Translational control of cyclins

Regulation of cyclin levels is important for many cell cycle-related processes and can occur at several different steps of gene expression. Translational regulation of cyclins, which occurs by a variety of regulatory mechanisms, permits a prompt response to signal transduction pathways induced by environmental stimuli. This review will summarize translational control of cyclins and its influence on cell cycle progression.     

Translational control of coronaviruses

Coronaviruses represent a large family of enveloped RNA viruses that infect a large spectrum of animals. In humans, the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic and is genetically related to SARS-CoV and Middle East respiratory syndrome-related coronavirus (MERS-CoV), which caused outbreaks in 2002 and 2012, respectively. All viruses described to date entirely rely on the protein synthesis machinery of the host cells to produce proteins required for their replication and spread. As such, virus often need to control the cellular translational apparatus to avoid the first line of the cellular defense intended to limit the viral propagation. Thus, coronaviruses have developed remarkable strategies to hijack the host translational machinery in order to favor viral protein production. In this review, we will describe some of these strategies and will highlight the role of viral proteins and RNAs in this process.     

Translational control of retroviruses

All replication-competent retroviruses contain three main reading frames, gag, pol and env, which are used for the synthesis of structural proteins, enzymes and envelope proteins respectively. Complex retroviruses, such as lentiviruses, also code for regulatory and accessory proteins that have essential roles in viral replication. The concerted expression of these genes ensures the efficient polypeptide production required for the assembly and release of new infectious progeny virions. Retroviral protein synthesis takes place in the cytoplasm and depends exclusively on the translational machinery of the host infected cell. Therefore, not surprisingly, retroviruses have developed RNA structures and strategies to promote robust and efficient expression of viral proteins in a competitive cellular environment.     

Translational control during mitosis

Translation is now recognized as an important process in the regulation of gene expression. During the cell cycle, translation is tightly regulated. Protein synthesis is necessary for entry into and progression through mitosis and conversely, modifications of translational activity are observed during the cell cycle. This review focuses on translational control during mitosis (or M-phase) and the role of CDK1/cyclin B, the universal cell cycle regulator implicated in the G2/M transition, in protein synthesis regulation.     

Translational control of synaptic plasticity

Synapses, points of contact between axons and dendrites, are conduits for the flow of information in the circuitry of the central nervous system. The strength of synaptic transmission reflects the interconnectedness of the axons and dendrites at synapses; synaptic strength in turn is modified by the frequency with which the synapses are stimulated. This modulation of synaptic strength, or synaptic plasticity, probably forms the cellular basis for learning and memory. RNA metabolism, particularly translational control at or near the synapse, is one process that controls long-lasting synaptic plasticity and, by extension, memory formation and consolidation. In the present paper, I review some salient features of translational control of synaptic plasticity.     

Translational control and cancer therapy

Our recent findings on Rheb and eIF4E address key questions of translational control in cancer and have implications for tumor therapy 1. Briefly, we find that Rheb a proximal activator of mTORC1 and protein translation can cooperate with c-Myc in tumorigenesis in vivo in a manner resembling Akt or the oncogenic eIF4E translation initiation factor. Rheb is highly expressed in some human lymphomas as well as other cancers and likely contributes to malignancies in different tissues 2. The cancer-relevant activities emanating from increased Rheb depend on activation of mTORC1 and are sensitive to rapamycin. Moreover,farnesyltransferase inhibitors (FTIs) can directly block Rheb activity and this is responsible for the therapeutic effect of these drugs in certain tumors. We will discuss here how translational control mechanisms contribute to oncogenesis and speculate on the potential and limitations of targeting these co-operating oncogenic events for therapy.     

Translational control in oocyte development

Translational control of specific mRNAs is a widespread mechanism of gene regulation, and it is especially important in pattern formation in the oocytes of organisms in which the embryonic axes are established maternally. Drosophila and Xenopus have been especially valuable in elucidating the relevant molecular mechanisms. Here, we comprehensively review what is known about translational control in these two systems, focusing on examples that illustrate key concepts that have emerged. We focus on protein-mediated translational control, rather than regulation mediated by small RNAs, as the former appears to be predominant in controlling these developmental events. Mechanisms that modulate the ability of the specific mRNAs to be recruited to the ribosome, that regulate polyadenylation of specific mRNAs, or that control the association of particular mRNAs into translationally inert ribonucleoprotein complexes will all be discussed.     

