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PubMed1985

Defective assembly of the mitochondrial ribosomes in yeast cells grown in the presence of mitochondrial protein synthesis inhibitors.

The involvement of mitochondrial protein synthesis in the assembly of the mitochondrial ribosomes was investigated by studying the extent to which the assembly process can proceed in the presence of mitochondrial protein synthesis inhibitors erythromycin and chloramphenicol. Yeast cells grown in the presence of erythromycin (2 mg/ml) do not appear to contain any detectable amounts of the mitochondrial small (37 S) ribosomal subunit. Instead, a ribonucleoparticle with a sedimentation coefficient of 30 S was observed; this particle could be shown to be related to the mitochondrial small ribosomal subunit by two-dimensional gel electrophoretic analysis of its protein components. Since the var1 protein is the only mitochondrial translation product known to be associated with the mitochondrial ribosome, our results suggest that this protein is essential for the assembly of the mature small subunit, and that the var1 protein enters the pathway for the assembly of the small subunit at a late step. In at least one strain of yeast the accumulation of the 30-S particle appears to be very sensitive to catabolite repression. When yeast cells are grown in the presence of chloramphenicol instead of erythromycin, assembly of the small subunit appears to be only partially inhibited, and the presence of the 30-S particle could not be clearly demonstrated. This observation is consistent with the fact that in yeast, chloramphenicol inhibits mitochondrial protein synthesis by about 95% only and that the synthesis of the var1 protein appears to be the least sensitive to this inhibition.

Cell Fractionation↗
PubMed1991

Augmentation of monocyte-mediated antibody-dependent cellular cytotoxicity by protein synthesis inhibitors: evidence for an endogenous regulatory mechanism.

Protein synthesis inhibitors, cycloheximide and puromycin, were used in cytotoxic assays employing human peripheral blood monocytes as effectors and sheep erythrocytes as target cells. ADCC could be initiated and could also achieve its full lytic activity in the absence of new protein synthesis. Furthermore, an augmentation of ADCC was observed in the presence of protein synthesis inhibitors. This augmentation was due to an increase in the cytotoxic ability of effector cells rather than a change in the lytic susceptibility of the target. Enhanced cytotoxic potential could not be attributed to an increase in the expression of FcRI but could be due to increased availability of antibody for mediating ADCC as a result of reduced numbers of FcRII. Suppression of prostaglandin-E2 release by monocytes was noted in the presence of cycloheximide, possibly as a result of inhibition of synthesis of cyclooxygenase. However, prostaglandin-E2 and other arachidonic acid metabolites did not appear likely to play a role in negatively regulating human monocyte ADCC since neither cytotoxicity nor cycloheximide-induced augmentation was affected by the presence of exogenous prostaglandin-E2 or arachidonic acid. Cycloheximide was found to induce the secretion of superoxide anions by monocytes, but a role for reactive oxygen species in cycloheximide-induced augmentation of ADCC could not be established by experiments involving the use of catalase or superoxide dismutase. These results raise the possibility that a rapidly turning over protein which negatively regulates monocyte-mediated ADCC exists.

Antibody-Dependent Cell Cytotoxicity↗
PubMed2006

Programmed cell death in plants: effect of protein synthesis inhibitors and structural changes in pea guard cells.

Pea leaf epidermis incubated with cyanide displayed ultrastructural changes in guard cells that are typical of apoptosis. Cycloheximide, an inhibitor of cytoplasmic protein synthesis, and lincomycin, an inhibitor of protein synthesis in chloroplasts and mitochondria, produced different effects on the dynamics of programmed death of guard cells. According to light microscopy data, cycloheximide reinforced and lincomycin suppressed the CN(-)-induced destruction of cell nuclei. Lincomycin lowered the effect of cycloheximide in the light and prevented it in the dark. According to electron microscopy data, the most pronounced effects of cycloheximide in the presence of cyanide were autophagy and a lack of apoptotic condensation of nuclear chromatin, the prevention of chloroplast envelope rupturing and its invagination inside the stroma, and the appearance of particular compartments with granular inclusions in mitochondria. Lincomycin inhibited the CN(-)-induced ultrastructural changes in guard cell nuclei. The data show that programmed death of guard cells may have a combined scenario involving both apoptosis and autophagy and may depend on the action of both cytoplasm synthesized and chloroplast and mitochondrion synthesized proteins.

