Search, capture and signal: games microtubules and centrosomes play

2001 ◽  
Vol 114 (2) ◽  
pp. 247-255 ◽  
Author(s):  
S.C. Schuyler ◽  
D. Pellman
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cytoplasmic Dynein ◽  
Cell Cycle Checkpoint ◽  
Cellular Polarity ◽  
Cycle Progression ◽  
Cycle Checkpoint ◽  
Dividing Cells ◽  
Actin Cables ◽  
Type V

Accurate distribution of the chromosomes in dividing cells requires coupling of cellular polarity cues with both the orientation of the mitotic spindle and cell cycle progression. Work in budding yeast has demonstrated that cytoplasmic dynein and the kinesin Kip3p define redundant pathways that ensure proper spindle orientation. Furthermore, it has been shown that the Kip3p pathway components Kar9p and Bim1p (Yeb1p) form a complex that provides a molecular link between cortical polarity cues and spindle microtubules. Recently, other studies indicated that the cortical localization of Kar9p depends upon actin cables and Myo2p, a type V myosin. In addition, a BUB2-dependent cell cycle checkpoint has been described that inhibits the mitotic exit network and cytokinesis until proper centrosome position is achieved. Combined, these studies provide molecular insight into how cells link cellular polarity, spindle position and cell cycle progression.

scholarly journals Kinetochore chemistry is sensitive to tension and may link mitotic forces to a cell cycle checkpoint.

1995 ◽  
Vol 130 (4) ◽  
pp. 929-939 ◽  
Author(s):  
R B Nicklas ◽  
S C Ward ◽  
G J Gorbsky
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cell Cycle Checkpoint ◽  
Cycle Progression ◽  
Anaphase Onset ◽  
Cycle Checkpoint ◽  
A Cell ◽  
Protein Dephosphorylation ◽  
Regulation Of Cell Cycle ◽  
Checkpoint Signal

Some cells have a quality control checkpoint that can detect a single misattached chromosome and delay the onset of anaphase, thus allowing time for error correction. The mechanical error in attachment must somehow be linked to the chemical regulation of cell cycle progression. The 3F3 antibody detects phosphorylated kinetochore proteins that might serve as the required link (Gorbsky, G. J., and W. A. Ricketts. 1993. J. Cell Biol. 122:1311-1321). We show by direct micromanipulation experiments that tension alters the phosphorylation of kinetochore proteins. Tension, whether from a micromanipulation needle or from normal mitotic forces, causes dephosphorylation of the kinetochore proteins recognized by 3F3. If tension is absent, either naturally or as a result of chromosome detachment by micromanipulation, the proteins are phosphorylated. Equally direct experiments identify tension as the checkpoint signal: tension from a microneedle on a misattached chromosome leads to anaphase (Li, X., and R. B. Nicklas. 1995. Nature (Lond.). 373:630-632), and we show here that the absence of tension caused by detaching chromosomes from the spindle delays anaphase indefinitely. Thus, the absence of tension is linked to both kinetochore phosphorylation and delayed anaphase onset. We propose that the kinetochore protein dephosphorylation caused by tension is the all clear signal to the checkpoint. The evidence is circumstantial but rich. In any event, tension alters kinetochore chemistry. Very likely, tension affects chemistry directly, by altering the conformation of a tension-sensitive protein, which leads directly to dephosphorylation.

scholarly journals Cell Cycle Changes after Glioblastoma Stem Cell Irradiation: The Major Role of RAD51

2018 ◽  
Vol 19 (10) ◽  
pp. 3018 ◽  
Author(s):  
Gaelle Tachon ◽  
Ulrich Cortes ◽  
Pierre-Olivier Guichet ◽  
Pierre Rivet ◽  
Anais Balbous ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Potential Effect ◽  
Cell Cycle Checkpoint ◽  
G2 Arrest ◽  
Cycle Progression ◽  
Checkpoint Response ◽  
Glioblastoma Stem Cell ◽  
Cycle Checkpoint ◽  
Radiation Induced

“Glioma Stem Cells” (GSCs) are known to play a role in glioblastoma (GBM) recurrence. Homologous recombination (HR) defects and cell cycle checkpoint abnormalities can contribute concurrently to the radioresistance of GSCs. DNA repair protein RAD51 homolog 1 (RAD51) is a crucial protein for HR and its inhibition has been shown to sensitize GSCs to irradiation. The aim of this study was to examine the consequences of ionizing radiation (IR) for cell cycle progression in GSCs. In addition, we intended to assess the potential effect of RAD51 inhibition on cell cycle progression. Five radiosensitive GSC lines and five GSC lines that were previously characterized as radioresistant were exposed to 4Gy IR, and cell cycle analysis was done by fluorescence-activated cell sorting (FACS) at 24, 48, 72, and 96 h with or without RAD51 inhibitor. Following 4Gy IR, all GSC lines presented a significant increase in G2 phase at 24 h, which was maintained over 72 h. In the presence of RAD51 inhibitor, radioresistant GSCs showed delayed G2 arrest post-irradiation for up to 48 h. This study demonstrates that all GSCs can promote G2 arrest in response to radiation-induced DNA damage. However, following RAD51 inhibition, the cell cycle checkpoint response differed. This study contributes to the characterization of the radioresistance mechanisms of GSCs, thereby supporting the rationale of targeting RAD51-dependent repair pathways in view of radiosensitizing GSCs.

