles at the cyh2, cyh3 and cyh4 loci gorw well on 40 mug/ml but poorly on 100 mug/ml. Some alleles at the cyh2 and cyh3 loci are also temperature sensitive (ts), the ts phenotype being conferred by the same gene as the resistance. In diploids, cyh1 and cyh4 are re-essive to wild type whereas cyh2 and cyh3 are semi-dominant. There was no intragenic complementation between three cyh1 alleles. Cross-resistance to trichodermin and anisomycin was shown by cyh2, cyh3 and cyh4 but not cyh1. Most cyh1 alleles, of spontaneous and UV origin only, were cold sensitive (cs) at 14 degrees and some of these were also cycloheximide dependent at the same temperature. It is suggested that the cyh1 and cyh4 genes are involved in ribosome formation or function and the other loci probably affect the uptake of cycloheximide by the cells.

Anisomycin↗
PubMed1998

Cycloheximide facilitates the identification of aberrant transcripts resulting from a novel splice-site mutation in COL17A1 in a patient with generalized atrophic benign epidermolysis bullosa.

Patients with generalized atrophic benign epidermolysis bullosa often show decreased expression of type XVII collagen, a transmembrane hemidesmosomal protein encoded by COL17A1. This report documents a novel splice-site mutation in COL17A1 in a patient with generalized atrophic benign epidermolysis bullosa, and applies a new methodology to define and characterize the resulting mRNA splice variants. Mutational analysis of COL17A1 identified a maternally inherited G-to-T transversion at the -1 position of exon 32. This acceptor splice-site mutation led to the formation of aberrant transcripts present at extremely low levels. Based on our recent finding that cycloheximide stabilized mutant COL17A1 transcripts in keratinocytes homozygous for a frameshift mutation, the effects of the splice-site mutation on splicing of COL17A1 transcripts were determined using reverse transcriptase polymerase chain reaction of total RNA from keratinocytes incubated for 2.5 h in the presence or absence of 10 microg cycloheximide per ml. Using this approach, an abnormally spliced transcript was identified that contains an extra 264 bases upstream from exon 32, resulting in a premature termination codon 27 bp downstream from the cryptic splice site. Three other splice variants, including one derived from the skipping of exon 32, were also identified. These results indicate the usefulness of cycloheximide treatment in evaluating the abnormal processing of mRNA due to splice-site mutations, because: (i) aberrant splicing often generates a premature termination codon, (ii) transcripts with premature termination codons can occur at low or undetectable levels due to nonsense-mediated mRNA decay, and (iii) the levels of these transcripts can be increased by cycloheximide.

Adult↗
PubMed1988

Influence of cycloheximide on acute diabetogenic effects of S-carboxymethylated human growth hormone in obese (ob/ob) mice.

Acute treatment of ob/ob mice with S-carboxymethylated hGH (RCM-hGH), a diabetogenic derivative of GH which lacks significant insulin-like and growth-promoting activities, results in an increase in fasting plasma insulin and blood glucose levels and enhanced peripheral tissue insulin resistance. Plasma insulin level increases within 3 h after RCM-hGH is administered, whereas increased blood glucose concentration and enhanced peripheral tissue insulin resistance became evident 6 h after the hormone derivative is given. The lag period seen in the manifestation of these diabetogenic effects of RCM-hGH is consistent with the time required for gene expression. Therefore, the present study was undertaken to determine whether the above acute responses to the diabetogenic action of RCM-hGH would be expressed in ob/ob mice in which protein synthesis was blocked with cycloheximide. Female ob/ob mice were given either saline or cycloheximide (0.1 mg/g BW) ip and 1 h later were fasted and treated with either saline or 200 micrograms RCM-hGH ip. The mice were given a second injection of cycloheximide during the middle of the hormone treatment period to insure that protein synthesis remained blocked for the entire 6 h. In the animals not receiving cycloheximide, fasting plasma insulin level and blood glucose concentration were markedly elevated 6 h after the injection of RCM-hGH. Also, the GH derivative attenuated the ability of insulin added in vitro to stimulate glucose oxidation by adipose tissue segments isolated from the animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1997

Effect of cytochalasin B and cycloheximide on the activation rate, chromosome constituent and in vitro development of porcine oocytes following parthenogenetic stimulation.

