scholarly journals TTK/hMps1 Mediates the p53-Dependent Postmitotic Checkpoint by Phosphorylating p53 at Thr18

2009 ◽  
Vol 29 (11) ◽  
pp. 2935-2944 ◽  
Author(s):  
Yi-Fu Huang ◽  
Margaret Dah-Tsyr Chang ◽  
Sheau-Yann Shieh
Keyword(s):  
Cell Division ◽  
Genome Stability ◽  
Spindle Checkpoint ◽  
Underlying Mechanism ◽  
Dependent Manner ◽  
Deficient Mutant ◽  
Present Evidence ◽  
Checkpoint Kinase ◽  
Terminal Domain

ABSTRACT Upon prolonged arrest in mitosis, cells undergo adaptation and exit mitosis without cell division. These tetraploid cells are either eliminated by apoptosis or arrested in the subsequent G1 phase in a spindle checkpoint- and p53-dependent manner. p53 has long been known to be activated by spindle poisons, such as nocodazole and Taxol, although the underlying mechanism remains elusive. Here we present evidence that stabilization and activation of p53 by spindle disruption requires the spindle checkpoint kinase TTK/hMps1. TTK/hMps1 phoshorylates the N-terminal domain of p53 at Thr18, and this phosphorylation disrupts the interaction with MDM2 and abrogates MDM2-mediated p53 ubiquitination. Phosphorylation at Thr18 enhances p53-dependent activation of not only p21 but also Lats2, two mediators of the postmitotic checkpoint. Furthermore, a phospho-mimicking substitution at Thr18 (T18D) is more competent than the phospho-deficient mutant (T18A) in rescuing the tetraploid checkpoint defect of p53-depleted cells. Our findings therefore provide a mechanism connecting the spindle checkpoint with p53 in the maintenance of genome stability.

scholarly journals FAM29A promotes microtubule amplification via recruitment of the NEDD1–γ-tubulin complex to the mitotic spindle

2008 ◽  
Vol 183 (5) ◽  
pp. 835-848 ◽  
Author(s):  
Hui Zhu ◽  
Judith A. Coppinger ◽  
Chang-Young Jang ◽  
John R. Yates ◽  
Guowei Fang
Keyword(s):  
Mitotic Spindle ◽  
Mammalian Cells ◽  
Spindle Checkpoint ◽  
Underlying Mechanism ◽  
Dependent Manner ◽  
Biochemical Mechanism ◽  
Mitotic Progression ◽  
Subsequent Increase ◽  
Chromosome Congression ◽  
Drosophila Cells

Microtubules (MTs) are nucleated from centrosomes and chromatin. In addition, MTs can be generated from preexiting MTs in a γ-tubulin–dependent manner in yeast, plant, and Drosophila cells, although the underlying mechanism remains unknown. Here we show the spindle-associated protein FAM29A promotes MT-dependent MT amplification and is required for efficient chromosome congression and segregation in mammalian cells. Depletion of FAM29A reduces spindle MT density. FAM29A is not involved in the nucleation of MTs from centrosomes and chromatin, but is required for a subsequent increase in MT mass in cells released from nocodazole. FAM29A interacts with the NEDD1–γ-tubulin complex and recruits this complex to the spindle, which, in turn, promotes MT polymerization. FAM29A preferentially associates with kinetochore MTs and knockdown of FAM29A reduces the number of MTs in a kinetochore fiber, activates the spindle checkpoint, and delays the mitotic progression. Our study provides a biochemical mechanism for MT-dependent MT amplification and for the maturation of kinetochore fibers in mammalian cells.

scholarly journals PomX, a ParA/MinD ATPase activating protein, is a triple regulator of cell division in Myxococcus xanthus

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Dominik Schumacher ◽  
Andrea Harms ◽  
Silke Bergeler ◽  
Erwin Frey ◽  
Lotte Sogaard-Andersen
Keyword(s):  
Cell Division ◽  
Myxococcus Xanthus ◽  
Dependent Manner ◽  
Ftsz Ring ◽  
Work Support ◽  
Terminal Domain ◽  
Division Site ◽  
The Social ◽  
Underlying Mechanisms ◽  
Positively Charged

