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PubMed1981

Effect of cycloheximide, beta-D-xylosides and beta-D-galactosides on heparin biosynthesis in mouse mastocytoma.

Heparin biosynthesis has been investigated with mouse mastocytoma in vitro. Minced tumour tissue catalysed the incorporation of [35S]sulphate and [3H]glucosamine into heparin and to a smaller extent into chondroitin sulphate. Addition of cycloheximide caused an inhibition (greater than 80%) of incorporation of each labelled precursor into both polysaccharides. Addition of benzyl beta-D-xyloside relieved the inhibition of incorporation into chondroitin sulphate and restored it to more than threefold that of the control incubation. The effect of beta-D-xyloside on incorporation into heparin was less marked although a consistent small increase of incorporation into this polysaccharide was observed. beta-D-Xyloside did, however, cause a marked incorporation of 35S and 3H labels into material of low molecular weight, which appeared to comprise heparin-like fragments. It is proposed that these fragments arise through a breakdown of the usual process of heparin biosynthesis.

Animals↗
PubMed1984

Cycloheximide blocks changes in rat liver carnitine palmitoyltransferase 1 activity in starvation.

Starvation (24h) increased the maximum activity of carnitine palmitoyltransferase 1 in rat liver and increased the concentration of malonyl-CoA required to cause 50% inhibition of the enzyme (I50). Re-feeding (24h) with a standard cube diet or a high-carbohydrate diet reversed both of these changes, whereas re-feeding with a high-fat diet did not. Administration of cycloheximide (200 micrograms/100 g body wt.) blocked the increases in carnitine palmitoyltransferase 1 activity and I50 on starvation. It is suggested that increase in carnitine palmitoyltransferase 1 activity in starvation may involve synthesis of new enzyme.

Acyltransferases↗
PubMed1986

Effects of glucocorticoid and cycloheximide on the activity and amount of RNA polymerase I in nuclei of rat liver.

The activity of the template-engaged form of RNA polymerase I from livers of adrenalectomized rats was about 50-60% of that of normal control rats, and increased about 2-fold at 6 h after the administration of dexamethasone. However, no change was found in the activity of the 'free' form of RNA polymerase I or the template-engaged form of RNA polymerase II. Immunochemical studies using guinea-pig anti-(RNA polymerase I) serum disclosed that the total number of RNA polymerase I molecules did not vary during the treatment with dexamethasone. Cycloheximide caused a rapid decrease in the template-engaged form of RNA polymerase I activity in normal rats and in dexamethasone-treated (6 h) adrenalectomized rats, to the value in adrenalectomized rats, but affected it only slightly in adrenalectomized rats. The elongation rate of rRNA-precursor synthesis in liver nuclei was not affected by a change in the concentration of circulating dexamethasone. From these results, it is concluded that about half the rRNA-precursor synthesis in rat liver is regulated by glucocorticoids, probably through the synthesis of short-lived protein(s) which may play a role in conversion of the 'dormant' form of RNA polymerase I into the 'engaged' form.

Adrenalectomy↗
PubMed1988

Isoprenaline-induced transcription of 4 beta-galactosyltransferase is inhibited by both cycloheximide and actinomycin D in rat parotid acinar cells.

A cDNA clone for the Golgi enzyme 4 beta-galactosyltransferase (EC 2.4.1.38) was used to determine the steady-state mRNA content in cultured rat parotid acinar cells. Isoprenaline, a beta-adrenergic-receptor agonist, caused an increase in steady-state amounts of mRNA for 4 beta-galactosyltransferase in cultured acinar cells as well as in specific activity of the enzyme. The amount of 4 beta-galactosyltransferase-specific mRNA was dependent on transcription of the gene, as determined by incubation of cells with the RNA polymerase inhibitor actinomycin D, concomitant with the time of isoprenaline treatment. Transcription of the 4 beta-galactosyltransferase gene also required the active biosynthesis of additional cellular factors, since isoprenaline-induced increases in mRNA amounts were not observed on co-incubation with the protein-synthesis inhibitor cycloheximide.

Animals↗
PubMed1988

Factors regulating the secretion of lysophosphatidylcholine by rat hepatocytes compared with the synthesis and secretion of phosphatidylcholine and triacylglycerol. Effects of albumin, cycloheximide, verapamil, EGTA and chlorpromazine.

