# Role of Cyclin-Dependent Kinase 1 in Translational Regulation in the M-Phase
## 4 CDK1 Substitutes for mTOR Control of Cap-Dependent Translation  
mTOR, a serine/threonine protein kinase, regulates diverse cellular functions (reviewed in [72]) and mTOR clearly contributes to the translation of both TOP and nonTOP mRNAs (reviewed in [73]). Besides CDK1, mTOR is the main regulator of 4E-BP1 activity (Figure 3, Figure 4) [73], thereby releasing eIF4E and activating translation [74]. Upon inhibition of mTOR, 4E-BP1 is dephosphorylated and the affinity of 4E-BP1 for eIF4E increases [75]. mTOR enhances the translation of mRNAs containing the 5\({}^{\prime}\) terminal oligopyrimidine (5' TOP) motif [76; 77]. It has been documented that overexpression of a rapamycin-resistant mTOR mutant restored the rapamycin-inhibited activity of mTOR effectors ribosomal protein S6 kinase B1 (p70S6K) and 4E-BP1 and removed rapamycin-induced inhibition of cell cycle progression [78]. Although mTOR is considered to be the main kinase phosphorylating 4E-BP1, several other kinases are involved in the phosphorylation of various 4E-BP1 residues (reviewed in [74]). Phosphorylation of the main mTOR substrates, p70S6K and 4E-BP1, is also dependent on CDK1 during mitosis [8; 13; 33] (Table 1) and CDK1 can substitute for mTOR kinase in the activation of cap-dependent translation in mitotic cells, suggesting that an alternate pathway for the regulation of cap-dependent translation exists [29; 33]. It has been observed in mouseophase lymphoblasts that CDK1 promotes mitotic growth through the increased phosphorylation of 4E-BP1 and cap-dependent protein synthesis [79]. When 4E-BP1 is hyperphosphorylated at Thr37/Thr46, Thr70 and Ser65, the eIF4G:elF4E interaction is enabled and the initiation of cap-dependent translation begins (reviewed in [24]). It has been proposed that phosphorylation of 4E-BP1 at Thr37/Thr46 is rather constitutive, and phosphorylation at Ser65 is more related to its effect on cap-dependent translation [59; 80]. Although the priming phosphorylation sites Thr-37/Thr-46 of 4E-BP1 are targeted by mTOR [81], the Thr37/Thr46 residues can also be phosphorylated by CDK1 [33]. CDK1 also phosphorylates 4E-BP1 at the Thr70 residue, which is one of several phosphorylation sites required for the inactivation of 4E-BP1 [7; 8]. It has been suggested that mTOR may act in concert with CDK1 to generate fully inactivated/phosphorylated 4E-BP1 isoforms during mitosis [24]. Increased phosphorylation of 4E-BP1 occurs during the meiotic M-phase in porcine, bovine and mouse oocytes [26; 27; 42; 82]. Although it is also diffusely located in the oocyte cytoplasm, the presence of phosphorylated 4E-BP1 on the meiotic spindle poles, kinetochores and along the polar microtubules suggests that it represents a possible means of supporting spatially localized protein production [82]. CDK1 and mTOR are the main positive regulators of 4E-BP1 phosphorylation during meiosis in mouse oocytes and CDK1 affects the activity of mTOR localized in the vicinity of the chromosomes and on the MII spindle, suggesting that CDK1 acts indirectly on 4E-BP1 phosphorylation via mTOR activation [7]. It can be concluded that the phosphorylation of 4E-BP1 promotes translation during the M-phase to support spindle assembly, highlighting the importance of the role of CDK1 and mTOR kinase in this process. During the M-phase CDK1 also phosphorylates and inactivates p70S6K, the other mTOR substrate [83; 84]. It has been proposed that p70S6K is involved in the regulation of TOP mRNA translation because the substrates of p70S6K include the eukaryotic translation elongation factor 1A (eEF1A), eukaryotic elongation factor 2 (eEF2) and several ribosomal proteins [76]. Therefore, CDK1 activity could be involved in the regulation of translation during the M-phase by decreasing the amount of translation factors available. Although p70S6K is phosphorylated by CDK1 at several sites, CDK1 does not phosphorylate p70S6K at Thr389, the mTOR phosphorylation site [84].