Activation rate, chromosome constituent and developmental pattern of porcine oocytes was examined in the presence and absence of cytochalasin B and cycloheximide following parthenogenetic stimulation. Treatment with cycloheximide after ethanol or Ca2+ ionophore treatment increased the incidence of activation. The percentage of oocytes with two or more female pronuclei was higher (P < 0.05) in oocytes treated with cytochalasin B than in control or cycloheximide-treated oocytes. Treatment with both electrical stimulation and cytochalasin B increased the incidence of diploid chromosome spreads, and accelerated development to the morula and blastocyst stage compared with the control and cycloheximide-treated groups, suggesting a role of ploidy in the development of parthenote.

Animals↗
PubMed1974

Induction of type-C RNA virus by cycloheximide: increased expression of virus-specific RNA.

Mouse cells contain the genetic information for multiple endogenous type-C RNA viruses. The mechanisms by which the cell controls expression of these naturally integrated viruses are not yet known. Recently, chemicals that inhibit protein synthesis have been shown to induce a specific type-C virus at high frequency from BALB/c mouse embryo cells. In the present studies, virus activation in response to a representative translational inhibitor, cycloheximide, is demonstrated to be transient, with virus release primarily occurring within the first 12-24 hr following drug exposure. Analysis of virus-specific RNA in cells by molecular hybridization revealed an absolute increase in viral RNA concentration in cycloheximide-treated cells. This was blocked by simultaneous exposure of the cells to actinomycin D. Further, inhibition of RNA synthesis during but not subsequent to cycloheximide exposure prevented virus activation. These findings show that virus induction by cycloheximide requires de novo RNA synthesis during but not after drug exposure and suggest that the required RNA species may be that of the virus itself. The present results are consistent with the hypothesis that translational inhibitors prevent synthesis of a labile protein whose normal action is to inhibit viral RNA transcription or to cause degradation of viral RNA.

Animals↗
PubMed1991

Transformation of Tetrahymena to cycloheximide resistance with a ribosomal protein gene through sequence replacement.

A method for transforming Tetrahymena has been established earlier, but its application has been limited because of the lack of selectable markers other than the rRNA-encoding DNA (rDNA). Mutations in the yeast ribosomal protein L29 gene (CYH2) are known that confer cycloheximide resistance. We have cloned and sequenced the homologue of this gene from both a wild-type and a cycloheximide-resistant (ChxA) strain of Tetrahymena. Surprisingly, a comparison shows that the ChxA mutation is not present in the CYH2 homologue. We therefore created the yeast mutations in the Tetrahymena gene by site-directed mutagenesis and used them to transform Tetrahymena either with or without linking to an rDNA vector. All clones transformed by the rDNA vector also became resistant to cycloheximide when the rDNA contained the engineered mutant genes. Without the rDNA vector, the mutant genes transform approximately 1% of injected cells to become resistant to cycloheximide. DNA analysis indicates that transformation occurs by replacement of the host sequence and not by random integration of the injected sequence. The replacement occurs to some but not all copies of this gene in the polyploid macronuclear genome. Thus, transformation in Tetrahymena occurs by specific sequence replacement, and the injected mutant genes can serve as dominant selectable transformation markers in this organism.

Amino Acid Sequence↗
PubMed1995

Selective inactivation of two components of the multiprotein transcription factor TFIIIB in cycloheximide growth-arrested yeast cells.