Apoptosis↗
PubMed1988

Oncogenic ras protein induces meiotic maturation of amphibian oocytes in the presence of protein synthesis inhibitors.

Microinjection of the activated ras oncogenic protein can induce the meiotic maturation of Xenopus laevis oocytes, a process that can also be triggered by progesterone or high concentrations of insulin. Cycloheximide and puromycin, well-known inhibitors of protein synthesis, block the maturation process induced by progesterone and insulin but do not affect the maturation caused by H-raslys12 protein microinjection. Theophylline, an inhibitor of cAMP phosphodiesterase that also affects oocyte protein synthesis, does cause a partial inhibition of ras protein-induced maturation. These findings indicate that ras protein acts on the oocyte maturation process at a point that is downstream of the protein synthesis requirement, a characteristic shared with the maturation promoting factor, an activity that appears in oocytes and mitotic cells at the onset of cell division.

Animals↗
PubMed1986

Purification and characterization of a protein synthesis inhibitor associated with vaccinia virus.

A protein synthesis inhibitor, solubilized from vaccinia virus (Ben-Hamida, F., Person, A., and Beaud, G. (1983) J. Virol. 45, 452-455), has been purified to homogeneity, yielding a basic protein with molecular mass of 11 kDa. This purified protein migrates as a single spot in two-dimensional gel analysis (isoelectric point above 8.6). It is phosphorylated by the vaccinia-associated protein kinase, and it aggregates in the absence of reducing agents. This 11-kDa protein inhibits protein synthesis when added to a reticulocyte lysate at a stoichiometric ratio of approximately one protein molecule/ribosome, and it associates with the ribosome fraction after incubation in reticulocyte lysates or in Ehrlich ascites tumor cell lysates. As previously described for the inhibitor associated with vaccinia cores, the purified inhibitor inhibits the formation of the 40 S ribosomal subunit X Met-tRNAi ribosomal initiation complex. It has no detectable effect on the formation of the ternary complex (Met-tRNAi X GTP X eucaryotic initiation factor 2). This inhibitor associated with vaccinia virus particles may be involved in the shutoff of host protein synthesis and may also be responsible for the absence of virus replication in some cell-virus systems.

Animals↗
PubMed1991

The protein-coding region of c-myc mRNA contains a sequence that specifies rapid mRNA turnover and induction by protein synthesis inhibitors.

The stability of certain mRNAs is known to be affected by translation. Some mRNAs appear to be protected from rapid degradation by translation, whereas degradation is coupled to translation for other mRNAs. The molecular determinants of this selective effect of translation are unknown. One example of this effect is the induction of early-response gene mRNAs in the presence of translation inhibitors. To define the molecular basis of induction of early-response gene mRNA expression by inhibitors of protein synthesis, we have performed a mutational analysis of one member of the early response gene family, the c-myc gene. We find that induction by cycloheximide is due to stabilization of c-myc transcripts. The requirements for increased expression of c-myc mRNA by cycloheximide are the presence of the sequence encoding c-myc amino acids 335-439 on a mRNA that can be translated; all other portions of the c-myc gene are dispensable, and this sequence can confer induction of mRNA expression by protein synthesis inhibitors on a heterologous gene. By direct measurement of mRNA turnover in the absence of transcription-blocking drugs, we show that this sequence can function as a selective mRNA destabilizing element, that turnover mediated by this element is translation dependent, and turnover mediated by this element is inhibited by actinomycin D. Our results support the hypothesis that degradation of c-myc mRNA is coupled to translation, that the sequences specifying this form of degradation are contained in the protein-coding sequence, and that translation inhibitors induce expression of c-myc mRNA by blocking turnover mediated by this element.

