scholarly journals TgAP2IX-5 is a key transcriptional regulator of the asexual cell cycle division in Toxoplasma gondii

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Asma S. Khelifa ◽  
Cecilia Guillen Sanchez ◽  
Kevin M. Lesage ◽  
Ludovic Huot ◽  
Thomas Mouveaux ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Toxoplasma Gondii ◽  
Molecular Mechanisms ◽  
Developmental Pathways ◽  
Limiting Factor ◽  
Specific Cell ◽  
Master Regulator ◽  
Apicomplexan Parasites ◽  
Daughter Cells ◽  
Expression Program

AbstractApicomplexan parasites have evolved efficient and distinctive strategies for intracellular replication where the timing of emergence of the daughter cells (budding) is a decisive element. However, the molecular mechanisms that provide the proper timing of parasite budding remain unknown. Using Toxoplasma gondii as a model Apicomplexan, we identified a master regulator that controls the timing of the budding process. We show that an ApiAP2 transcription factor, TgAP2IX-5, controls cell cycle events downstream of centrosome duplication. TgAP2IX-5 binds to the promoter of hundreds of genes and controls the activation of the budding-specific cell cycle expression program. TgAP2IX-5 regulates the expression of specific transcription factors that are necessary for the completion of the budding cycle. Moreover, TgAP2IX-5 acts as a limiting factor that ensures that asexual proliferation continues by promoting the inhibition of the differentiation pathway. Therefore, TgAP2IX-5 is a master regulator that controls both cell cycle and developmental pathways.

scholarly journals A single master regulator controls asexual cell cycle division patterns in Toxoplasma gondii

2020 ◽  
Author(s):  
Asma S. Khelifa ◽  
Cecilia Sanchez Guillen ◽  
Kevin M. Lesage ◽  
Ludovic Huot ◽  
Pierre Pericard ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Toxoplasma Gondii ◽  
Molecular Mechanisms ◽  
Cell Cycle Control ◽  
Life Cycles ◽  
Specific Cell ◽  
Master Regulator ◽  
Apicomplexan Parasites ◽  
Organelle Division ◽  
Single Nucleus

ABSTRACTAll apicomplexan parasites have complex life cycles exhibiting division characterized by a tightly regulated cell cycle control, resulting in the emergence of daughter parasites in possession of a single nucleus and a complete set of organelles. Apicomplexa have evolved efficient and distinctive strategies for intracellular replication where the timing of emergence of the daughter cells, a process termed “budding”, is a decisive element. However, the molecular mechanisms that provide the proper timing of parasite budding remain unknown. Using Toxoplasma gondii as a model Apicomplexa, we identified a master regulator that controls the timing of the budding process. We show that an ApiAP2 transcription factor, TgAP2IX-5, controls cell cycle events downstream of centrosome duplication including organelle division and segregation. TgAP2IX-5 binds to the promoter of hundreds of genes and controls the activation of the budding-specific cell cycle expression program. We show that TgAP2IX-5 regulates the expression of specific transcription factors that are necessary for the completion of the budding cycle. TgAP2IX-5 acts as a licensing factor that ensures that asexual proliferation continues by promoting the inhibition of the differentiation pathway at each round of the cell cycle. Therefore, TgAP2IX-5 is a master regulator that controls both cell cycle and developmental pathways.

scholarly journals Toxoplasma gondii myosins B/C

2001 ◽  
Vol 155 (4) ◽  
pp. 613-624 ◽  
Author(s):  
Frédéric Delbac ◽  
Astrid Sänger ◽  
Eva M. Neuhaus ◽  
Rolf Stratmann ◽  
James W. Ajioka ◽  
...  
Keyword(s):  
Cell Division ◽  
Toxoplasma Gondii ◽  
Daughter Cell ◽  
Gliding Motility ◽  
Apicomplexan Parasites ◽  
Daughter Cells ◽  
Membrane Complex ◽  
Alternatively Spliced ◽  
Butanedione Monoxime ◽  
Inner Membrane Complex