Cell division site positioning is precisely regulated but the underlying mechanisms are incompletely understood. In the social bacterium Myxococcus xanthus, the ~15 MDa tripartite PomX/Y/Z complex associates with and translocates across the nucleoid in a PomZ ATPase-dependent manner to directly position and stimulate formation of the cytokinetic FtsZ-ring at midcell, and then undergoes fission during division. Here, we demonstrate that PomX consists of two functionally distinct domains and has three functions. The N-terminal domain stimulates ATPase activity of the ParA/MinD ATPase PomZ. The C-terminal domain interacts with PomY and forms polymers, which serve as a scaffold for PomX/Y/Z complex formation. Moreover, the PomX/PomZ interaction is important for fission of the PomX/Y/Z complex. These observations together with previous work support that the architecturally diverse ATPase activating proteins of ParA/MinD ATPases are highly modular and use the same mechanism to activate their cognate ATPase via a short positively charged N-terminal extension.

scholarly journals PomX, a ParA/MinD ATPase activating protein, is a triple regulator of cell division in Myxococcus xanthus

2020 ◽  
Author(s):  
Dominik Schumacher ◽  
Andrea Harms ◽  
Silke Bergeler ◽  
Erwin Frey ◽  
Lotte Søgaard-Andersen
Keyword(s):  
Cell Division ◽  
Myxococcus Xanthus ◽  
Dependent Manner ◽  
Ftsz Ring ◽  
Daughter Cells ◽  
Terminal Domain ◽  
Division Site ◽  
The Social ◽  
Interaction Interaction ◽  
Positively Charged

SummaryCell division is precisely regulated to generate daughter cells of correct size and shape. In the social bacterium Myxococcus xanthus, the tripartite PomX/Y/Z complex directly stimulates positioning of the cytokinetic FtsZ-ring at midcell to mark the division site. The ∼15 MDa PomX/Y/Z complex associates with the nucleoid in a PomZ-dependent manner, translocates to midcell to stimulate FtsZ-ring formation, and undergoes fission during division. We demonstrate that PomX consists of two functionally distinct domains and has three functions. The N-terminal domain interacts with the ParA/MinD ATPase PomZ and stimulates PomZ ATPase activity. The C-terminal domain mediates PomX self-interaction, interaction to PomY, and serves as a scaffold for PomX/Y/Z complex formation. Moreover, the PomX/PomZ interaction is important for fission. These observations together with previous work support that the architecturally diverse ATPase activating proteins of ParA/MinD ATPases are highly modular and use the same mechanism to activate their cognate ATPase via a short positively charged N-terminal extension.

scholarly journals Volatile 1-octanol of tea (Camellia sinensis L.) fuels cell division and indole-3-acetic acid production in phylloplane isolate Pseudomonas sp. NEEL19

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Poovarasan Neelakandan ◽  
Chiu-Chung Young ◽  
Asif Hameed ◽  
Yu-Ning Wang ◽  
Kui-Nuo Chen ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Cell Division ◽  
Petri Dish ◽  
Gas Chromatography Mass Spectrometry ◽  
Dependent Manner ◽  
Tea Leaves ◽  
Acetic Acid Production ◽  
Iaa Production ◽  
Solvent Tolerant ◽  
Indole 3 Acetic Acid

AbstractTea leaves possess numerous volatile organic compounds (VOC) that contribute to tea’s characteristic aroma. Some components of tea VOC were known to exhibit antimicrobial activity; however, their impact on bacteria remains elusive. Here, we showed that the VOC of fresh aqueous tea leaf extract, recovered through hydrodistillation, promoted cell division and tryptophan-dependent indole-3-acetic acid (IAA) production in Pseudomonas sp. NEEL19, a solvent-tolerant isolate of the tea phylloplane. 1-octanol was identified as one of the responsible volatiles stimulating cell division, metabolic change, swimming motility, putative pili/nanowire formation and IAA production, through gas chromatography-mass spectrometry, microscopy and partition petri dish culture analyses. The bacterial metabolic responses including IAA production increased under 1-octanol vapor in a dose-dependent manner, whereas direct-contact in liquid culture failed to elicit such response. Thus, volatile 1-octanol emitting from tea leaves is a potential modulator of cell division, colonization and phytohormone production in NEEL19, possibly influencing the tea aroma.

scholarly journals Influence of icariin on inflammation, apoptosis, invasion, and tumor immunity in cervical cancer by reducing the TLR4/MyD88/NF-κB and Wnt/β-catenin pathways

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chunyang Li ◽  
Shuangqing Yang ◽  
Huaqing Ma ◽  
Mengjia Ruan ◽  
Luyan Fang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Underlying Mechanism ◽  
Tissue Growth ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Siha Cells ◽  
Cervical Cancer Cells