1. The synthesis and secretion of glycerolipid by monolayer cultures of rat hepatocytes was measured by determining the incorporations of [3H]glycerol, [3H]oleate and [14C]choline and by the absolute concentration of triacylglycerol. 2. The presence of albumin in the medium stimulated the accumulation of lysophosphatidylcholine in the medium by 11-13-fold. 3. Cycloheximide did not significantly alter the accumulation of lysophosphatidylcholine. 4. This process was particularly sensitive to inhibition by chlorpromazine and verapamil, compared with the secretion of triacylglycerol and phosphatidylcholine. By contrast, it was relatively less sensitive to EGTA. 5. It is suggested that intracellular Ca2+ may be important in the production of lysophosphatidylcholine, which then accumulates in the medium by binding to albumin. In vivo this lysophosphatidycholine may be a means of delivering choline and polyunsaturated fatty acids to other organs.

Albumins↗
PubMed1989

Effect of cycloheximide on palmitylation of PO protein of the peripheral nervous system myelin.

Incubation of rat sciatic nerve slices with Krebs-Ringer bicarbonate buffer containing [3H]palmitic acid resulted in the acylation of the PO glycoprotein and a 24 kDa protein of the peripheral nerve myelin. Radioactivity was removed from PO after treating PO with hydroxylamine (83%) and methanolic KOH (97%). These results provided evidence that the radioactivity incorporated into PO was not due to the metabolic conversion of [3H]palmitic acid into amino acids or sugars. PO was more heavily labelled in the homogenate than in the myelin membrane in 8-day-old rat nerve between 5 min and 2 h of incubation. These results suggested that PO may be primarily acylated in the cell body. Incubation of purified myelin with [1-14C]palmitoyl-CoA resulted in the non-enzymic acylation of PO. This provided evidence of the absence of fatty acyltransferase from the purified peripheral nerve myelin. Glycosylation of PO has been shown to occur in the Golgi complex, and monensin inhibited glycosylation of PO in the homogenate and myelin by 53 and 61% respectively. These results suggest that the processing of PO in the Golgi complex and the assembly of PO into myelin is impaired by monensin. However, fatty acylation of PO was unimpaired by monensin, suggesting that the addition of fatty acids may not occur in the Golgi complex. There was a progressive decrease in the acylation of PO between 5 min (28%) and 2 h (61%) in the presence of cycloheximide, as the pool of previously synthesized PO was gradually depleted. These results also provide evidence that palmitylation of PO is not coupled to protein synthesis, and acylation of this protein probably occurs in the early subcompartment of the Golgi complex, which appears to be insensitive to monensin.

Acylation↗
PubMed1997

Stimulation of Sendai virus C' protein synthesis by cycloheximide.

The polycistronic Sendai virus P/C mRNA is translated into five proteins (P, C', C, Y1 and Y2) from distinct start sites in virus-infected cells. The translation mechanism(s) of these proteins from two overlapping open reading frames in the P/C mRNA are poorly understood [Gupta, Ono and Xu (1996) Biochemistry 35, 1223-1231]. While investigating the initiation mechanism of C' from an ACG start site, we found that C' synthesis was resistant to inhibitors of peptide chain elongation such as cycloheximide (CHX) and anisomycin, but not to pactamycin (an inhibitor of chain initiation) or puromycin (a peptide chain terminator). Moreover, low levels (less than 30 microg/ml) of CHX significantly stimulated C' synthesis. Whereas C' synthesis was stimulated, synthesis of the P and C proteins, which are translated from the same mRNA, decreased by more than 95%. Stimulation of C' synthesis by CHX is not related to its initiation at an ACG codon. Mutation of ACG to alternative start sites had no effect on the CHX-stimulated C' synthesis. Similarly, C' synthesis was preferentially stimulated when Sendai virus-infected cells were exposed to hypotonic growth medium. These results suggest that the P/C mRNA may exist in at least two reversible conformations: whereas one conformation allows synthesis of the P and C proteins, the alternative conformation allows synthesis of the C' protein. It might be that low concentrations of CHX somehow increase the alternative conformation, which increases C' synthesis. The C' protein synthesis is reminiscent of the synthesis of stress-related proteins. Perhaps Sendai virus has evolved a novel mechanism to express both non-stress-related and stress-related proteins from the same mRNA.

Animals↗
PubMed1997

Differential regulation of nitric oxide synthase mRNA expression by lipopolysaccharide and pro-inflammatory cytokines in fetal hepatocytes treated with cycloheximide.

