Translational regulation: versatile mechanisms for metabolic and developmental control

doi:10.1016/0955-0674(95)80095-6

Current Opinion in Cell Biology

Volume 7, Issue 3, 1995, Pages 393-398

https://doi.org/10.1016/0955-0674(95)80095-6 Get rights and content

Abstract

It has become clear that many vital metabolic circuits and early developmental programs are regulated translationally. Until recently, the mechanisms underlying most of these observations were poorly understood. The past year has witnessed several important advances in the understanding of how the translational apparatus is controlled by different regulatory mechanisms.

References (36)

JWB Hershey
Translational control in mammalian cells
Annu Rev Biochem
(1991)
WC Merrick
Mechanism and regulation of eukaryotic protein synthesis
Microbiol Rev
(1992)
A Pause et al.
Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function
Nature
(1994)
A Lazaris-Karatzas et al.
Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′ cap
Nature
(1990)
A De Benedetti et al.
Overexpression of eukaryotic protein synthesis initiation factor 4E in HeLa cells results in aberrant growth and morphology
Proc Natl Acad Sci USA
(1990)
IB Rosenwald et al.
Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E
Mol Cell Biol
(1993)
LM Shantz et al.
Overproduction of omithine decarboxylase caused by relief of translational repression is associated with neoplastic transformation
Cancer Res
(1994)
PS Klein et al.
Induction of mesoderm in Xenopus laevis embryos by translation initiation factor 4E
Science
(1994)
T-A Lin et al.
PHAS-I as a link between mitogen-activated protein kinase and translational initiation
Science
(1994)
RM Denton et al.
A partial view of the mechanism of insulin action
Diabetologia
(1981)

M Kozak

The scanning model for translation: an update

J Cell Biol

(1989)

Ö Melefors et al.

Translational regulation by mRNA/protein interactions in eukaryotic cells: ferritin and beyond

Bioessays

(1993)

B Goossen et al.

Position is the critical determinant for function of iron-responsive elements as translational regulators

Mol Cell Biol

(1992)

R Stripecke et al.

Proteins binding to 5′ untranslated region sites: a general mechanism for translational regulation of mRNAs in human and yeast cells

Mol Cell Biol

(1994)

R Stripecke et al.

Bacteriophage and spliceosomal proteins function as position-dependent cis/trans repressors of mRNA translation in vitro

Nucleic Acids Res

(1992)

R Stripecke

mRNA-specific translational control in eukaryotic cells by proteins binding to the 5′ untranslated region

(1993)

NK Gray et al.

Iron regulatory protein prevents binding of the 43S translation pre-initiation complex to ferritin and eALAS mRNAs

EMBO J

(1994)

PH Brown et al.

Requirements for the translational repression of ferritin transcripts in wheat germ extracts by a 90-kDa protein from rabbit liver

J Biol Chem

(1989)

Cited by (66)

