Translational regulation of the cell cycle: when, where, how and why?

Abstract

Translational regulation contributes to the control of archetypal and specialized cell cycles, such as the meiotic and early embryonic cycles. Late meiosis and early embryogenesis unfold in the absence of transcription, so they particularly rely on translational repression and activation of stored maternal mRNAs. Here, we present examples of cell cycle regulators that are translationally controlled during different cell cycle and developmental transitions in model organisms ranging from yeast to mouse. Our focus also is on the RNA-binding proteins that affect cell cycle progression by recognizing special features in untranslated regions of mRNAs. Recent research highlights the significance of the cytoplasmic polyadenylation element-binding protein (CPEB). CPEB determines polyadenylation status, and consequently translational efficiency, of its target mRNAs in both transcriptionally active somatic cells as well as in transcriptionally silent mature Xenopus oocytes and early embryos. We discuss the role of CPEB in mediating the translational timing and in some cases spindle-localized translation of critical regulators of Xenopus oogenesis and early embryogenesis. We conclude by outlining potential directions and approaches that may provide further insights into the translational control of the cell cycle.

Figure 1.

Translational initiation during progression through the archetypal and specialized cell cycle. (a) During archetypal cell cycles, with the exception of M phase, translation is cap-dependent and is initiated by a cap-binding protein, eIF4E, binding to the 7-methylguanosine cap structure at the 5′ end of mRNA. Subsequently, eIF4E recruits eIF4G, which further associates with eIF4A. The RNA helicase activity of eIF4A is supported by its accessory proteins, eIF4B (or eIF4H, not shown). The eIF4A can only bind one of its auxiliary proteins at a time, because these interactions are mutually exclusive. Upon binding of eIF4G to the poly(A) binding protein (PABP), mRNA circularizes. This closed-loop mRNA structure may facilitate recruitment of the multi-subunit 43S pre-initiation complex (40S small ribosomal subunit and at least five additional factors; subunits are shown in different shades of green) to the mRNA. The interaction between eIF4G and one of the subunits of the 43S pre-initiation complex ultimately brings the pre-initiation complex to the mRNA. (b) During mitosis, translational initiation is cap-independent. The 5′ UTRs (and occasionally ORFs) of mRNAs translated during mitosis are thought to carry an internal ribosome entry site (IRES). It is proposed that the IRESs often assume a complex secondary structure and recruit 43S pre-initiation machinery with the help of IRES-trans-acting factors (ITAFs). (c) Schematic of translational regulation during Xenopus oocyte maturation. The left panel shows translationally repressed mRNAs in immature Xenopus oocytes. In immature oocytes, mRNAs that contain cytoplasmic polyadenylation element (CPE) in their 3′ UTRs interact with CPE-binding protein (CPEB), which associates with an eIF4E-binding protein, Maskin. Maskin inhibits interaction between eIF4E and eIF4G, thereby blocking recruitment of the 43S pre-initiation complex to mRNA. Simultaneously, CPEB binds to the poly(A) polymerase Gld2 and more active poly(A) ribonuclease (PARN), resulting in short poly(A) tails and consequently repressed translation. To regulate the polyadenylation status of an mRNA, CPEB relies on cleavage and polyadenylation specificity factor (CPSF) that binds to the hexanucleotide AAUAAA sequence (HEX). As shown in the right panel, upon progesterone stimulation during oocyte maturation, CPEB becomes phosphorylated, which causes its dissociation from PARN deadenylase. Consequently, Gld2 polyadenylation activity prevails, leading to the binding of PABP to the elongated poly(A) tail. Then, PABP interacts with eIF4G, and the mRNA assumes a closed-loop structure. Because this mRNA circularization is accompanied by disassembly of at least a portion of the Maskin–eIF4E complex, translation can be initiated.

Figure 2.