The effect of cycloheximide (CHX) on the mRNA expression of the cytokine-inducible, calcium-independent nitric oxide synthase (iNOS) was investigated in fetal hepatocytes stimulated with lipopolysaccharide (LPS) or pro-inflammatory cytokines. In the presence of CHX the LPS-dependent iNOS mRNA levels were reduced, whereas the response to pro-inflammatory cytokines was enhanced. Because iNOS transcription is highly dependent on the activation of nuclear factor kappaB (NF-kappaB), this factor was evaluated by electrophoretic mobility shift assays, and a close correlation between NF-kappaB activity and iNOS mRNA levels was observed. CHX itself potentiated the degradation of the IkappaB alpha and IkappaB beta inhibitory subunits (IkappaB is inhibitory kappaB) of the NF-kappaB complex, and therefore the loss of LPS-dependent iNOS mRNA expression cannot be attributed to a blockage in the activation of NF-kappaB. These results suggest the existence of a CHX-sensitive pathway in the expression of iNOS mediated by LPS, a mechanism that is not involved in the response to pro-inflammatory cytokines.

Animals↗
PubMed1998

S-phase-dependent action of cycloheximide in relieving chromatin-mediated general transcriptional repression.

Chromatin plays a major role in the tight regulation of gene expression and in constraining inappropriate gene activity. Replication-coupled chromatin assembly ensures maintenance of these functions of chromatin during S phase of the cell cycle. Thus treatment of cells with an inhibitor of translation, such as cycloheximide (CX), would be expected to have a dramatic effect on chromatin structure and function, essentially in S phase of the cell cycle, due to uncoupled DNA replication and chromatin assembly. In this work, we confirm this hypothesis and show that CX can induce a dramatic S-phase-dependent alteration in chromatin structure that is associated with general RNA polymerase II-dependent transcriptional activation. Using two specific RNA polymerase II-transcribed genes, we confirm the above conclusion and show that CX-mediated transcriptional activation is enhanced during the DNA replication phase of the cell cycle. Moreover, we show co-operation between an inhibitor of histone deacetylase and CX in inducing gene expression, which is again S-phase-dependent. The modest effect of CX in inducing the activity of a transiently transfected promoter shows that the presence of the promoter in an endogenous chromatin context is necessary in order to observe transcriptional activation. We therefore suggest that the uncoupled DNA replication and histone synthesis that occur after CX treatment induces a general modification of chromatin structure, and propose that this general disorganization of chromatin structure is responsible for a widespread activation of RNA polymerase II-mediated gene transcription.

Animals↗
PubMed1997

In the absence of Epstein-Barr virus infection, phorbol ester modulates apoptosis in cycloheximide-treated Burkitt's lymphoma (BJA-B) cells.

We have shown previously that cycloheximide (CHX), a potent protein synthesis inhibitor, induces high levels of apoptosis in Epstein-Barr virus free (EBV(-)) Burkitt's lymphoma (BJA-B) cells, with comparably reduced levels of apoptosis in the EBV positive (EBV(+)) cells. Modulation of CHX-induced apoptosis in EBV(-) and (+) B cells is reported here using concurrent treatment with phorbol ester (phorbol 12, 13-dibutyrate, PdBu). Cells were collected at 0, 3, 6, 12, 24 and 48 hours after treatment with (i) 1 microgram/ml CHX, (ii) 0.1 microgram/ml PdBu (1 hour pretreatment before 0 h), or (iii) CHX + PdBu (CHX added at 0 h, 1 hour after PdBu). Control cultures were untreated. Apoptotic, necrotic or viable cells were quantified using histological, ultrastructural and biochemical parameters. Protein synthesis was assessed using 35S-methionine incorporation. Intracellular calcium concentrations were measured using flow cytometry. PdBu alone had little effect on cell death: High levels of CHX-induced apoptosis in EBV(-) cells were significantly reduced by concurrent addition of PdBu (P < 0.005). In contrast, low levels of CHX-induced apoptosis in EBV(+) cells were not significantly altered by PdBu treatment. In EBV(-) cells, a negative relationship was observed between levels of apoptosis and calcium concentrations, whereas in EBV(+) cells, there was negligible correlation between these parameters. Thus high levels of CHX-induced apoptosis in EBV(-) cells occur via a PKC-dependent pathway, whereas CHX treatment of EBV(+) cells induces comparatively low levels of apoptosis that occur via a PKC-independent mechanism. The results application in the therapeutic intervention for cancers developing in association with EBV infection.