Cell Line↗
PubMed1991

Kinetics and requirements for activation of macrophages for fungicidal activity: effect of protein synthesis inhibitors and immunosuppressants on activation and fungicidal mechanism.

Peritoneal-and pulmonary macrophages can be activated in vitro with lymphokines (LK) or IFN-gamma, without exogenous lipopolysaccharide, for fungicidal activity against several pathogenic fungi. However, neither the biochemical nor metabolic events of the activation process or of the effector phase have been defined. In the present work we sought to elucidate these events with time-course studies using inhibitors of protein synthesis as well as immunosuppressive agents. We found that protein synthesis inhibitors abrogated the activation process, because cycloheximide (CHX) (1-2 micrograms/ml) prevented activation of macrophages for fungicidal activity against Candida albicans, Blastomyces dermatitidis, and Paracoccidioides brasiliensis. Blocking of the activation process by CHX was not due to macrophage cytotoxicity, and CHX did not impair the ability of nonactivated macrophages to kill Candida parapsilosis. In kinetic studies we showed that activation of macrophages was induced in 4 hr of LK treatment and that CHX had no effect if added after this time. In contrast to CHX, therapeutic concentrations of hydrocortisone (HC), such as less than or equal to 5 micrograms/ml, or cyclosporin A (CsA), 5 micrograms/ml, did not significantly inhibit LK activation of macrophages for killing of fungi. In the effector phase, the fungicidal capacity of activated macrophages in short-term (less than or equal to 4 hr) killing assays could not be abrogated by CHX (5 micrograms/ml), HC (100 micrograms/ml), or CsA (10 micrograms/ml). These results demonstrate that the activation but not the effector mechanism of macrophages for fungicidal activity is blocked by inhibition of protein synthesis. In contrast, therapeutic concentrations of HC or CsA may not interfere with activation of macrophages or their killing mechanisms, thus providing a rationale for antifungal immunotherapy in certain clinical situations (e.g., infection in the immunosuppressed patient).

Animals↗
PubMed1978

Genetic and biochemical characterization of mutants of CHO cells resistant to the protein synthesis inhibitor trichodermin.

Mutants resistant to the protein synthesis inhibitor trichodermin have been selected in Chinese hamster ovary (CHO) cells. The mutants vary in their stability from those which rapidly lose their resistance to others which are relatively stable after prolonged growth in nonselective medium. Protein synthesis in extracts from the latter class of mutants (Trir) is resistant to the inhibitory action of trichodermin as compared to similar extracts from wild-type cells. After dissociation into subunits, the ability of the 60S ribosomal subunits from Trir cells to function in a protein-synthesizing system is greatly diminished. This subunit also shows reduced binding of [acetyl-14C]TRICHODERMIN. The lesion in Trir mutants therefore seems to have affected this ribosomal subunit. Trir X Tris hybrids are sensitive to trichodermin indicating that the Trir mutation behaves recessively to Tris in hybrids. The Emtr and Trir markers segregate independently from hybrid cells showing that the Trir mutation is probably not linked to the Emtr locus, which as we have shown earlier affects the 40S ribosomal subunit.

Cell Line↗
PubMed1985

Modulation of pig epidermal adenylate-cyclase responses by protein-synthesis inhibitors: its relation to glucocorticoid and colchicine effects.