In apicomplexan parasites, actin-disrupting drugs and the inhibitor of myosin heavy chain ATPase, 2,3-butanedione monoxime, have been shown to interfere with host cell invasion by inhibiting parasite gliding motility. We report here that the actomyosin system of Toxoplasma gondii also contributes to the process of cell division by ensuring accurate budding of daughter cells. T. gondii myosins B and C are encoded by alternatively spliced mRNAs and differ only in their COOH-terminal tails. MyoB and MyoC showed distinct subcellular localizations and dissimilar solubilities, which were conferred by their tails. MyoC is the first marker selectively concentrated at the anterior and posterior polar rings of the inner membrane complex, structures that play a key role in cell shape integrity during daughter cell biogenesis. When transiently expressed, MyoB, MyoC, as well as the common motor domain lacking the tail did not distribute evenly between daughter cells, suggesting some impairment in proper segregation. Stable overexpression of MyoB caused a significant defect in parasite cell division, leading to the formation of extensive residual bodies, a substantial delay in replication, and loss of acute virulence in mice. Altogether, these observations suggest that MyoB/C products play a role in proper daughter cell budding and separation.

scholarly journals Generation of asymmetry during development. Segregation of type-specific proteins in Caulobacter.

1979 ◽  
Vol 81 (1) ◽  
pp. 123-136 ◽  
Author(s):  
N Agabian ◽  
M Evinger ◽  
G Parker
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Messenger Rna ◽  
Cell Types ◽  
Specific Protein ◽  
Soluble Proteins ◽  
Specific Cell ◽  
Daughter Cells ◽  
Specific Proteins ◽  
Entire Cell

An essential event in developmental processes is the introduction of asymmetry into an otherwise undifferentiated cell population. Cell division in Caulobacter is asymmetric; the progeny cells are structurally different and follow different sequences of development, thus providing a useful model system for the study of differentiation. Because the progeny cells are different from one another, there must be a segregation of morphogenetic and informational components at some time in the cell cycle. We have examined the pattern of specific protein segregation between Caulobacter stalked and swarmer daughter cells, with the rationale that such a progeny analysis would identify both structurally and developmentally important proteins. To complement the study, we have also examined the pattern of protein synthesis during synchronous growth and in various cellular fractions. We show here, for the first time, that the association of proteins with a specific cell type may result not only from their periodicity of synthesis, but also from their pattern of distribution at the time of cell division. Several membrane-associated and soluble proteins are segregated asymmetrically between progeny stalked and swarmer cells. The data further show that a subclass of soluble proteins becomes associated with the membrane of the progeny stalked cells. Therefore, although the principal differentiated cell types possess different synthetic capabilities and characteristic proteins, the asymmetry between progeny stalked and swarmer cells is generated primarily by the preferential association of specific soluble proteins with the membrane of only one daughter cell. The majority of the proteins which exhibit this segregation behavior are synthesized during the entire cell cycle and exhibit relatively long, functional messenger RNA half-lives.

scholarly journals The Plastid of Toxoplasma gondii Is Divided by Association with the Centrosomes

2000 ◽  
Vol 151 (7) ◽  
pp. 1423-1434 ◽  
Author(s):  
Boris Striepen ◽  
Michael J. Crawford ◽  
Michael K. Shaw ◽  
Lewis G. Tilney ◽  
Frank Seeber ◽  
...  
Keyword(s):  
Cell Division ◽  
Toxoplasma Gondii ◽  
Genetic Manipulation ◽  
Fluorescent Proteins ◽  
Recombinant Expression ◽  
Molecular Genetic ◽  
Time Lapse ◽  
Microtubule Organization ◽  
Apicomplexan Parasites ◽  
Daughter Cells