scholarly journals Irradiation induces p53 loss of heterozygosity in breast cancer expressing mutant p53

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Amr Ghaleb ◽  
Alisha Yallowitz ◽  
Natalia Marchenko
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Tp53 Gene ◽  
P53 Mutation ◽  
Cell Cycle Checkpoint ◽  
Mutant P53 ◽  
Wild Type ◽  
Γ Irradiation ◽  
Cycle Progression ◽  
Cycle Checkpoint

AbstractMutations in one allele of the TP53 gene in cancer early stages are frequently followed by the loss of the remaining wild-type allele (LOH) during tumor progression. However, the clinical impact of TP53 mutations and p53LOH, especially in the context of genotoxic modalities, remains unclear. Using MMTV;ErbB2 model carrying a heterozygous R172H p53 mutation, we report a previously unidentified oncogenic activity of mutant p53 (mutp53): the exacerbation of p53LOH after irradiation. We show that wild-type p53 allele is partially transcriptionally competent and enables the maintenance of the genomic integrity under normal conditions in mutp53 heterozygous cells. In heterozygous cells γ-irradiation promotes mutp53 stabilization, which suppresses DNA repair and the cell cycle checkpoint allowing cell cycle progression in the presence of inefficiently repaired DNA, consequently increases genomic instability leading to p53LOH. Hence, in mutp53 heterozygous cells, irradiation facilitates the selective pressure for p53LOH that enhances cancer cell fitness and provides the genetic plasticity for acquiring metastatic properties.

scholarly journals Differential expression of a phosphoepitope at the kinetochores of moving chromosomes

1993 ◽  
Vol 122 (6) ◽  
pp. 1311-1321 ◽  
Author(s):  
GJ Gorbsky ◽  
WA Ricketts
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Metaphase Plate ◽  
Cell Cycle Checkpoint ◽  
Chromosome Movement ◽  
Cycle Progression ◽  
Single Chromosome ◽  
Sister Kinetochore ◽  
Cycle Checkpoint ◽  
A Cell

A phosphorylated epitope is differentially expressed at the kinetochores of chromosomes in mitotic cells and may be involved in regulating chromosome movement and cell cycle progression. During prophase and early prometaphase, the phosphoepitope is expressed equally among all the kinetochores. In mid-prometaphase, some chromosomes show strong labeling on both kinetochores; others exhibit weak or no labeling; while in other chromosomes, one kinetochore is intensely labeled while its sister kinetochore is unlabeled. Chromosomes moving toward the metaphase plate express the phosphoepitope strongly on the leading kinetochore but weakly on the trailing kinetochore. This is the first demonstration of a biochemical difference between the two kinetochores of a single chromosome. During metaphase and anaphase, the kinetochores are unlabeled. At metaphase, a single misaligned chromosome can inhibit further progression into anaphase. Misaligned chromosomes express the phosphoepitope strongly on both kinetochores, even when all the other chromosomes of a cell are assembled at the metaphase plate and lack expression. This phosphoepitope may be involved in regulating chromosome movement to the metaphase plate during prometaphase and may be part of a cell cycle checkpoint by which the onset of anaphase is inhibited until complete metaphase alignment is achieved.

scholarly journals Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 750
Author(s):  
Kiyohiro Ando ◽  
Akira Nakagawara
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Mitotic Catastrophe ◽  
Malignant Neoplasms ◽  
Checkpoint Kinases ◽  
Molecular Features ◽  
Cycle Checkpoint

Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

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 Ras controls growth, survival and differentiation in the Drosophila eye by different thresholds of MAP kinase activity

Development ◽  
2001 ◽  
Vol 128 (9) ◽  
pp. 1687-1696 ◽  
Author(s):  
K. Halfar ◽  
C. Rommel ◽  
H. Stocker ◽  
E. Hafen
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Photoreceptor Cells ◽  
Loss Of Function ◽  
Cellular Functions ◽  
Partial Loss ◽  
Cycle Progression ◽  
Mapk Activity ◽  
Dividing Cells

Ras mediates a plethora of cellular functions during development. In the developing eye of Drosophila, Ras performs three temporally separate functions. In dividing cells, it is required for growth but is not essential for cell cycle progression. In postmitotic cells, it promotes survival and subsequent differentiation of ommatidial cells. In the present paper, we have analyzed the different roles of Ras during eye development by using molecularly defined complete and partial loss-of-function mutations of Ras. We show that the three different functions of Ras are mediated by distinct thresholds of MAPK activity. Low MAPK activity prolongs cell survival and permits differentiation of R8 photoreceptor cells while high or persistent MAPK activity is sufficient to precociously induce R1-R7 photoreceptor differentiation in dividing cells.