Abstract Background Cervical cancer is a type of the most common gynecology tumor in women of the whole world. Accumulating data have shown that icariin (ICA), a natural compound, has anti-cancer activity in different cancers, including cervical cancer. The study aimed to reveal the antitumor effects and the possible underlying mechanism of ICA in U14 tumor-bearing mice and SiHa cells. Methods The antitumor effects of ICA were investigated in vivo and in vitro. The expression of TLR4/MyD88/NF-κB and Wnt/β-catenin signaling pathways were evaluated. Results We found that ICA significantly suppressed tumor tissue growth and SiHa cells viability in a dose-dependent manner. Also, ICA enhanced the anti-tumor humoral immunity in vivo. Moreover, ICA significantly improved the composition of the microbiota in mice models. Additionally, the results clarified that ICA significantly inhibited the migration, invasion capacity, and expression levels of TGF-β1, TNF-α, IL-6, IL-17A, IL-10 in SiHa cells. Meanwhile, ICA was revealed to promote the apoptosis of cervical cancer cells by down-regulating Ki67, survivin, Bcl-2, c-Myc, and up-regulating P16, P53, Bax levels in vivo and in vitro. For the part of mechanism exploration, we showed that ICA inhibits the inflammation, proliferation, migration, and invasion, as well as promotes apoptosis and immunity in cervical cancer through impairment of TLR4/MyD88/NF-κB and Wnt/β-catenin pathways. Conclusions Taken together, ICA could be a potential supplementary agent for cervical cancer treatment.

scholarly journals RASSF1A inhibits PDGFB-driven malignant phenotypes of nasopharyngeal carcinoma cells in a YAP1-dependent manner

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Ying-Ying Liang ◽  
Xu-Bin Deng ◽  
Xian-Tao Lin ◽  
Li-Li Jiang ◽  
Xiao-Ting Huang ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Underlying Mechanism ◽  
Carcinoma Cells ◽  
Dependent Manner ◽  
Transcriptional Coactivator ◽  
Actin Remodeling ◽  
Aggressive Tumor ◽  
Subunit B

Abstract Nasopharyngeal carcinoma (NPC) is a highly aggressive tumor characterized by distant metastasis. Deletion or down-regulation of the tumor suppressor protein ras-association domain family protein1 isoform A (RASSF1A) has been confirmed to be a key event in NPC progression; however, little is known about the effects or underlying mechanism of RASSF1A on the malignant phenotype. In the present study, we observed that RASSF1A expression inhibited the malignant phenotypes of NPC cells. Stable silencing of RASSF1A in NPC cell lines induced self-renewal properties and tumorigenicity in vivo/in vitro and the acquisition of an invasive phenotype in vitro. Mechanistically, RASSF1A inactivated Yes-associated Protein 1 (YAP1), a transcriptional coactivator, through actin remodeling, which further contributed to Platelet Derived Growth Factor Subunit B (PDGFB) transcription inhibition. Treatment with ectopic PDGFB partially increased the malignancy of NPC cells with transient knockdown of YAP1. Collectively, these findings suggest that RASSF1A inhibits malignant phenotypes by repressing PDGFB expression in a YAP1-dependent manner. PDGFB may serve as a potential interest of therapeutic regulators in patients with metastatic NPC.

scholarly journals The δ subunit and NTPase HelD institute a two-pronged mechanism for RNA polymerase recycling

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hao-Hong Pei ◽  
Tarek Hilal ◽  
Zhuo A. Chen ◽  
Yong-Heng Huang ◽  
Yuan Gao ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Nucleic Acids ◽  
Rna Polymerase ◽  
Active Site ◽  
Genome Stability ◽  
Slow Growth ◽  
Coiled Coil ◽  
Main Channel ◽  
Dependent Manner ◽  
Secondary Channel

AbstractCellular RNA polymerases (RNAPs) can become trapped on DNA or RNA, threatening genome stability and limiting free enzyme pools, but how RNAP recycling into active states is achieved remains elusive. In Bacillus subtilis, the RNAP δ subunit and NTPase HelD have been implicated in RNAP recycling. We structurally analyzed Bacillus subtilis RNAP-δ-HelD complexes. HelD has two long arms: a Gre cleavage factor-like coiled-coil inserts deep into the RNAP secondary channel, dismantling the active site and displacing RNA, while a unique helical protrusion inserts into the main channel, prying the β and β′ subunits apart and, aided by δ, dislodging DNA. RNAP is recycled when, after releasing trapped nucleic acids, HelD dissociates from the enzyme in an ATP-dependent manner. HelD abundance during slow growth and a dimeric (RNAP-δ-HelD)2 structure that resembles hibernating eukaryotic RNAP I suggest that HelD might also modulate active enzyme pools in response to cellular cues.