Apicomplexan parasites harbor a single nonphotosynthetic plastid, the apicoplast, which is essential for parasite survival. Exploiting Toxoplasma gondii as an accessible system for cell biological analysis and molecular genetic manipulation, we have studied how these parasites ensure that the plastid and its 35-kb circular genome are faithfully segregated during cell division. Parasite organelles were labeled by recombinant expression of fluorescent proteins targeted to the plastid and the nucleus, and time-lapse video microscopy was used to image labeled organelles throughout the cell cycle. Apicoplast division is tightly associated with nuclear and cell division and is characterized by an elongated, dumbbell-shaped intermediate. The plastid genome is divided early in this process, associating with the ends of the elongated organelle. A centrin-specific antibody demonstrates that the ends of dividing apicoplast are closely linked to the centrosomes. Treatment with dinitroaniline herbicides (which disrupt microtubule organization) leads to the formation of multiple spindles and large reticulate plastids studded with centrosomes. The mitotic spindle and the pellicle of the forming daughter cells appear to generate the force required for apicoplast division in Toxoplasma gondii. These observations are discussed in the context of autonomous and FtsZ-dependent division of plastids in plants and algae.

scholarly journals YAP integrates the regulatory Snail/HNF4α circuitry controlling epithelial/hepatocyte differentiation

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Valeria Noce ◽  
Cecilia Battistelli ◽  
Angela Maria Cozzolino ◽  
Veronica Consalvi ◽  
Carla Cicchini ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Liver Cell ◽  
Molecular Mechanisms ◽  
Dynamic Balance ◽  
Transcriptional Level ◽  
Specific Cell ◽  
Hepatocyte Differentiation ◽  
Master Regulator ◽  
Mesenchymal Transition ◽  
Hepatic Diseases

Abstract Yes-associated protein (YAP) is a transcriptional co-factor involved in many cell processes, including development, proliferation, stemness, differentiation, and tumorigenesis. It has been described as a sensor of mechanical and biochemical stimuli that enables cells to integrate environmental signals. Although in the liver the correlation between extracellular matrix elasticity (greatly increased in the most of chronic hepatic diseases), differentiation/functional state of parenchymal cells and subcellular localization/activation of YAP has been previously reported, its role as regulator of the hepatocyte differentiation remains to be clarified. The aim of this study was to evaluate the role of YAP in the regulation of epithelial/hepatocyte differentiation and to clarify how a transducer of general stimuli can integrate tissue-specific molecular mechanisms determining specific cell outcomes. By means of YAP silencing and overexpression we demonstrated that YAP has a functional role in the repression of epithelial/hepatocyte differentiation by inversely modulating the expression of Snail (master regulator of the epithelial-to-mesenchymal transition and liver stemness) and HNF4α (master regulator of hepatocyte differentiation) at transcriptional level, through the direct occupancy of their promoters. Furthermore, we found that Snail, in turn, is able to positively control YAP expression influencing protein level and subcellular localization and that HNF4α stably represses YAP transcription in differentiated hepatocytes both in cell culture and in adult liver. Overall, our data indicate YAP as a new member of the HNF4/Snail epistatic molecular circuitry previously demonstrated to control liver cell state. In this model, the dynamic balance between three main transcriptional regulators, that are able to control reciprocally their expression/activity, is responsible for the induction/maintenance of different liver cell differentiation states and its modulation could be the aim of therapeutic protocols for several chronic liver diseases.

scholarly journals A Novel Actin-Related Protein Is Associated with Daughter Cell Formation in Toxoplasma gondii

2008 ◽  
Vol 7 (9) ◽  
pp. 1500-1512 ◽  
Author(s):  
Jennifer L. Gordon ◽  
Wandy L. Beatty ◽  
L. David Sibley
Keyword(s):  
Cell Division ◽  
Toxoplasma Gondii ◽  
Daughter Cell ◽  
Cell Formation ◽  
The Body ◽  
Apicomplexan Parasites ◽  
Daughter Cells ◽  
Membrane Complex ◽  
Transport Vesicles ◽  
Inner Membrane Complex

