scholarly journals EIF3 p170, a Mediator of Mimosine Effect on Protein Synthesis and Cell Cycle Progression

2003 ◽  
Vol 14 (9) ◽  
pp. 3942-3951 ◽  
Author(s):  
Zizheng Dong ◽  
Jian-Ting Zhang
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
De Novo ◽  
Mrna Translation ◽  
Early Response ◽  
Initiation Factors ◽  
Cycle Arrest ◽  
Eukaryotic Initiation Factors ◽  
Complex Process

l-Mimosine, a plant amino acid, can reversibly block mammalian cells at late G1 phase and has been suggested to affect translation of mRNAs such as p27, the CDK inhibitor. However, the mechanism of this effect is not known. Regulation of translation generally occurs at the initiation step that, in mammalian cells, is a complex process that requires multiple eukaryotic initiation factors (eIFs) and ribosome. The effects of mimosine on initiation factors or regulators consequently will influence translation initiation. P170, a putative subunit of eIF3, has been suggested to be nonessential for eIF3 function to form preinitiation complexes and it may function as a regulator for translation of a subset of mRNAs. In this article, we tested this hypothesis and investigated whether eIF3 p170 mediates mimosine effect on mRNA translation. We found that p170 translation was dramatically reduced by mimosine due to its iron-chelating function. The decreased expression of p170 by mimosine caused diminished de novo synthesis of tyrosinated α-tubulin and elevated translation of p27 before cell cycle arrest. These observations suggest that p170 is likely an early response gene to mimosine treatment and a mediator for mimosine effect on mRNA translation. The effect of p170 on the synthesis of tyrosinated α-tubulin and p27 in a reciprocal manner also suggests that p170 functions as a regulator for mRNA translation.

scholarly journals Poliovirus 2APro Increases Viral mRNA and Polysome Stability Coordinately in Time with Cleavage of eIF4G

2008 ◽  
Vol 82 (12) ◽  
pp. 5847-5859 ◽  
Author(s):  
Brian J. Kempf ◽  
David J. Barton
Keyword(s):  
De Novo ◽  
Mrna Translation ◽  
Viral Mrna ◽  
Site Mutation ◽  
Initiation Factors ◽  
Eukaryotic Initiation Factors ◽  
Messenger Ribonucleoprotein ◽  
Infected Cells ◽  
The Stability ◽  
Polysome Stability

ABSTRACT Poliovirus (PV) 2A protease (2APro) cleaves eukaryotic initiation factors 4GI and 4GII (eIF4GI and eIF4GII) within virus-infected cells, effectively halting cap-dependent mRNA translation. PV mRNA, which does not possess a 5′ cap, is translated via cap-independent mechanisms within viral protease-modified messenger ribonucleoprotein (mRNP) complexes. In this study, we determined that 2APro activity was required for viral polysome formation and stability. 2APro cleaved eIF4GI and eIF4GII as PV polysomes assembled. A 2ACys109Ser (2APro with a Cys109Ser mutation) protease active site mutation that prevented cleavage of eIF4G coordinately inhibited the de novo formation of viral polysomes, the stability of viral polysomes, and the stability of PV mRNA within polysomes. 2ACys109Ser-associated defects in PV mRNA and polysome stability correlated with defects in PV mRNA translation. 3CPro activity was not required for viral polysome formation or stability. 2APro-mediated cleavage of eIF4G along with poly(rC) binding protein binding to the 5′ terminus of uncapped PV mRNA appear to be concerted mechanisms that allow PV mRNA to form mRNP complexes that evade cellular mRNA degradation machinery.

scholarly journals Histone supply regulates S phase timing and cell cycle progression

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Ufuk Günesdogan ◽  
Herbert Jäckle ◽  
Alf Herzig
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
De Novo ◽  
S Phase ◽  
Histone Genes ◽  
Nucleosome Assembly ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
A Cell ◽  
Surveillance Mechanism

Eukaryotes package DNA into nucleosomes that contain a core of histone proteins. During DNA replication, nucleosomes are disrupted and re-assembled with newly synthesized histones and DNA. Despite much progress, it is still unclear why higher eukaryotes contain multiple core histone genes, how chromatin assembly is controlled, and how these processes are coordinated with cell cycle progression. We used a histone null mutation of Drosophila melanogaster to show that histone supply levels, provided by a defined number of transgenic histone genes, regulate the length of S phase during the cell cycle. Lack of de novo histone supply not only extends S phase, but also causes a cell cycle arrest during G2 phase, and thus prevents cells from entering mitosis. Our results suggest a novel cell cycle surveillance mechanism that monitors nucleosome assembly without involving the DNA repair pathways and exerts its effect via suppression of CDC25 phosphatase String expression.