Translational control by RGS2

The regulator of G protein signaling (RGS) proteins are a family of guanosine triphosphatase (GTPase)–accelerating proteins. We have discovered a novel function for RGS2 in the control of protein synthesis. RGS2 was found to bind to eIF2Bϵ (eukaryotic initiation factor 2B ϵ subunit) and inhibit the translation of messenger RNA (mRNA) into new protein. This effect was not observed for other RGS proteins tested. This novel function of RGS2 is distinct from its ability to regulate G protein–mediated signals and maps to a stretch of 37 amino acid residues within its conserved RGS domain. Moreover, RGS2 was capable of interfering with the eIF2–eIF2B GTPase cycle, which is a requisite step for the initiation of mRNA translation. Collectively, this study has identified a novel role for RGS2 in the control of protein synthesis that is independent of its established RGS domain function.     

Translational control during early development

Early development in many animals is programmed by maternally inherited messenger RNAs. Many of these mRNAs are translationally dormant in immature oocytes, but are recruited onto polysomes during meiotic maturation, fertilization, or early embryogenesis. In contrast, other mRNAs that are translated in oocytes are released from polysomes during these later stages of development. Recent studies have begun to define the cis and trans elements that regulate both translational repression and translational induction of maternal mRNA. The inhibition of translation of some mRNAs during early development is controlled by discrete sequences residing in the 3' and 5' untranslated regions, respectively. The translation of other RNAs is due to polyadenylation which, at least in oocytes of the frog Xenopus laevis, is regulated by a U-rich cytoplasmic polyadenylation element (CPE). Although similar, the CPE sequences of various mRNAs are sufficiently different to be bound by different proteins. Two of these proteins and their interactions are described here.     

Translational control of the picornavirus phenotype

Picornaviruses are small animal viruses with positive-stranded genomic RNA, which is translated using cap-independent internal translation initiation. The key role in this is played by cis elements of the 5'-untranslated region (5'-UTR) and, in particular, by the internal ribosome entry site (IRES). The function of translational cis elements requires both canonical translation initiation factors (eIFs) and additional IRES trans-acting factors (ITAFs). All known ITAFs are cell RNA-binding proteins which play a variety of functions in noninfected cells. Specific features of translational cis elements substantially affect the phenotype and, in particular, tissue tropism and pathogenic properties of picornaviruses. It is clear that, in some cases, the molecular mechanism of this is a change in interactions between viral cis elements and ITAFs. The properties and tissue distribution of ITAFs may determine the biological properties of other viruses that also use the IRES-dependent translation initiation. Since this mechanism is also involved in translation of several cell mRNAs, ITAF may contribute to the regulation of the most important aspects of the living activity in noninfected cells.     

Translational control in influenza virus-infected cells

Influenza virus type A has been shown to establish a translational control system such that during infection there is a dramatic inhibition of host cell protein synthesis and viral mRNAs are selectively and efficiently translated. The following review summarizes the complex strategies employed by influenza to accomplish these goals. These include: (i) preventing newly made cellular mRNAs from entering the cytoplasm of infected cells; (ii) inhibiting the initiation and elongation steps of translation of preexisting cellular mRNAs; (iii) possessing RNAs with structural features which enhance translation; (iv) encoding mechanisms to downregulate the interferon induced protein kinase thus allowing overall protein synthesis levels to remain high.     

Translational control by the eukaryotic ribosome

The ribosome plays a universally conserved role in catalyzing protein synthesis. Kondrashov et?al. (2011) now provide evidence that the loss of function of ribosomal protein L38 in mice leads to a selective reduction in the translation of Hox mRNAs, thus suggesting that ribosomal proteins play a critical role during embryonic development.     

Translational control: the cancer connection

There is now a growing body of evidence which suggests links between the regulation of protein synthesis and the disruption of cell behaviour that typifies cancer. This directed issue of the International Journal of Biochemistry and Cell Biology presents several review articles of relevance to this field. The topics covered include the significance of the regulation and overexpression of polypeptide chain initiation factors for cell transformation and malignancy, the role of mRNA structure in the control of synthesis of key growth regulatory proteins, the actions of the eIF2 alpha-specific protein kinase PKR in the control cell growth and apoptosis, and the involvement of the elongation factor eEF1 in oncogenesis. The purpose of this article is to give an overview of the field and to indicate where we may expect developments to occur in the next few years.