ABSTRACT Cell division in Toxoplasma gondii occurs by an unusual budding mechanism termed endodyogeny, during which twin daughters are formed within the body of the mother cell. Cytokinesis begins with the coordinated assembly of the inner membrane complex (IMC), which surrounds the growing daughter cells. The IMC is compiled of both flattened membrane cisternae and subpellicular filaments composed of articulin-like proteins attached to underlying singlet microtubules. While proteins that comprise the elongating IMC have been described, little is known about its initial formation. Using Toxoplasma as a model system, we demonstrate that actin-like protein 1 (ALP1) is partially redistributed to the IMC at early stages in its formation. Immunoelectron microscopy localized ALP1 to a discrete region of the nuclear envelope, on transport vesicles, and on the nascent IMC of the daughter cells prior to the arrival of proteins such as IMC-1. The overexpression of ALP1 under the control of a strong constitutive promoter disrupted the formation of the daughter cell IMC, leading to delayed growth and defects in nuclear and apicoplast segregation. Collectively, these data suggest that ALP1 participates in the formation of daughter cell membranes during cell division in apicomplexan parasites.

scholarly journals Nucleolar stress causes the entry into replicative senescence in budding yeast

2018 ◽  
Author(s):  
Sandrine Morlot ◽  
Song Jia ◽  
Isabelle Léger-Silvestre ◽  
Audrey Matifas ◽  
Olivier Gadal ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Molecular Mechanisms ◽  
Replicative Senescence ◽  
Cellular Aging ◽  
Daughter Cells ◽  
Nucleolar Stress ◽  
Unique Framework ◽  
Massive Accumulation

SummaryThe accumulation of Extrachromosomal rDNA Circles (ERCs) and their asymmetric segregation upon division have been hypothesized to be responsible for replicative senescence in mother yeasts and rejuvenation in daughter cells. However, it remains unclear by which molecular mechanisms ERCs would trigger the irreversible cell cycle slow-down leading to cell death. We show that ERCs accumulation is concomitant with a nucleolar stress, characterized by a massive accumulation of pre-rRNAs in the nucleolus, leading to a loss of nucleus-to-cytoplasm ratio, decreased growth rate and cell-cycle slow-down. This nucleolar stress, observed in old mothers, is not inherited by rejuvenated daughters. Unlike WT, in the long-lived mutant fob1∆, a majority of cells is devoid of nucleolar stress and does not experience replicative senescence before death. Our study provides a unique framework to order the successive steps that govern the transition to replicative senescence and highlights the causal role of nucleolar stress in cellular aging.

scholarly journals Targeting of TP53-independent cell cycle checkpoints overcomes FOLFOX resistance in Metastatic Colorectal Cancer

2021 ◽  
Author(s):  
Corina Behrenbruch ◽  
Momeneh Foroutan ◽  
Phoebe Lind ◽  
Jai Smith ◽  
Mélodie Grandin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Dna Damage ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
S Phase ◽  
Cell Cycle Checkpoints ◽  
Surgical Removal ◽  
Specific Cell ◽  
Molecular Features

ABSTRACTPatients with colorectal cancer (CRC) frequently develop liver metastases during the course of their disease. A substantial proportion of them receive neoadjuvant FOLFOX (5-Fluorouracil, Oxaliplatin, Leucovorin) prior to surgery in an attempt to enable successful surgical removal of their metastases and to reduce the risk of recurrence. Yet, the majority of patients progress during treatment or recur following surgery, and molecular mechanisms that contribute to FOLFOX resistance remain poorly understood. Here, using a combination of phenotypic, transcriptomic and genomic analyses of both tumor samples derived from patients with metastatic CRC and matching patient-derived tumor organoids (PDTOs), we characterize a novel FOLFOX resistance mechanism and identify inhibitors that target this mechanism to resensitize metastatic organoids to FOLFOX. Resistant PDTOs, identified after in vitro exposure to FOLFOX, exhibited elevated expression of E2F pathway, S phase, G2/M and spindle assembly checkpoints (SAC) genes. Similar molecular features were detected in CRLM from patients with progressive disease while under neoadjuvant FOLFOX treatment, highlighting the relevance of this finding. FOLFOX resistant PDTOs displayed inactivating mutations of TP53 and exhibited transcriptional features of P53 pathway downregulation. We found that they accumulated in early S-phase and underwent significant DNA damage during FOLFOX exposure, thereafter arresting in G2/M while they repaired their DNA after FOLFOX withdrawal. In parallel, results of a large kinase inhibitor screen indicated that drugs targeting regulators of the DNA damage response, G2M checkpoint and SAC had cytotoxic effects on PDTOs generated from patients whose disease progressed during treatment with FOLFOX. Corroborating this finding, CHK1 and WEE1 inhibitors were found to synergize with FOLFOX and sensitize previously resistant PDTOs. Additionally, targeting the SAC master regulator MPS1 using empesertib after exposure to FOLFOX, when cells accumulate in G2M, was also very effective to kill FOLFOX-resistant PDTOs. Our results indicate that targeted and timely inhibition of specific cell cycle checkpoints shows great potential to improve response rates to FOLFOX in patients with metastatic CRC, for whom therapeutic alternatives remain extremely limited.