Kinetochore localization and microtubule interaction of the human spindle checkpoint kinase Mps1

Chromosoma ◽  
2004 ◽  
Vol 113 (1) ◽  
Author(s):  
VolkerM. Stucke ◽  
Christoph Baumann ◽  
ErichA. Nigg
Keyword(s):  
Spindle Checkpoint ◽  
Checkpoint Kinase

scholarly journals Inositol-Requiring Enzyme 1-Dependent Activation of AMPK Promotes Brucella abortus Intracellular Growth

2016 ◽  
Vol 198 (6) ◽  
pp. 986-993 ◽  
Author(s):  
Ning Liu ◽  
Yingying Li ◽  
Chunyan Dong ◽  
Xiaohan Xu ◽  
Pan Wei ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Underlying Mechanism ◽  
Peritoneal Macrophages ◽  
Dependent Manner ◽  
Ros Production ◽  
Ampk Activation ◽  
Intracellular Growth ◽  
Serine Threonine Kinase ◽  
Content Type ◽  
Amp Activated Protein Kinase

ABSTRACTAMP-activated protein kinase (AMPK) is a serine/threonine kinase that is well conserved during evolution. AMPK activation inhibits production of reactive oxygen species (ROS) in cells via suppression of NADPH oxidase. However, the role of AMPK during the process ofBrucellainfection remains unknown. Our data demonstrate thatB. abortusinfection induces AMPK activation in HeLa cells in a time-dependent manner. The known AMPK kinases LKB1, CAMKKβ, and TAK1 are not required for the activation of AMPK byB. abortusinfection. Instead, this activation is dependent on the RNase activity of inositol-requiring enzyme 1 (IRE1). Moreover, we also found thatB. abortusinfection-induced IRE1-dependent activation of AMPK promotesB. abortusintracellular growth with peritoneal macrophages via suppression of NADPH-derived ROS production.IMPORTANCEPrevious studies showed thatB. abortusinfection does not promote any oxidative burst regulated by NADPH oxidase. However, the underlying mechanism remains elusive. We report for the first time that AMPK activation caused byB. abortusinfection plays important role in NADPH oxidase-derived ROS production.

MondoA Drives B-ALL Malignancy through Enhanced Adaptation to Metabolic Stress

Blood ◽  
2021 ◽  
Author(s):  
Alexandra Sipol ◽  
Erik Hameister ◽  
Busheng Xue ◽  
Julia Hofstetter ◽  
Maxim Barenboim ◽  
...  
Keyword(s):  
Stress Responses ◽  
Lymphoblastic Leukemia ◽  
Metabolic Stress ◽  
Tca Cycle ◽  
Underlying Mechanism ◽  
Patient Data ◽  
Data Sets ◽  
Dependent Manner

Cancer cells are in most instances characterized by rapid proliferation and uncontrolled cell division. Hence, they must adapt to proliferation-induced metabolic stress through intrinsic or acquired anti-metabolic stress responses to maintain homeostasis and survival. One mechanism to achieve this is to reprogram gene expression in a metabolism-dependent manner. MondoA (also known as MLXIP), a member of the MYC interactome, has been described as an example of such a metabolic sensor. However, the role of MondoA in malignancy is not fully understood and the underlying mechanism in metabolic responses remains elusive. By assessing patient data sets we found that MondoA overexpression is associated with a worse survival in pediatric common acute lymphoblastic leukemia (B-ALL). Using CRISPR/Cas9 and RNA interference approaches, we observed that MondoA depletion reduces transformational capacity of B-ALL cells in vitro and dramatically inhibits malignant potential in an in vivo mouse model. Interestingly, reduced expression of MondoA in patient data sets correlated with enrichment in metabolic pathways. The loss of MondoA correlated with increased tricarboxylic acid (TCA) cycle activity. Mechanistically, MondoA senses metabolic stress in B-ALL cells by restricting oxidative phosphorylation through reduced PDH activity. Glutamine starvation conditions greatly enhance this effect and highlight the inability to mitigate metabolic stress upon loss of MondoA in B-ALL. Our findings give a novel insight into the function of MondoA in pediatric B-ALL and support the notion that MondoA inhibition in this entity offers a therapeutic opportunity and should be further explored.

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