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Translational control is a key step in eukaryotic gene expression. The majority of translational control occurs at the level of initiation, thus implicating the 5′ untranslated region as a major site of translational regulation. Many growth-related mRNAs have atypical 5′ UTRs, which are often long and GC-rich. Such features promote formation of stable secondary structure, and many mRNAs encoding proteins involved in cell growth, proliferation and apoptosis have structured 5′ UTRs, which in many cases harbour internal ribosome entry sites (IRESs) and upstream open-reading frames (uORFs). In this review we discuss how secondary structural elements in the 5′ UTR can regulate translation and how mutations that perturb these secondary structural elements can have implications for disease and tumourigenesis.
Bacterial translational control at atomic resolution
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Translational regulation allows rapid adaptation of protein synthesis to environmental conditions. In prokaryotes, the synthesis of many RNA-binding proteins is regulated by a translational feedback mechanism involving a competition between their natural substrate and their binding site on mRNA, which are often thought to resemble each other. This article describes the case of threonyl-tRNA synthetase, which represses the translation of its own mRNA. Recent data provide the first opportunity to describe at the atomic level both the extent and the limit of mimicry between the way this enzyme recognizes tRNA^Thr and its regulatory site in mRNA. The data also give some clues about how the binding of the synthetase to its mRNA inhibits translation.
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An examination of differences in gene expression between memory and naive phenotype T cells revealed elevated levels of mRNA for several chemokines, especially RANTES, in memory phenotype T cells. Although RANTES mRNA is spliced and cytoplasmic, these cells do not contain or secrete significant amounts of RANTES protein without TCR stimulation. This secretion is independent of transcription, but requires translation. In vivo, CD8+ memory T cells proliferate continuously and slowly in response to IL-15; however, IL-15 does not stimulate RANTES secretion. These results show that memory phenotype CD8+ T cells use preexisting mRNA to produce and secrete RANTES rapidly following TCR stimulation. Such storage of preformed mRNAs for important inflammatory mediators may contribute to the speed of secondary immune responses.
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The expression of connexin 43 (cx43) and cell–cell communication were studied in replicative senescence of cultured HEL-299 fibroblasts. A progressive decrease in fluorescent dye transfer was detected by a scrape-loading technique in aging fibroblasts. This change was accounted for by a marked decrease in the amount of cx43 in aging cells, as detected by western blot analysis (cell extracts) and indirect fluorescence (cells in culture). However, semiquantitative RT-PCR assays of cx43 mRNA did not reveal appreciable changes, which suggests several possible explanations for the mechanism(s) underlying the decrease of cx43 in aging cells. These findings support the idea that the reduced expression of cx43 might be a biomarker of cell senescence.
Suppression of 15-lipoxygenase synthesis by hnRNP E1 is dependent on repetitive nature of LOX mRNA 3′-UTR control element DICE
2002, Journal of Molecular Biology
Cytidine-rich 15-lipoxygenase differentiation control element (15-LOX DICE) is a multifunctional cis-element found in the 3′-UTR of numerous eukaryotic mRNAs. It binds KH domain proteins of the type hnRNP E and K, thus mediating mRNA stabilization and translational control.
Translational silencing is caused by formation of a simple binary complex between DICE and recombinant hnRNP E1 (E1). Electromobility shift assays and sucrose gradient centrifugation demonstrate that rabbit 15-LOX DICE, which is composed of ten subunits of the sequence (CCCCPuCCCUCUUCCCCAAG)₁₀ = 10R, is able to bind up to ten molecules of E1. Protein/RNA interaction was studied with different subunits and submotifs of the 10R structure. Binding appears to be dependent on the degree of polymerization of the C-clusters (1R < 2R < 4R < 10R), but not on their order. The minimal motif, which still functioned in E1 binding, contained two C-clusters (CCCCPuCCCUCUU).
For efficient translational control, E1 binding is a necessary, but not sufficient, condition. Translational inhibition by E1 is only observed when at least a dimeric 2R configuration of the DICE is present in the 3′-UTR of a reporter mRNA. We conclude that binding of at least two E1 molecules activate or expose a binding site to enable the complex to interact with the 5′-end of the mRNA and the translational machinery.
DICE-motifs are widely distributed in nature. The UTR database UTRnr contains 78 entries of mRNAs with 15-LOX DICEs. Most DICEs were two- to fourfold repetitive, but also highly repetitive structures were found, as in quail myelin protein mRNA (31 repeats) and hyperglycemic hormone mRNA of two crayfish species (nine and 11 repeats).

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View full text

Translational regulation: versatile mechanisms for metabolic and developmental control

Abstract

Translational control in mammalian cells

Annu Rev Biochem

Mechanism and regulation of eukaryotic protein synthesis

Microbiol Rev

Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function

Nature

Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′ cap

Nature

Overexpression of eukaryotic protein synthesis initiation factor 4E in HeLa cells results in aberrant growth and morphology

Proc Natl Acad Sci USA

Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E

Mol Cell Biol

Overproduction of omithine decarboxylase caused by relief of translational repression is associated with neoplastic transformation

Cancer Res

Induction of mesoderm in Xenopus laevis embryos by translation initiation factor 4E

Science

PHAS-I as a link between mitogen-activated protein kinase and translational initiation

Science

A partial view of the mechanism of insulin action

Diabetologia

The scanning model for translation: an update

J Cell Biol

Translational regulation by mRNA/protein interactions in eukaryotic cells: ferritin and beyond

Bioessays

Position is the critical determinant for function of iron-responsive elements as translational regulators

Mol Cell Biol

Proteins binding to 5′ untranslated region sites: a general mechanism for translational regulation of mRNAs in human and yeast cells

Mol Cell Biol

Bacteriophage and spliceosomal proteins function as position-dependent cis/trans repressors of mRNA translation in vitro

Nucleic Acids Res

mRNA-specific translational control in eukaryotic cells by proteins binding to the 5′ untranslated region

Iron regulatory protein prevents binding of the 43S translation pre-initiation complex to ferritin and eALAS mRNAs

EMBO J

Requirements for the translational repression of ferritin transcripts in wheat germ extracts by a 90-kDa protein from rabbit liver

J Biol Chem