Protein synthesis inhibitor omacetaxine is effective against hepatocellular carcinoma

ABSTRACT Upon the stimulation of extracellular cues, a significant number of proteins are synthesized distally along the axon. Although local protein synthesis is crucial for various stages throughout neuronal development, its involvement in presynaptic differentiation at developing neuromuscular junctions remains unknown. By using axon severing and microfluidic chamber assays, we first showed that treatment of a protein synthesis inhibitor, cycloheximide, inhibits agrin-induced presynaptic differentiation in cultured Xenopus spinal neurons. Newly synthesized proteins are prominently detected, as revealed by the staining of click-reactive cell-permeable puromycin analog O-propargyl-puromycin, at agrin bead-neurite contacts involving the mTOR/4E-BP1 pathway. Next, live-cell time-lapse imaging demonstrated the local capturing and immobilization of ribonucleoprotein granules upon agrin bead stimulation. Given that our recent study reported the roles of membrane-type 1 matrix metalloproteinase (MT1-MMP) in agrin-induced presynaptic differentiation, here we further showed that MT1-MMP mRNA is spatially enriched and locally translated at sites induced by agrin beads. Taken together, this study reveals an essential role for axonal MT1-MMP translation, on top of the well-recognized long-range transport of MT1-MMP proteins synthesized from neuronal cell bodies, in mediating agrin-induced presynaptic differentiation.

Download Full-text

Protein synthesis requirement of the Aplysia circadian clock. Tested by active and inactive derivatives of the inhibitor anisomycin

Journal of Experimental Biology ◽

10.1242/jeb.85.1.33 ◽

1980 ◽

Vol 85 (1) ◽

pp. 33-42

Author(s):

J. W. Jacklet

Keyword(s):

Protein Synthesis ◽

Circadian Clock ◽

Compound Action Potential ◽

Phase Shifts ◽

Protein Synthesis Inhibitor ◽

Synthesis Inhibitor ◽

Inhibitor Molecule ◽

Group 5 ◽

Characteristic Effect ◽

Derivatives Of

1.The circadian rhythm of compound action potential frequency recorded from the isolated eye of Aplysia in culture medium and darkness was subjected to 6 h pulse treatments with either anisomycin, a protein synthesis inhibitor, or inactive derivatives of anisomycin. 2. Anisomycin caused phase-dependent phase shifts of the rhythm as expected from previous experiments, but none of the derivative molecules caused phase shifts or perturbed the rhythm. 3. Anisomycin inhibited eye-protein synthesis by 75% at the concentrations (10(−6) M) used in the phase shifting experiments but none of the derivatives inhibited synthesis. 4. Only those molecules that actually inhibited protein synthesis caused phase shifts of the clock, although the inactive derivatives differed from anisomycin by only an acetyl group. 5. The results strengthen the conclusion that the inhibition of protein synthesis caused by anisomycin is important in perturbing the timing of the circadian clock and not some other characteristic effect of the inhibitor molecule. Together with the results from other systems, these findings imply that the daily synthesis of protein is a general requirement for circadian clocks.

Download Full-text

Transforming Potential of the Herpesvirus Oncoprotein MEQ: Morphological Transformation, Serum-Independent Growth, and Inhibition of Apoptosis

Journal of Virology ◽

10.1128/jvi.72.1.388-395.1998 ◽

1998 ◽

Vol 72 (1) ◽

pp. 388-395 ◽

Cited By ~ 86

Author(s):

Juinn-Lin Liu ◽

Ying Ye ◽

Lucy F. Lee ◽

Hsing-Jien Kung

Keyword(s):

Protein Synthesis ◽

Target Genes ◽

Rapid Development ◽

Fibroblast Cell ◽

Protein Synthesis Inhibitor ◽

Morphological Transformation ◽

Synthesis Inhibitor ◽

Necrosis Factor Alpha ◽

Downstream Target ◽

T Cell Lymphomas

ABSTRACT Marek’s disease virus (MDV) induces the rapid development of overwhelming T-cell lymphomas in chickens. One of its candidate oncogenes, meq (MDV Eco Q) which encodes a bZIP protein, has been biochemically characterized as a transcription factor. Interestingly, MEQ proteins are expressed not only in the nucleoplasm but also in the coiled bodies and the nucleolus. Its novel subcellular localization suggests that MEQ may be involved in other functions beyond its transcriptional potential. In this report we show that MEQ proteins are expressed ubiquitously and abundantly in MDV tumor cell lines. Overexpression of MEQ results in transformation of a rodent fibroblast cell line, Rat-2. The criteria of transformation are based on morphological transfiguration, anchorage-independent growth, and serum-independent growth. Furthermore, MEQ is able to distend the transforming capacity of MEQ-transformed Rat-2 cells through inhibition of apoptosis. Specifically, MEQ can efficiently protect Rat-2 cells from cell death induced by multiple modes including tumor necrosis factor alpha, C2-ceramide, UV irradiation, and serum deprivation. Its antiapoptotic function requires new protein synthesis, as treatment with a protein synthesis inhibitor, cycloheximide, partially reversed MEQ’s antiapoptotic effect. Coincidentally, transcriptional induction of bcl-2 and suppression of bax are also observed in MEQ-transformed Rat-2 cells. Taken together, our results suggest that MEQ antagonizes apoptosis through regulation of its downstream target genes involved in apoptotic and/or antiapoptotic pathways.

Download Full-text

Determinants of kinin release in isolated rat hindquarters

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.274.1.r120 ◽

1998 ◽

Vol 274 (1) ◽

pp. R120-R125 ◽

Cited By ~ 2

Author(s):

Tohru Sakakibara ◽

Thomas H. Hintze ◽

Alberto Nasjletti

Keyword(s):

Protein Synthesis ◽

Trypsin Inhibitor ◽

De Novo ◽

Soybean Trypsin Inhibitor ◽

Protein Synthesis Inhibitor ◽

Synthesis Inhibitor ◽

Bicarbonate Buffer ◽

Kallikrein Inhibitor ◽

Isolated Rat

We studied the determinants of kinin release into the venous effluent of rat hindquarters perfused with Krebs bicarbonate buffer. Kinin release in preparations perfused with control media (14.6 ± 2.5–20.7 ± 6.7 pg/15 min) was surpassed by that in preparations perfused with media containing kininase inhibitors (243 ± 53 to 276 ± 78 pg/15 min). Kinin release increased when purified kininogen (from 242 ± 43 to 3,365 ± 725 pg/15 min) or kallikrein (from 270 ± 49 to 30,649 ± 8,040 pg/15 min) was added to the perfusate. Conversely, kinin release fell when the kallikrein inhibitor aprotinin (from 272 ± 58 to 122 ± 27 pg/15 min) or soybean trypsin inhibitor (from 273 ± 52 to 195 ± 25 pg/15 min) was added. Both basal and kininogen-induced kinin release were attenuated in preparations perfused with media containing cycloheximide, a protein synthesis inhibitor, but kallikrein-induced kinin release was not. These data suggest that kinin release from perfused rat hindquarters reflects the activity of both the kinin-degrading and kinin-generating pathways and that the latter is sustained by a kallikrein manufactured de novo and by preexistent kininogen(s).

Download Full-text