scholarly journals Spy1 Interacts with p27Kip1 to Allow G1/S Progression

2003 ◽  
Vol 14 (9) ◽  
pp. 3664-3674 ◽  
Author(s):  
Lisa A. Porter ◽  
Monica Kong-Beltran ◽  
Daniel J. Donoghue
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Regulatory Protein ◽  
Cell Cycle Regulatory Protein ◽  
Proliferative Effect ◽  
Cycle Arrest ◽  
Mammalian Cell Cycle

Progression through the G1/S transition commits cells to synthesize DNA. Cyclin dependent kinase 2 (CDK2) is the major kinase that allows progression through G1/S phase and subsequent replication events. p27 is a CDK inhibitor (CKI) that binds to CDK2 to prevent premature activation of this kinase. Speedy (Spy1), a novel cell cycle regulatory protein, has been found to prematurely activate CDK2 when microinjected into Xenopus oocytes and when expressed in mammalian cells. To determine the mechanism underlying Spy1-induced proliferation in mammalian cell cycle regulation, we used human Spy1 as bait in a yeast two-hybrid screen to identify interacting proteins. One of the proteins isolated was p27; this novel interaction was confirmed both in vitro, using bacterially expressed and in vitro translated proteins, and in vivo, through the examination of endogenous and transfected proteins in mammalian cells. We demonstrate that Spy1 expression can overcome a p27-induced cell cycle arrest to allow for DNA synthesis and CDK2 histone H1 kinase activity. In addition, we utilized p27-null cells to demonstrate that the proliferative effect of Spy1 depends on the presence of endogenous p27. Our data suggest that Spy1 associates with p27 to promote cell cycle progression through the G1/S transition.

scholarly journals The de novo centriole assembly pathway in HeLa cells

2005 ◽  
Vol 168 (5) ◽  
pp. 713-722 ◽  
Author(s):  
Sabrina La Terra ◽  
Christopher N. English ◽  
Polla Hergert ◽  
Bruce F. McEwen ◽  
Greenfield Sluder ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Hela Cells ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
De Novo ◽  
Variable Number ◽  
S Phase ◽  
Cycle Progression ◽  
Assembly Pathway ◽  
Centriole Assembly

It has been reported that nontransformed mammalian cells become arrested during G1 in the absence of centrioles (Hinchcliffe, E., F. Miller, M. Cham, A. Khodjakov, and G. Sluder. 2001. Science. 291:1547–1550). Here, we show that removal of resident centrioles (by laser ablation or needle microsurgery) does not impede cell cycle progression in HeLa cells. HeLa cells born without centrosomes, later, assemble a variable number of centrioles de novo. Centriole assembly begins with the formation of small centrin aggregates that appear during the S phase. These, initially amorphous “precentrioles” become morphologically recognizable centrioles before mitosis. De novo–assembled centrioles mature (i.e., gain abilities to organize microtubules and replicate) in the next cell cycle. This maturation is not simply a time-dependent phenomenon, because de novo–formed centrioles do not mature if they are assembled in S phase–arrested cells. By selectively ablating only one centriole at a time, we find that the presence of a single centriole inhibits the assembly of additional centrioles, indicating that centrioles have an activity that suppresses the de novo pathway.

scholarly journals Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1.

1997 ◽  
Vol 17 (9) ◽  
pp. 5598-5611 ◽  
Author(s):  
D Woods ◽  
D Parry ◽  
H Cherwinski ◽  
E Bosch ◽  
E Lees ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Arrest ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
G1 Arrest ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Primary Mouse