Following protein synthesis inhibition in cycloheximide growth-arrested yeast cells, the rates of tRNA and 5 S RNA synthesis decrease with apparent half-times of about 20 and 10 min, respectively. This effect is mimicked by extracts of treated cells, and the impairment of tRNA gene transcription activity that is observed in vitro parallels the in vivo inactivation of RNA polymerase III transcription. As revealed by experiments in which partially purified class III transcription factors were singly added to extracts of treated cells, only the activity of the multiprotein transcription factor TFIIIB is severely impaired after 3 h of cycloheximide treatment. Similar assays carried out in an in vitro transcription system in which TFIIIB activity was reconstituted by a combination of the TATA box-binding protein (TBP), the 70-kDa component TFIIIB70, plus a partially purified fraction known as B" have shown that the latter two components are both necessary and sufficient to restore control levels of transcription. Their activity, but not TBP activity, is considerably reduced in extracts of treated cells. TFIIIB70 and a component of fraction B" thus appear to be the selective targets of the down-regulation of polymerase III transcription that is brought about by cycloheximide. A substantial depletion of the TFIIIB70 polypeptide was detected by Western immunoblot analysis of extracts derived from cycloheximide growth-arrested cells, indicating that the inactivation of this TFIIIB component results primarily from its enhanced destabilization under conditions of protein synthesis inhibition.

Cell Division↗
PubMed1998

Cycloheximide blocks the toxic effect of streptomycin in guinea pig vestibular hair cells.

Apoptosis has been suggested to be a predominant cell death process for streptomycin-induced degeneration of vestibular hair cells. However, the biochemical aspects of this have not been studied. The purpose of this study was to examine the biochemical aspects of apoptosis of vestibular hair cells caused by streptomycin. Cycloheximide is a widely used protein synthesis inhibitor in studies of apoptosis. We therefore investigated cycloheximide effects on degeneration of vestibular hair cells following streptomycin applications. Supplements of cycloheximide significantly prevented DNA fragmentation in hair cell nuclei and reduced the loss of hair cells. This suggests that cycloheximide possibly inhibits apoptosis of hair cells and attenuates streptomycin-induced degeneration of the vestibular epithelium.

Animals↗
PubMed1997

Cycloheximide reduces the size of lesion caused in rats by a photothrombotic model of brain injury.

A reproducible brain lesion can be triggered in rats by treating them systematically with rose bengal and irradiating their skulls with light. This procedure is often referred to as the photothrombotic model of stroke/ injury. Recently we reported that in this model some cells show signs of apoptosis, programmed cell death. Apoptosis can be attenuated by inhibitors of macromolecular synthesis. In the work described here, we tested the hypothesis that the protein synthesis inhibitor cycloheximide will reduce the actual size of a photothrombotic brain lesion. Ten male rats were treated subcutaneously with 2.5 mg kg-1 cycloheximide; 10 rats received saline. One hour later, a photothrombotic injury was induced in the left cortex in all animals; they were sacrificed 24 h after photothrombosis. Nissl staining and computer-assisted analyses were used to assess the volume of the lesion, and to count the Nissl-positive cells. Both assays revealed significant protective action of cycloheximide treatment. In line with previous reports in which we described the occurrence of apoptosis in the model of photothrombotic brain injury our results with cycloheximide suggest that this model of focal brain ischemia can be used to test the neuroprotective efficacy of putative antiapoptotic compounds.

Animals↗
PubMed1992

Effects of cycloheximide and actinomycin D on radiation-induced apoptotic cell death in the developing mouse cerebellum.

Effects of cycloheximide and actinomycin D on radiation-induced cell death in the external granular layer (EGL) of the cerebellum were studied in vivo. Newborn mice were exposed to 0.24 Gy gamma-radiation, and dying cells which exhibited pyknosis of nuclei in the EGL were examined at various post-irradiation periods. The number of pyknotic cells began to increase 3 h after irradiation, reached a peak incidence at 6 h, and then gradually fell to the sham-irradiated level by 18 h. When pups were injected with cycloheximide 1 h after irradiation, cell death was suppressed for 6 h, but a peak mortality as high as in the case of radiation alone was attained at 15 h after irradiation. When pups were treated with cycloheximide twice, at 1 and 6 h after irradiation, cell death did not occur for 15 h, but then the incidence rose to a level similar to that after irradiation alone. These findings showed that radiation-induced cell death in the EGL is suppressed by cycloheximide until the chemical is metabolized. Hence, death is by apoptosis which is known to require macromolecular synthesis, and the 'signal' for apoptosis in the cell persists for at least 15 h after irradiation. On the other hand, actinomycin D injected immediately before or after irradiation did not affect the initiation of cell death; actinomycin D alone induced cell death.

Animals↗