The effects of protein-synthesis inhibitors (actinomycin D, puromycin, and cycloheximide) on epidermal adenylate-cyclase responses were investigated. When pig skin (epidermis) was incubated in RPMI-1640 medium, the beta-adrenergic adenylate-cyclase response (epinephrine-induced cyclic-AMP accumulations) decreased, whereas the adenosine and histamine responses increased after long-term (up to 48 h) incubation. The addition of actinomycin D or puromycin to the incubation medium resulted in a marked increase in epinephrine-induced cyclic-AMP accumulations and a decrease in adenosine- and histamine-induced cyclic-AMP accumulations. Cycloheximide had a weak effect on the epinephrine response, and had apparently stronger effects on the adenosine and histamine responses than actinomycin D or puromycin. Histologically, various degenerative changes of keratinocytes (with or without acantholytic changes) were observed after long-term incubation with these protein-synthesis inhibitors. Both low- and high-Km cyclic-AMP phosphodiesterase activities were moderately decreased by the protein-synthesis inhibitors. However, augmentation effects on the beta-adrenergic response were also observed in the presence of the cyclic-AMP phosphodiesterase inhibitor, theophylline. We have described previously similar augmentation effects on the beta-adrenergic response caused by glucocorticoids and colchicine. Comparison of the effects of these chemicals with those of protein-synthesis inhibitors revealed that the most marked effects on the beta-adrenergic response were produced by actinomycin D, puromycin and colchicine; glucocorticoid had a moderate effect (hydrocortisone), while cycloheximide had only a weak effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1990

Axonal transport of synaptic vesicles and muscarinic receptors: effect of protein synthesis inhibitors.

The effect of cycloheximide, a protein synthesis inhibitor, was studied on the axonal transport of noradrenergic synaptic vesicles and presynaptic muscarinic receptors, identified by in vitro binding of [3H]dihydrotetrabenazine and [3H]quinuclidinylbenzilate, respectively, in rat sciatic nerve. Cycloheximide (1.5 mg/kg) administered subcutaneously 2 h before ligation decreased by approximately 50% the accumulation of vesicles and receptors in the proximal segment above the ligature placed on the nerve; its action was detectable after a lag period of 10 h and disappeared 96 h after administration. Double ligatures were placed on the nerve at various time intervals between the first (distal) and the second (proximal) ligature, and the accumulation of vesicles and receptors proximal to the second ligature was measured; the first ligature diminished the accumulation above the second ligature. At an interval of 96 h between the first and the second ligature, cycloheximide completely prevented the accumulation of vesicles and receptors proximal to the second ligature. The effects of double ligatures and the response to cycloheximide treatment can best be explained on the assumption that an important proportion of synaptic vesicles and presynaptic receptors is being recycled in the nerve cell bodies after retrograde transport.

Animals↗
PubMed1999

Protein synthesis inhibitors and ethanol selectively enhance heterologous expression of P450s and related proteins in Escherichia coli.

The antibiotics chloramphenicol (Cm), tetracycline, and erythromycin, which inhibit bacterial protein synthesis and are known to induce the cold shock response, unexpectedly enhance the heterologous expression of P450s and related proteins in Escherichia coli. In contrast, antibiotics that mimic heat shock in E. coli such as puromycin, streptomycin, and kanamycin decrease the expression of the same proteins. A sublethal dose of Cm (1 microgram/ml) effectively enhances the expression of both membrane-bound proteins (microsomal and mitochondrial P450s) and a soluble mitochondrial protein (adrenodoxin) over the range of two- to eightfold. The expression level of N-terminal truncated P450c17 (1600 nmol/liter culture without Cm), for instance, reached 3500 nmol/liter culture by the addition of Cm, approximately 8.4% of the total cellular protein. Cm also enabled expression at useful levels of active P450s previously difficult to express in E. coli. In contrast, the expression of P450scc, a mitochondrial protein, is decreased by Cm but enhanced by ethanol, a powerful elicitor of heat shock response in E. coli. These results show that both the cold shock response induced by some antibiotics and the heat shock response induced by ethanol may lead to enhanced expression of certain heterologous proteins in E. coli. This study also indicates that protein synthesis inhibitors associated with the cold shock response may act as protein synthesis enhancers under certain conditions.

Adrenodoxin↗
PubMed1993

Activation by protein synthesis inhibitors of glucose transport into L6 muscle cells.