The Raf family of protein kinases display differences in their abilities to promote the entry of quiescent NIH 3T3 cells into the S phase of the cell cycle. Although conditional activation of deltaA-Raf:ER promoted cell cycle progression, activation of deltaRaf-1:ER and deltaB-Raf:ER elicited a G1 arrest that was not overcome by exogenously added growth factors. Activation of all three deltaRaf:ER kinases led to elevated expression of cyclin D1 and cyclin E and reduced expression of p27Kip1. However, activation of deltaB-Raf:ER and deltaRaf-1:ER induced the expression of p21Cip1, whereas activation of deltaA-Raf:ER did not. A catalytically potentiated form of deltaA-Raf:ER, generated by point mutation, strongly induced p21Cip1 expression and elicited cell cycle arrest similarly to deltaB-Raf:ER and deltaRaf-1:ER. These data suggested that the strength and duration of signaling by Raf kinases might influence the biological outcome of activation of this pathway. By titration of deltaB-Raf:ER activity we demonstrated that low levels of Raf activity led to activation of cyclin D1-cdk4 and cyclin E-cdk2 complexes and to cell cycle progression whereas higher Raf activity elicited cell cycle arrest correlating with p21Cip1 induction and inhibition of cyclin-cdk activity. Using green fluorescent protein-tagged forms of deltaRaf-1:ER in primary mouse embryo fibroblasts (MEFs) we demonstrated that p21Cip1 was induced by Raf in a p53-independent manner, leading to cell cycle arrest. By contrast, activation of Raf in p21Cip1(-/-) MEFs led to a robust mitogenic response that was similar to that observed in response to platelet-derived growth factor. These data indicate that, depending on the level of kinase activity, Raf can elicit either cell cycle progression or cell cycle arrest in mouse fibroblasts. The ability of Raf to elicit cell cycle arrest is strongly associated with its ability to induce the expression of the cyclin-dependent kinase inhibitor p21Cip1 in a manner that bears analogy to alpha-factor arrest in Saccharomyces cerevisiae. These data are consistent with a role for Raf kinases in both proliferation and differentiation of mammalian cells.

scholarly journals Cytolethal Distending Toxin Demonstrates Genotoxic Activity in a Yeast Model

2001 ◽  
Vol 69 (9) ◽  
pp. 5752-5759 ◽  
Author(s):  
Duane C. Hassane ◽  
Robert B. Lee ◽  
Michael D. Mendenhall ◽  
Carol L. Pickett
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Human Pathogens ◽  
Checkpoint Control ◽  
Chromosomal Dna ◽  
Cycle Arrest ◽  
Genotoxic Activity ◽  
Yeast Model

ABSTRACT Cytolethal distending toxins (CDTs) are multisubunit proteins produced by a variety of bacterial pathogens that cause enlargement, cell cycle arrest, and apoptosis in mammalian cells. While their function remains uncertain, recent studies suggest that they can act as intracellular DNases in mammalian cells. Here we establish a novel yeast model for understanding CDT-associated disease. Expression of the CdtB subunit in yeast causes a G2/M arrest, as seen in mammalian cells. CdtB toxicity is not circumvented in yeast genetically altered to lack DNA damage checkpoint control or that constitutively promote cell cycle progression via mutant Cdk1, because CdtB causes a permanent type of damage that results in loss of viability. Finally, we establish that CDTs are likely to be potent genotoxins, as indicated by in vivo degradation of chromosomal DNA associated with expression of CdtB—suggesting that the varied distribution of CDT in bacteria implicates many human pathogens as possessors of genotoxic activity.

scholarly journals Cell cycle progression and de novo centriole assembly after centrosomal removal in untransformed human cells

2007 ◽  
Vol 176 (2) ◽  
pp. 173-182 ◽  
Author(s):  
Yumi Uetake ◽  
Jadranka Lončarek ◽  
Joshua J. Nordberg ◽  
Christopher N. English ◽  
Sabrina La Terra ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
De Novo ◽  
S Phase ◽  
Human Cells ◽  
G1 Arrest ◽  
Cycle Progression ◽  
Normal Human ◽  
Centrosomal Proteins

How centrosome removal or perturbations of centrosomal proteins leads to G1 arrest in untransformed mammalian cells has been a mystery. We use microsurgery and laser ablation to remove the centrosome from two types of normal human cells. First, we find that the cells assemble centrioles de novo after centrosome removal; thus, this phenomenon is not restricted to transformed cells. Second, normal cells can progress through G1 in its entirety without centrioles. Therefore, the centrosome is not a necessary, integral part of the mechanisms that drive the cell cycle through G1 into S phase. Third, we provide evidence that centrosome loss is, functionally, a stress that can act additively with other stresses to arrest cells in G1 in a p38-dependent fashion.

