Nutrient limitations alter cell division control and chromosome segregation through growth-related kinases and phosphatases

The G0 Cell Unit, Okinawa Institute of Science and Technology Promotion Corporation, Tancha 1919-1, Onna, Okinawa 904-0412, Japan.
Philosophical Transactions of The Royal Society B Biological Sciences (Impact Factor: 7.06). 12/2011; 366(1584):3508-20. DOI: 10.1098/rstb.2011.0124
Source: PubMed


In dividing fission yeast Schizosaccharomyces pombe cells, the balance between Wee1 kinase and Cdc25 phosphatase which control the cyclin-dependent kinase (CDK) at the G2-M transition determines the rod-shaped cell length. Under nitrogen source starvation or glucose limitation, however, cell size determination is considerably modulated, and cell size shortening occurs for wild-type cells. For several mutants of kinases or phosphatases, including CDK, target of rapamycin complex (TORC) 1 and 2, stress-responsive mitogen-activated protein kinase (MAPK) Sty1/Spc1, MAPK kinase Wis1, calcium- and calmodulin-dependent protein kinase kinase-like Ssp1, and type 2A and 2A-related phosphatases inhibitor Sds23, this cell shortening does not normally occur. In tor1 and ssp1 mutants, cell elongation is observed. Sds23 that binds to and inhibits 2A and 2A-related phosphatases is synergistic with Ssp1 in the cell size determination and survival under low glucose and nitrogen source. Tor2 (TORC1) is required for growth, whereas Tor1 (TORC2) is needed for determining division size according to different nutrient conditions. Surprisingly, in growth-diminished tor2 mutant or rapamycin-treated cells, the requirement of separase/Cut1-securin/Cut2 essential for chromosome segregation is greatly alleviated. By contrast, defects of tor1 with secruin/cut2 or overproduction of Cut1 are additive. While Tor1 and Tor2 are opposite in their apparent functions, both may actually coordinate cell division with growth in response to the changes in nutrients.