The effects of protein synthesis inhibitors on glucose transport into L6 myotubes was examined. Similar to the acute effects of insulin, short-term treatment with anisomycin or cycloheximide increased transport 2-fold. Kinetic studies demonstrated that this activation was due to a doubling in the Vmax values. The effects of anisomycin or cycloheximide were not additive to that of insulin. Both protein synthesis inhibitors caused only small increases in GLUT4 expression and negligible effects on GLUT1 expression. Anisomycin, as well as insulin, induced the translocation of both transporters from intracellular vesicles to the plasma membrane through not in quantities sufficient to entirely account for the activation of transport. The results indicate that protein synthesis inhibitors stimulate hexose transport in L6 myotubes by increasing the number of transporters in the plasma membrane and augmenting the intrinsic catalytic activity of the transporters.

Animals↗
PubMed1977

Reversal of ultraviolet-killing in an Escherichia coli lon mutant. Differential effects of protein synthesis inhibitors.

The effects of protein synthesis inhibition in post-irradiation treatments on the ultraviolet-survival of an Escherichia coli lon mutant were examined with six antibiotics. Kasugamycin was the most potent in enhancing the ultraviolet survival, whereas puromycin promoted ultraviolet killing rather than survival. Rifampicin, chloramphenicol, chlortetracycline, and spectinomycin were weakly active in the enhancement of survival.

Anti-Bacterial Agents↗
PubMedDate not supplied

[Effect of protein synthesis inhibitors on sensitization of defence reaction and on cholinosensitivity of command neurons in Helix lucorum].

We studied influence of protein synthesis inhibitors on short-term sensitization of Helix escape reaction and potentiation cholinosensitivity in command neurons. Inhibitor of protein synthesis anisomycin does not prevent behavioral sensitization. Anisomycin and irreversible inhibitor of protein synthesis saporin change the dynamics of cholinosensitivity potentiation in command neurons. The results Suggest that investigated sensitization of Helix escape reaction does not require synthesis of new proteins.

Acetylcholine↗
PubMed1995

Effects of antioxidants on the anti-proliferation induced by protein synthesis inhibitors in human brain tumor cells.

The effects of protein synthesis inhibitors (cycloheximide, anisomycin, puromycin and emetine) on the growth of human brain tumor cells were investigated using U-373 MG human astrocytoma and SK-N-MC human neuroblastoma cell lines. These agents inhibited the growth of the tumor cells in a dose-dependent manner. However, these agents did not affect cell viability evaluated by the trypan blue exclusion method, indicating that growth inhibition was due to the inhibition of cell proliferation rather than the induction of cytotoxicity. Anti-proliferation induced by these agents was significantly blocked by the treatments with either free radical scavengers or antioxidants. These results suggest that enhanced oxidative stress may be involved in the anti-proliferation induced by the protein synthesis inhibitors in human brain tumor cells.

Anisomycin↗
PubMedDate not supplied

Effect of protein synthesis inhibitors on leukocytic pyrogen-induced in vitro hypothalamic prostaglandin production.

In order to study the antipyretic effect of inhibitors of protein synthesis, hypothalamic tissue was incubated in vitro under controlled conditions and the amount of prostaglandin E2 (PGE2) measured in the supernatant medium. Rabbit anterior hypothalamic tissue was incubated with purified human leukocytic pyrogen (LP) and after 60 minutes the supernatant fluid was assayed for PGE2 by radioimmunoassay. Control tissue incubated with Eagle's medium (MEM) released elevated levels of PGE2; however, the addition of polymyxin B (PmxB), a cationic antibiotic which blocks the activities of bacterial endotoxins, significantly reduced PGE2. In addition, endotoxin added to MEM induced from the brain tissue PGE2 production which could be reduced by the addition of PmxB. Thus, commercial culture media such as MEM may contain sufficient amounts of endotoxin to stimulate brain PGE2 production in vitro. Purified human LP incubated with hypothalamic tissue in the presence of PmxB induced PGE2 production in a dose-dependent fashion. This release could be reduced (p less than 0.001) by the presence of either cycloheximide or puromycin during incubation with LP. The addition of these inhibitors to unstimulated hypothalamic tissue incubations did not reduce background levels of PGE2. It is concluded that the antipyretic effect of protein synthesis inhibitors results in a specific decrease in LP-induced levels of PGE2.