Prolonged arrest of mammalian cells at the G1/S boundary results in permanent S phase stasis

2002 ◽  
Vol 115 (14) ◽  
pp. 2829-2838
Author(s):  
Franck Borel ◽  
Françoise B. Lacroix ◽  
Robert L. Margolis
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
T Antigen ◽  
S Phase ◽  
Inhibitory Circuits ◽  
Cycle Arrest ◽  
Mcm Proteins

Mammalian cells in culture normally enter a state of quiescence during G1 following suppression of cell cycle progression by senescence, contact inhibition or terminal differentiation signals. We find that mammalian fibroblasts enter cell cycle stasis at the onset of S phase upon release from prolonged arrest with the inhibitors of DNA replication, hydroxyurea or aphidicolin. During arrest typical S phase markers remain present, and G0/G1 inhibitory signals such as p21WAF1 and p27 are absent. Cell cycle stasis occurs in T-antigen transformed cells, indicating that p53 and pRB inhibitory circuits are not involved. While no DNA replication is evident in arrested cells, nuclei isolated from these cells retain measurable competence for in vitro replication. MCM proteins are required to license replication origins, and are put in place in nuclei in G1 and excluded from chromatin by the end of replication to prevent rereplication of the genome. Strikingly, MCM proteins are strongly depleted from chromatin during prolonged S phase arrest,and their loss may underlie the observed cell cycle arrest. S phase stasis may thus be a `trap' in which cells otherwise competent for S phase have lost a key component required for replication and thus can neither go forward nor retreat to G1 status.

scholarly journals A DNA-Damage-Induced Cell Cycle Checkpoint in Arabidopsis

Genetics ◽  
2003 ◽  
Vol 164 (1) ◽  
pp. 323-334
Author(s):  
S B Preuss ◽  
A B Britt
Keyword(s):  
Cell Cycle ◽  
Gamma Radiation ◽  
Cell Cycle Progression ◽  
Cell Cycle Checkpoint ◽  
Phase Cell ◽  
Cycle Arrest ◽  
Cycle Checkpoint ◽  
Radiation Induced ◽  
High Doses ◽  
Regulation Of Cell Cycle

Abstract Although it is well established that plant seeds treated with high doses of gamma radiation arrest development as seedlings, the cause of this arrest is unknown. The uvh1 mutant of Arabidopsis is defective in a homolog of the human repair endonuclease XPF, and uvh1 mutants are sensitive to both the toxic effects of UV and the cytostatic effects of gamma radiation. Here we find that gamma irradiation of uvh1 plants specifically triggers a G2-phase cell cycle arrest. Mutants, termed suppressor of gamma (sog), that suppress this radiation-induced arrest and proceed through the cell cycle unimpeded were recovered in the uvh1 background; the resulting irradiated plants are genetically unstable. The sog mutations fall into two complementation groups. They are second-site suppressors of the uvh1 mutant's sensitivity to gamma radiation but do not affect the susceptibility of the plant to UV radiation. In addition to rendering the plants resistant to the growth inhibitory effects of gamma radiation, the sog1 mutation affects the proper development of the pollen tetrad, suggesting that SOG1 might also play a role in the regulation of cell cycle progression during meiosis.

scholarly journals Hyperbaric oxygen promotes not only glioblastoma proliferation but also chemosensitization by inhibiting HIF1α/HIF2α-Sox2

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Pan Wang ◽  
Sheng Gong ◽  
Jinyu Pan ◽  
Junwei Wang ◽  
Dewei Zou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Hyperbaric Oxygen ◽  
Cell Cycle Progression ◽  
Malignant Progression ◽  
Cycle Progression ◽  
Chemotherapy Sensitivity ◽  
Hypoxic Conditions ◽  
Cycle Arrest

AbstractThere exists a consensus that combining hyperbaric oxygen (HBO) and chemotherapy promotes chemotherapy sensitivity in GBM cells. However, few studies have explored the mechanism involved. HIF1α and HIF2α are the two main molecules that contribute to GBM malignant progression by inhibiting apoptosis or maintaining stemness under hypoxic conditions. Moreover, Sox2, a marker of stemness, also contributes to GBM malignant progression through stemness maintenance or cell cycle arrest. Briefly, HIF1α, HIF2α and Sox2 are highly expressed under hypoxia and contribute to GBM growth and chemoresistance. However, after exposure to HBO for GBM, whether the expression of the above factors is decreased, resulting in chemosensitization, remains unknown. Therefore, we performed a series of studies and determined that the expression of HIF1α, HIF2α and Sox2 was decreased after HBO and that HBO promoted GBM cell proliferation through cell cycle progression, albeit with a decrease in stemness, thus contributing to chemosensitization via the inhibition of HIF1α/HIF2α-Sox2.

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