Translational initiation factor expression and ribosomal protein gene expression are repressed coordinately but by different mechanisms in murine lymphosarcoma cells treated with glucocorticoids.

Abstract

P1798 murine lymphosarcoma cells cease to proliferate upon exposure to 10-7 M dexamethasone and exhibit a dramatic inhibition of rRNA and ribosomal protein synthesis (0. Meyuhas, E. Thompson, Jr., and R. P. Perry, Mol. Cell Biol. 7:2691-2699. These workers demonstrated that ribosomal protein synthesis is regulated primarily at the level of translation, since dexamethasone did not alter mRNA levels but shifted the mRNAs from active polysomes into inactive messenger ribonucleoproteins. We have examined the effects of dexamethasone on the biosynthesis of initiation factor proteins in the same cell line. The relative protein synthesis rates of eIF-4A and eIF-2a were inhibited by about 70% by the hormone, a reduction comparable to that for ribosomal proteins. The mRNA levels of eIF-4A, eIF-4D, and eIF-2a also were reduced by 60 to 70%, indicating that synthesis rates are proportional to mRNA concentrations. Analysis of polysome profiles showed that the average number of ribosomes per initiation factor polysome was only slightly reduced by dexamethasone, and little or no mRNA was present in messenger ribonucleoproteins. The results indicate that initiation factor gene expression is coordinately regulated with ribosomal protein synthesis but is controlled primarily by modulating mRNA levels rather than mRNA efficiency.Biosynthesis of the translational apparatus, namely, ribosomes and their associated soluble factors, involves the coordinate accumulation of a large number of proteins. The expression of ribosomal protein genes in bacteria is coordinated in large part at the level of translation, where autogenous regulation of the translation of operon mRNA occurs by feedback inhibition with one of the ribosomal protein products (30). In mammalian cells, ribosomal protein synthesis appears not to be regulated autogenously (6,18,20,40); instead, protein turnover plays a key role in their balanced accumulation (1,18,21). Much less is known about the regulation of gene expression for the mammalian soluble factors. Studies of the elongation factor eEF-la show that its synthesis is strongly reduced in Friend erythroleukemia cells at stationary phase and is stimulated when cells are treated with fresh serum-containing medium. Regulation involves changes in mRNA translation efficiency (polysome size) and mRNA levels, the latter by affecting mRNA stability (34,35).In earlier reports, we evaluated the levels and synthesis rates of a number of initiation factors in HeLa cells deprived of or stimulated by serum (9, 10). Of those factors examined, most (eIF-2, eIF-3, eIF-4B, and eIF-4Fp220) were approximately equimolar with ribosomes in these cells, whereas two (eIF-4A and eIF-4D) were three-to fourfold higher in concentration and at least one (eIF-4E) was about threefold lower. The relative synthesis and turnover rates of both ribosomal proteins and initiation factors are not altered in these cells by growth rate changes caused by serum; the translational components follow total protein synthesis and degradation rates (10). We are i...

Oligopyrimidine tract at the 5' end of mammalian ribosomal protein mRNAs is required for their translational control.

“…It was previously observed that in exponentially growing P1798 mouse lymphosarcoma cells, the proportion of rp mRNA actively engaged in protein synthesis-i.e., the proportion incorporated into polyribosomes-is significantly lower than that characteristic of other mRNAs such as those encoding actin, nucleolin, various enzymes, and translational initiation factors (14,15,43). On average, only 63 ± 6%7o ofrp mRNA was engaged with ribosomes compared with 91 ± 4% for the other mRNA species.…”

Steroids induce a disequilibrium of secreted interleukin-1 receptor antagonist and interleukin-1β synthesis by human neutrophils

“…The mechanism by which dexamethasone shows differential effects on (pro-)IL-1b and sIL-1Ra protein synthesis and secretion is unknown, but could lie in post-transcriptional mechanisms, such as mRNA stability [50], protein translation [51] and/or protein stability [22]. A shifted balance between proinflammatory IL-1b and anti-inflammatory sIL-1Ra has been found in vivo in several chronic inflammatory diseases, such as rheumatoid arthritis, ulcerative colitis, Crohn's disease and COPD [52][53][54][55].…”

Classification of gas5 as a Multi-Small-Nucleolar-RNA (snoRNA) Host Gene and a Member of the 5′-Terminal Oligopyrimidine Gene Family Reveals Common Features of snoRNA Host Genes

“…First, while all snoRNA host genes contain characteristics of the 5ЈTOP gene family (Table 1), they are not all translationally regulated in a 5ЈTOP growth-dependent manner. For example, eIF4A I and eIF4A II have been shown not to shift into mRNPs during growth arrest (28). Second, UHG possesses an absolutely conserved pyrimidine-rich 5Ј-end sequence but does not appear to be translationally regulated in the way gas5 is regulated.…”