Apoptosis↗
PubMed2003

Regulation by cycloheximide and lowered temperature of cell-surface alpha7-nicotinic acetylcholine receptor expression on transfected SH-EP1 cells.

Heterologous expression of functional, nicotinic acetylcholine receptors (nAChR) in mammalian cells has been difficult to achieve or optimize, even for nAChR containing only one kind of subunit. In this study, we determined effects of lowered temperature or of exposure to the protein synthesis inhibitor cycloheximide (CHX) on cell surface expression of homomeric alpha7-nAChR in transfected SH-EP1 human epithelial cells. We found that incubation of cells for 2 days at 25 degrees C or in the presence of 0.5-2 microg/mL of CHX caused approximately four- or approximately eight-fold increases, respectively, in surface binding sites for 125I-labeled alpha-bungarotoxin (I-Bgt). These increases were accompanied by increases in peak whole-cell current responses to nicotinic agonists. Either treatment lowered protein synthesis and cell proliferation, but experiments using puromycin indicated that a reduction in protein synthesis or cell proliferation per se was not sufficient to increase surface binding. I-Bgt binding to whole-cell membrane pools increased in response to either treatment, suggesting that the increase in surface binding was due, at least in part, to an increase in intracellular receptor levels. The cyclophilin inhibitor cyclosporin A reduced surface expression in untreated as well as CHX- or 25 degrees C-treated cells. The results suggest practical means for increasing cell surface and functional expression of alpha7-nAChR. Although these effects are not simply due to protein synthesis inhibition or reduced cell proliferation, they do involve an increase in intracellular receptor pool size.

Binding, Competitive↗
PubMed2002

Effects of cycloheximide treatment and interval between fusion and activation on in vitro development of pig nuclear transfer embryos.

The effects of cycloheximide (CHX) treatment and the interval between fusion and activation on the development of pig nuclear transfer (NT) embryos constructed with enucleated oocytes and serum-starved granulosa/cumulus cells were examined. One group of couplets was fused and activated simultaneously (FAS) by a single electrical pulse (activation pulse). Another three groups of couplets were fused electricaly 1.5, 2.5 or 4.5 h before being subjected to the activation pulse (FBA). Each group was divided into two subgroups and incubated with or without CHX. The NT embryos treated with CHX showed a high and stable cleavage rate, regardless of the interval between fusion and activation; however, development to blastocysts was improved only when the NT embryos were subjected to FAS with CHX. These results indicate that CHX-sensitive events occurring shortly after FAS may be responsible for the development to blastocysts. Fusion pulse rarely activated M II oocytes, but rapidly dropped the p34cdc2 kinase activity in NT embryos. A pronucleus-like structure was observed 2-2.5 h after the activation pulse with CHX in NT embryos of both the FAS and FBA groups. Therefore, successive inactivation of M-phase promoting factor and cytostatic factor at a certain short interval may also play an important role in the development of NT embryos.

Animals↗
PubMed1971

Inhibition of the metabolism of 25-hydroxycholecalciferol by actinomycin D and cycloheximide.

Actinomycin D (or cycloheximide) administered prior to radioactive 25-hydroxycholecalciferol blocks the metabolism of 25-hydroxycholecalciferol to polar metabolites that accumulate in intestinal tissue, while it does not prevent the 25-hydroxylation of vitamin D(3) in the liver. Actinomycin D given after radioactive 25-hydroxycholecalciferol does not inhibit 25-hydroxycholecalciferol metabolism. These results indicate that 25-hydroxycholecalciferol must interact with the nuclei of cells to bring about the production of an enzyme(s) that converts it to its polar metabolites.

Animals↗
PubMed1972

Variable decay of memory and its recovery in cycloheximide-treated mice.

Mice were trained in an automated visual-discrimination task. When injected with cycloheximide before training, mice showed: (a) some impairment of memory within minutes after the beginning of training, (b) gradual development of total amnesia in less than 3 hr or in more than 6 hr after training, depending on the extent of training, and (c) spontaneous recovery of memory within 3 days after training. The results are consistent with the operation of three processes of memory storage: (i) a short-term process that is independent of protein synthesis, (ii) a long-term that is dependent on protein synthesis, and (iii) a slow-developing memory storage that becomes apparent during the days after training.

