Selective Translational Control and Nonspecific Posttranscriptional Regulation of Ribosomal Protein Gene Expression during Development and Regeneration of Rat Liver

Abstract

Mammalian liver development is accompanied by a transition from rapid growth in the fetus to a quiescent state in the adult. However, extensive proliferation can be induced in the adult liver by partial hepatectomy. In this study, we examined the regulation of ribosomal protein (rp) gene expression in the developing and regenerating rat liver. Our results indicate that the translation of rp mRNAs is selectively repressed by about 70% upon development from fetal to adult life, as illustrated by the decrease in ribosomal loading. In addition, the relative abundance of these mRNAs, like that of several other, but not all, housekeeping mRNAs, declines during development through a posttranscriptional mechanism. When liver cells commence growth following partial hepatectomy, translation of rp mRNAs is resumed to near-maximal capacity, as judged by their very efficient recruitment into polysomes. The concomitant increase in the abundance rp mRNAs under these circumstances is achieved by a posttranscriptional mechanism. The apparent fluctuations in the translation efficiency of rp mRNAs are accompanied by parallel changes in the expression of the genes encoding the initiation factors eIF-4E and eIF-4A. Our results indicate that selective translational control of rp mRNAs in mammals is not confined to manipulated cells in culture but constitutes an important regulatory mechanism operating in vivo in the course of liver development and regeneration.

The global downregulation of protein synthesis observed during hepatogenic maturation is associated with a decrease in TOP mRNA translation

“…The results also highlight that translation of TOP mRNAs, encoding many ribosomal proteins and translational factors, is decreased during hepatogenic differentiation. Interestingly, pioneering work in the field of translational regulation of ribosomal proteins includes the observation of a decreased ribosome loading of mRNAs encoding ribosomal proteins in mouse adult liver compared with fetal liver, which is in agreement with our results ( Aloni et al., 1992 ). The precise mechanism of translational control of TOP mRNAs is still debated, but LARP1 appears to be a major actor controlling TOP mRNA fate downstream of mTORC1 ( Berman et al., 2020 ).…”

Vertebrate mRNAs with a 5′-Terminal Pyrimidine Tract Are Candidates for Translational Repression in Quiescent Cells: Characterization of the Translational cis-Regulatory Element

“…If this factor had a particularly low affinity for rp mRNAs, because their unique 5' termini, a decrease in its activity or content could lead to a selective diminution in the utilization of these mRNAs. Indeed, we have observed parallel fluctuations in the utilization of rp mRNAs and in the abundance of eIF-4E (2,61). Moreover, supplementing reticulocyte lysate with the initiation complex eIF-4F, which contains eIF-4E, could selectively increase the translation efficiency of rp mRNAs, which was otherwise repressed (29).…”

“…This has been demonstrated during transition of various cells types between growing and nongrowing states in response to a wide variety of physiological stimuli, including dexamethasone-treated mouse lymphosarcoma cells (45,48), serum starvation of mouse fibroblasts (24,38) or Xenopus kidney cells (41), and differentiation of mouse myoblasts (1) and concanavalin A-treated bovine T cells (37). Similar specific translational fluctuations have been observed for rp mRNAs during the transition from the rapidly growing state in the fetal liver to the quiescent state in the adult and upon resumption of the hepatocyte proliferation in the regenerating liver (2). The mammalian, avian, and amphibian rp mRNAs that have been rigorously analyzed thus far contain a 5'-terminal oligopyrimidine tract (5' TOP), which consists of a C residue at the cap site, followed by an uninterrupted sequence of up to 13 pyrimidines (3,18,54,69,71).…”

“…P1798.C7 mouse lymphosarcoma cells were grown as suspension cultures in RPMI 1640 containing 10% fetal calf serum, 50 ,iM ,-mercaptoethanol, 2 mM glutamine, 100 U of penicillin per ml, and 0.1 mg of streptomycin per ml. Cells (2 x 107) at a density of 5 x 105 to 7 x 105/ml were used for DEAE-dextran-mediated DNA transfection (27). Briefly, cells were incubated at room temperature with 2.5 jig of DNA per 106 cells in 6 ml containing 0.5 mg of DEAE-dextran (Pharmacia) per ml of Tris-buffered saline (TS in reference 27).…”

LARP1 on TOP of ribosome production

“…The ability of cells to divide, regardless of nutritional supply and oxygen availability, defines the ribosomal protein mRNA translational response. Cells undergoing mitotic arrest due to terminal differentiation, contact inhibition, or pharmacological inhibition in the progression of the cell cycle at any stage do not engage in ribosomal protein mRNA translationeven under a surplus supply of nutrients and oxygen (Aloni, Peleg, & Meyuhas, 1992;Shama, Avni, Frederickson, Sonenberg, & Meyuhas, 1995;Stolovich, Lerer, Bolkier, Cohen, & Meyuhas, 2005).…”