scholarly journals PP2A-B55 promotes nuclear envelope reformation after mitosis in Drosophila

2018 ◽  
Vol 217 (12) ◽  
pp. 4106-4123 ◽  
Author(s):  
Haytham Mehsen ◽  
Vincent Boudreau ◽  
Damien Garrido ◽  
Mohammed Bourouh ◽  
Myreille Larouche ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Nuclear Envelope ◽  
Protein Phosphatase ◽  
Molecular Mechanisms ◽  
Mitotic Exit ◽  
Regulatory Subunit ◽  
Mechanistic Studies ◽  
Daughter Cells ◽  
Phosphatase 2A ◽  
Drosophila Cells

As a dividing cell exits mitosis and daughter cells enter interphase, many proteins must be dephosphorylated. The protein phosphatase 2A (PP2A) with its B55 regulatory subunit plays a crucial role in this transition, but the identity of its substrates and how their dephosphorylation promotes mitotic exit are largely unknown. We conducted a maternal-effect screen in Drosophila melanogaster to identify genes that function with PP2A-B55/Tws in the cell cycle. We found that eggs that receive reduced levels of Tws and of components of the nuclear envelope (NE) often fail development, concomitant with NE defects following meiosis and in syncytial mitoses. Our mechanistic studies using Drosophila cells indicate that PP2A-Tws promotes nuclear envelope reformation (NER) during mitotic exit by dephosphorylating BAF and suggests that PP2A-Tws targets additional NE components, including Lamin and Nup107. This work establishes Drosophila as a powerful model to further dissect the molecular mechanisms of NER and suggests additional roles of PP2A-Tws in the completion of meiosis and mitosis.

scholarly journals Cell-cycle transitions: a common role for stoichiometric inhibitors

2017 ◽  
Vol 28 (23) ◽  
pp. 3437-3446 ◽  
Author(s):  
Michael Hopkins ◽  
John J. Tyson ◽  
Béla Novák
Keyword(s):  
Cell Cycle ◽  
Regulatory Protein ◽  
Interaction Network ◽  
Mitotic Checkpoint ◽  
Cell Cycle Checkpoints ◽  
Specific Cell ◽  
Toggle Switch ◽  
Proliferating Cells ◽  
Daughter Cells ◽  
Transition Points

The cell division cycle is the process by which eukaryotic cells replicate their chromosomes and partition them to two daughter cells. To maintain the integrity of the genome, proliferating cells must be able to block progression through the division cycle at key transition points (called “checkpoints”) if there have been problems in the replication of the chromosomes or their biorientation on the mitotic spindle. These checkpoints are governed by protein-interaction networks, composed of phase-specific cell-cycle activators and inhibitors. Examples include Cdk1:Clb5 and its inhibitor Sic1 at the G1/S checkpoint in budding yeast, APC:Cdc20 and its inhibitor MCC at the mitotic checkpoint, and PP2A:B55 and its inhibitor, alpha-endosulfine, at the mitotic-exit checkpoint. Each of these inhibitors is a substrate as well as a stoichiometric inhibitor of the cell-cycle activator. Because the production of each inhibitor is promoted by a regulatory protein that is itself inhibited by the cell-cycle activator, their interaction network presents a regulatory motif characteristic of a “feedback-amplified domineering substrate” (FADS). We describe how the FADS motif responds to signals in the manner of a bistable toggle switch, and then we discuss how this toggle switch accounts for the abrupt and irreversible nature of three specific cell-cycle checkpoints.

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