Amnesia↗
PubMed1973

Cycloheximide and acetoxycycloheximide: inhibition of tyrosine hydroxylase activity and amnestic effects.

Mice and rats trained after treatment with cycloheximide or acetoxycycloheximide in a conditioned avoidance response develop an amnesia of their training experience. This amnesia has been attributed to the profound inhibition of protein synthesis caused by the two antibiotics. Evidence is presented that additionally the antibiotics inhibit the activity of tyrosine hydroxylase, a finding that suggests that their amnestic effect may be due in part to reduction of the functional pool of norepinephrine.

Acetates↗
PubMed1978

Sodium-dependent amino acid transport by cultured hamster cells: membrane vesicles retain transport changes due to glucose starvation and cycloheximide.

Enhanced alpha-aminoisobutyric acid transport by hamster cells cultured in the absence of D-glucose has been demonstrated in isolated membrane vesicles. The observed enhancement was seen in the presence but not in the absence of Na+. Kinetic analysis of transport using both the intact cells and the membrane vesicles showed that the overall enhancement was associated with an increase in Vmax. Decreases in transport activity by intact cells resulting from extended exposure of the cells to inhibitors of protein synthesis, such as cycloheximide, were also evident in membrane vesicles. The use of metabolically inactive membrane vesicles demonstrated that amino acid uptake by intact cells is a transport property of the plasma membrane. In addition, this study shows that membrane vesicle preparations can be exploited for the purpose of studying the regulation of amino acid transport. Taken together, the data suggest that carrier turnover is involved in the regulation of amino acid transport in animal cells.

Amino Acids↗
PubMed1980

Prevalent deficiency in tumor cells of cycloheximide-induced cycle arrest.

Mammalian cell growth is regulated by a process that is completed at a restriction point in the late G1 part of the cycle. This process is highly sensitive to serum concentration and to moderate inhibition of protein synthesis by cycloheximide (CHM) or other agents. We have proposed that a cell must accumulate a labile protein in a critical amount before events related to its DNA synthesis can start. The accumulation of this protein requires conditions suitable for growth, including sufficient amounts of serum-derived factors. An important criterion for attributing a major role to such a regulatory mechanism is that cells whose growth control is modified--e.g., by mutation--should be defective in this process. Cells of this kind are produced by tumorigenic transformation. We show here that mouse 3T3 cells, human fibroblasts, and Chinese hamster CHEF/18 cells have stringent G1 growth control by CHM. In contrast, tumorigenic lines obtained from these cells by transformation with varius agents (DNA tumor virus, RNA tumor virus, chemical carcinogens) or spontaneously all showed relaxed growth control under the influence of CHM. In these lines, growth control was relaxed to different degrees; some lines were held in G1 by a combination of low serum concentration and CHM, but others were not. Serum concentration showed a synergistic effect with CHM. Low serum concentrations did not limit growth only by affecting the rate of protein synthesis. The labile-protein mechanism is likely to be basic to growth control by serum factors. Transformed tumorigenic cells in general may have relaxed this mechanism.

Animals↗
PubMed1983

Cholesterol side-chain cleavage in the rat adrenal cortex: isolation of a cycloheximide-sensitive activator peptide.

A cytosolic peptide activator (Mr approximately equal to 2,200) of cholesterol side-chain cleavage in the adrenal cortex has been isolated from normal corticotropin-treated rats and from rats implanted with the MtT/F4 corticotropin-secreting pituitary tumor. The isolation techniques were those common to peptide hormone purification, including tissue extraction into a highly acidic medium, gel filtration, and reverse-phase HPLC. The amino acid composition has been determined on acid hydrolysates. The activity of this adrenal peptide is acutely increased in hypophysectomized animals treated with corticotropin, and this increase is blocked by cycloheximide. The addition of activator peptide to adrenal mitochondrial preparations results in a rapid stimulation of pregnenolone formation that is dependent on activator concentration and a source of NADPH. In the absence of NADPH, addition of activator peptide to adrenal mitochondria increases the rate of cholesterol association with side-chain cleavage cytochrome P-450. The peptide therefore exhibits properties that are believed to characterize the hypothetical corticotropin-dependent labile activator of adrenal steroidogenesis.

Adrenal Cortex↗