Translational regulation of specialized cell cycles in different developmental contexts. (a) The upper panel of this figure illustrates an arm of the C. elegans gonad. The self-renewing germ cells undergoing mitosis (orange circles) are shown on the left, whereas cells that are in meiotic S phase (blue circles) and crescent-shaped nuclei of cells that are in meiotic prophase are depicted on the right. The dashed line demarcates the border between the mitotic and meiotic cells. Notch signalling from the distal tip cell (DTC, shown in black) promotes mitosis in the germ cells through two members of the PUF family of translational repressors, FBF-1 and FBF-2. FBF-1 and FBF-2 (levels are shown in grey) inhibit translation of a translational repressor GLD-1 and of a heterodimeric translational activator, GLD-2–GLD-3. GLD-1 (levels are shown in green) represses translation of Cyclin E, which promotes germ cell proliferation. Cyclin E levels (levels are shown in red) are high in mitotic germ cells that express the GLD-1 repressors, FBF-1 and FBF-2. Cyclin E–Cdk2 complex phosphorylates GLD-1, causing a further reduction in GLD-1 levels in mitotic germ cells. The levels of FBF-1 and FBF-2 decrease at a certain distance from DTC, so GLD-1 levels increase. Cells in which GLD-1 accumulates show a drop in Cyclin E levels, and they can enter meiosis. Adapted from fig. 1 by Jeong et al. [80]. (b) This panel depicts a sequence in which proteins that drive progression through Xenopus oogenesis are translated. Upon progesterone stimulation in prophase I, one of the first translated proteins is Ringo. Simultaneously, phosphorylation of CPEB allows the conversion of CPEB from a translational repressor into an activator that induces polyadenylation and translation of mos, cyclin B2, cyclin B5 and emi1 mRNA. These proteins activate and stabilize maturation-promoting factor (MPF) that is essential for transition into metaphase I. As the contribution of Emi1 to MPF stabilization in meiosis I is still controversial, it is represented by a dashed line. Another protein translated in prophase I in a CPEB-dependent manner is C3H-4, a translational repressor that recruits deadenylase to the ARE-containing mRNAs. Although CPEB4 is also polyadenylated upon progesterone stimulation, C3H-4 counteracts CPEB1-dependent polyadenylation of CPEB4, postponing CPEB4 accumulation until late metaphase I. At metaphase I, the CPEB1 is degraded, and polyadenylation events in late oogenesis are driven by CPEB4. For example, Cyclin B1 and Cyclin B4 that are required to support MPF through interkinesis are translated in a CPEB4-dependent manner. The transition into metaphase II and subsequent metaphase II arrest is mediated by accumulation of Emi2 and Cyclin E. As the polyadenylation of emi2 is determined by the balance of opposing activities of CPEB4 and C3H-4, its polyadenylation and translation peak only in metaphase II, leading to an accumulation of this factor late in oogenesis. Adapted from fig. 7 by Igea et al. [34]. (c) Outline of translational regulation of Cyclin A and Cyclin B at various developmental transitions during Drosophila oogenesis and early embryogenesis.

Figure 3.

Spindle-localized translation during Xenopus oogenesis and early embryogenesis. CPEB and Maskin, proteins that regulate polyadenylation and translation, localize to the spindles of mature oocytes and early embryos. TPX2 and Xkid mRNAs also localize to the spindles in mature Xenopus oocytes, and cyclin B1 as well as Xbub3 mRNAs are spindle-associated in early Xenopus embryos. Xkid and cyclin B1 are translated in a CPEB-dependent manner on the spindles of Xenopus oocytes and early embryos, respectively. The spindle-localized translation of Xkid is required for the transition from the first to the second meiotic division during Xenopus oogenesis. Moreover, cyclin B1 needs to be translated on the spindles of early embryos to allow for proper spindle assembly and execution of embryonic cleavages. The spindle-localized translation of TPX2 and Xbub3 awaits investigation. The mRNAs are designated by rectangles and the proteins by ovals; arrows show proposed translational regulation.