Animals↗
PubMed1988

Differential behaviour of 25-hydroxyvitamin D3 24-hydroxylase and 1-hydroxylase in response to protein synthesis inhibitors and cytochrome P-450 inhibitors.

To characterize 25-hydroxyvitamin D3 24-hydroxylase and 25-hydroxyvitamin D3 1-hydroxylase, the activities of the two enzymes were measured in the presence of two types of inhibitors. The effect of protein synthesis inhibitors on 25-hydroxyvitamin D3-stimulated 24-hydroxylase activity in 1-hydroxylating rat kidneys perfused in vitro was tested. Actinomycin D (4 microM) and cycloheximide (10 microM) each abolished 25-hydroxyvitamin D3 24-hydroxylase synthesis when added at the start of perfusion but not when added 4 h later; they did not affect 25-hydroxyvitamin D3 1-hydroxylase activity. The effects of cytochrome P-450 inhibitors on the two enzyme activities were then studied in vivo. Metyrapone and SKF-525A (50 mg/kg body weight) each inhibited 25-hydroxyvitamin D3 24-hydroxylase at 6 and 24 h; in contrast 1-hydroxylase increased and was 5 times the control value at 24 h. Finally, the in vitro effects of six cytochrome P-450 inhibitors at concentrations ranging from 10(-7) to 10(-3) M on enzyme activities in renal mitochondrial preparations were compared. Both enzymes were inhibited by all of the inhibitors, but inhibition of 25-hydroxyvitamin D3 24-hydroxylase was consistently greater than that of 25-hydroxyvitamin D3 1-hydroxylase. These studies demonstrate that 24-hydroxylation and 1-hydroxylation respond differently to protein synthesis inhibitors and to cytochrome P-450 inhibitors. The findings are consistent with the hypothesis that the two enzyme activities are associated with different cytochrome P-450 moieties.

Animals↗
PubMed1986

Reduced turnover of the elongation factor EF-1 X ribosome complex after treatment with the protein synthesis inhibitor II from barley seeds.

The effect of the protein synthesis inhibitor II from barley seeds (Hordeum sp.) on protein synthesis was studied in rabbit reticulocyte lysates. Inhibitor treatment of the lysates resulted in a rapid decrease in amino acid incorporation and an accumulation of heavy polysomes, indicating an effect of the inhibitor on polypeptide chain elongation. The protein synthesis inhibition was due to a catalytic inactivation of the large ribosomal subunit with no effect on the small subparticle. The inhibitor-treated ribosomes were fully active in participating in the EF-1-dependent binding of [14C]phenylalanyl-tRNA to poly(U)-programmed ribosomes in the presence of GTP and the binding of radioactively labelled EF-2 in the presence of GuoPP[CH2]P. Furthermore, the ribosomes were still able to catalyse peptide-bond formation. However, the EF-1- and ribosome-dependent hydrolysis of GTP was reduced by more than 40% in the presence of inhibitor-treated ribosomes, while the EF-2- and ribosome-dependent GTPase remained unaffected. This suggests that the active domains involved in the two different GTPases are non-identical. Treatment of reticulocyte lysates with the barley inhibitor resulted in a marked shift of the steady-state distribution of the ribosomal phases during the elongation cycle as determined by the ribosomal content of elongation factors. Thus, the content of EF-1 increased from 0.38 mol/mol ribosome to 0.71 mol/mol ribosome, whereas the EF-2 content dropped from 0.20 mol/mol ribosome at steady state to 0.09 mol/mol ribosome after inhibitor treatment. The data suggest that the inhibitor reduces the turnover of ribosome-bound ternary EF-1 X GTP X aminoacyl-tRNA complexes during proof-reading and binding of the cognate aminoacyl-tRNA by inhibiting the EF-1-dependent GTPase.

Animals↗