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Available from: Kenichi Sajiki, May 27, 2014
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    • "). Nitrogen starvation (or NS) induces sexual development in homothallic strains or heterothallic strains when mating partners are available (Yanagida et al. 2011). On the other hand, NS induces entry into a dormant state or at G0-phase in heterothallic strains when mating partners are not available (Yanagida et al. 2011). To investigate whether the sexual development-defective kinase-deletion strains would also exhibit defect in NS-induced G0-arrest (hereafter G0-arrest), all kinase-deletion strains were subjected to assays for competence of G0-arrest. "
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    ABSTRACT: Nitrogen starvation (NS) induces sexual development when mating partners are available or enter into quiescent state (G0) in heterothallic background in fission yeast. However, little is known whether the two processes share common signaling molecules or cells defective in the two processes share common transcriptional signatures. To address these questions, we first assessed 77 kinase-deletion strains for NS-induced G0-arrest phenotypes. Our result indicated that 10 out of 77 kinase-deletion strains exhibited defect in G0-arrest, only 3 of which were defective in sexual development based on a previous study, suggesting that the two processes hardly share common signaling components. We subsequently performed transcriptional profiling analysis. Our result indicated that NS-induced transcriptional change was so robust that it prevailed the alteration by individual kinase-deletion alleles. Based on comparison between kinase-deletion strains proficient and deficient in sexual development or G0-arrest, we identified subsets of genes that were associated with sexual development-deficient or G0-arrest-deficient kinase-deletion strains. Multiple pairing analyses allowed grouping of functional related kinases. Furthermore, we showed that Pka1-mediated pathways were required for upregulation of NS-induced genes upon NS and downregulation of the same set of genes under the N-replete conditions. Taken together, our analyses indicate that sexual development and NS-induced G0-arrest are unrelated; and sexual development-deficient and G0-arrest-deficient kinase-deletion strains possess distinct transcriptional signatures. We propose that Pka1 is a key regulator of nitrogen metabolic pathways and Pka1-mediated signaling pathways play roles in regulation of NS-induced genes under both N-depleted and N-replete conditions.
    Full-text · Article · Dec 2014 · Molecular Genetics and Genomics
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    • "For several mutants of kinases including Tor1, Sty1, Wis1, Cdc2, Cdc13 and Ssp1, this cell shortening does not normally occur (Kawai et al., 2001; Petersen and Nurse, 2007; Yanagida et al., 2011). Thus, resulting long rod-shaped sty1 and wis1 mutant cells displayed an abnormally expanded nucleus, whereas other mutants (cdc2, cdc13 and ssp1) also revealed rod-shaped cells, but maintained a normal-sized nucleus (Yanagida et al., 2011). On the other hand, previous studies revealed that eIF2a phosphorylation can promote changes in gene expression through preferential translation of stress response genes. "
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    ABSTRACT: In fission yeast, three distinct eukaryotic initiation factor 2α (eIF2α) kinases (Hri1, Hri2 and Gcn2), regulate protein synthesis in response to various environmental stresses. Thus, Gcn2 is activated early after exposure to hydrogen peroxide (H2O2) and methyl methanesulfonate (MMS), whereas Hri2 is the primary activated eIF2α kinase in response to heat shock. The function of Hri1 is still not completely understood. It is also known, that the MAPK Sty1 negatively regulates Gcn2 and Hri2 activities under oxidative stress. In this study, we demonstrate that Hri1 is mainly activated, and its expression up-regulated, during transition from exponential growth to the stationary phase in response to nutritional limitation. Accordingly, both Hri1 and Gcn2, but not Hri2, are activated upon nitrogen source deprivation. In contrast, Hri2 is stimulated early during glucose starvation. We also found that Gcn2 is implicated in nitrogen starvation-induced growth arrest in the cell cycle G1 phase as well as in the non-selective protein degradation process caused upon this particular cellular stress. Moreover, Gcn2, but not Hri1 or Hri2, is essential for survival of cells growing in minimal medium, upon oxidative stress or glucose limitation. We further show that eIF2α phosphorylation at serine 52 by the eIF2α kinases is necessary for efficient cell cycle arrest in the G1 phase, for the consequent protein degradation and for sexual differentiation, under nitrogen starvation. Therefore, the eIF2α kinase signalling pathway modulates G1 phase cell cycle arrest, cell survival and mating under nutritional stress in the fission yeast Schizosaccharomyces pombe.
    Full-text · Article · May 2013 · Journal of Cell Science
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    • "TORC1 may prevent premature entry into mitosis, so that tor2-S or rapamycin-treated cells alter strikingly the mode of mitosis and cell division, leading to small cells even in the rich medium. Wild-type cells brought under nitrogen starvation actually commit premature mitosis with regard to cell size, which is consistent with the notion that TORC1 becomes inactive upon removal of nitrogen source (reviewed by Yanagida et al. [68]). "
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    ABSTRACT: Target of rapamycin complexes (TORCs), which are vital for nutrient utilization, contain a catalytic subunit with the phosphatidyl inositol kinase-related kinase (PIKK) motif. TORC1 is required for cell growth, while the functions of TORC2 are less well understood. We show here that the fission yeast Schizosaccharomyces pombe TORC2 has a cell cycle role through determining the proper timing of Cdc2 Tyr15 dephosphorylation and the cell size under limited glucose, whereas TORC1 restrains mitosis and opposes securin-separase, which are essential for chromosome segregation. These results were obtained using the previously isolated TORC1 mutant tor2-L2048S in the phosphatidyl inositol kinase (PIK) domain and a new TORC2 mutant tor1-L2045D, which harbours a mutation in the same site. While mutated TORC1 and TORC2 displayed diminished kinase activity and FKBP12/Fkh1-dependent rapamycin sensitivity, their phenotypes were nearly opposite in mitosis. Premature mitosis and the G2-M delay occurred in TORC1 and TORC2 mutants, respectively. Surprisingly, separase/cut1-securin/cut2 mutants were rescued by TORC1/tor2-L2048S mutation or rapamycin addition or even Fkh1 deletion, whereas these mutants showed synthetic defect with TORC2/tor1-L2045D. TORC1 and TORC2 coordinate growth, mitosis and cell size control, such as Wee1 and Cdc25 do for the entry into mitosis.
    Full-text · Article · Nov 2011 · Open Biology
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