Che-1/AATF, a multivalent adaptor connecting transcriptional regulation, checkpoint control, and apoptosisThis paper is one of a selection of papers published in this Special Issue, entitled 28th International West Coast Chromatin and Chromosome Conference, and has undergone the Journal's usual peer review process.

2007 ◽  
Vol 85 (4) ◽  
pp. 477-483 ◽  
Author(s):  
Claudio Passananti ◽  
Aristide Floridi ◽  
Maurizio Fanciulli
Keyword(s):  
Cell Cycle ◽  
Transcriptional Regulation ◽  
Rna Polymerase Ii ◽  
Cell Cycle Progression ◽  
Peer Review Process ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Control ◽  
Interacting Protein ◽  
Cycle Checkpoint ◽  
Viral Factor

Che-1/AATF (Che-1) was originally characterized as an interacting protein for RNA polymerase II. In addition to transcriptional regulation, the evidence suggests that Che-1 has a viral factor-like S phase promoting role in counteracting Rb repression to facilitate E2F-dependent transactivation during G1–S transition. Recently, Che-1 was found to play an important role in the DNA damage response and cell-cycle checkpoint control. Genetic studies in mice revealed that Che-1 is essential for preimplantation development and the establishment of embryonic gene expression. Importantly, several findings showed that Che-1 participates in inhibiting apoptotic process. Thus, Che-1 emerges as an important adaptor that connects transcriptional regulation, cell-cycle progression, checkpoint control, and apoptosis.

scholarly journals Dynamics of sister chromatid resolution during cell cycle progression

2018 ◽  
Author(s):  
Rugile Stanyte ◽  
Johannes Nuebler ◽  
Claudia Blaukopf ◽  
Rudolf Hoefler ◽  
Roman Stocsits ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Sister Chromatid ◽  
Cell Cycle Progression ◽  
Human Cells ◽  
Cycle Progression ◽  
Sister Chromatids ◽  
Dividing Cells ◽  
G2 Phase ◽  
Almost All

Faithful genome transmission in dividing cells requires that the two copies of each chromosome’s DNA package into separate, but physically linked, sister chromatids. The linkage between sister chromatids is mediated by cohesin, yet where sister chromatids are linked and how they resolve during cell cycle progression has remained unclear. Here, we investigated sister chromatid organization in live human cells using dCas9-mEGFP labelling of endogenous genomic loci. We detected substantial sister locus separation during G2 phase, irrespective of the proximity to cohesin enrichment sites. Almost all sister loci separated within a few hours after their respective replication, and then rapidly equilibrated their average distances within dynamic chromatin polymers. Our findings explain why the topology of sister chromatid resolution in G2 largely reflects the DNA replication program. Further, these data suggest that cohesin enrichment sites are not persistent cohesive sites in human cells. Rather, cohesion might occur at variable genomic positions within the cell population.

Abstract 1: Sprr2b Drives Proliferation of Cardiac Fibroblasts by Relieving p53-mediated Cell Cycle Inhibition

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Ryan M Burke ◽  
Janet K Lighthouse ◽  
Pearl J Quijada ◽  
Ronald Dirkx ◽  
Michael A Trembley ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cardiac Remodeling ◽  
Cell Cycle Progression ◽  
Cardiac Fibrosis ◽  
Cardiac Tissue ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Primary Source ◽  
Cell Cycle Checkpoint ◽  
Cycle Progression

Pathological cardiac remodeling is initially a compensatory attempt to increase cardiac output, but ultimately leads to the development of fibrosis, a form of scarring that contributes to heart failure (HF). In contrast, physiological cardiac remodeling in response to exercise is not associated with the development of fibrosis and typically remains compensatory. Understanding how cardiac fibroblasts (CF), the primary source of extracellular matrix in the heart, respond to pathological and physiological cues might lead to novel approaches to limit the maladaptive effects of pathological cardiac remodeling. We performed RNA sequencing to define genes that are differentially regulated in CF during physiological (swimming) or pathological (pressure overload) remodeling. This study revealed that cardiac expression of the s mall pr oline r ich 2b ( Sprr2b) gene is restricted to CFs and is significantly elevated in disease and lost in exercise. We demonstrate that SPRR2B drives CF proliferation, but not myofibroblast differentiation, in response to pathological cues. SPRR2B facilitates an interaction between MDM2 and USP7, a nuclear deubiquitinase that leads to proteasomal degradation of p53. SPRR2B-USP7-MDM2 complex formation and p53 degradation is at least partially dependent upon phosphorylation of SPRR2B by Src-family NRTKs. SPRR2B thus relieves p53-mediated constraints on cell cycle progression in response to Src-dependent signaling, leading to CF accumulation. Importantly, SPRR2B expression is elevated in cardiac tissue from human HF patients relative to individuals without heart disease and positively correlates with a proliferative, activated gene expression profile in HF patient CF. Treatment of human HF fibroblasts with IGF-1/H 2 O 2 to mimic physiological cues significantly abrogated SPRR2B expression and increased expression of p53-dependent cell cycle checkpoint genes, which correlated with a less activated phenotype. Taken together, this study defines a unique tissue-specific role of Sprr2b in driving pathological CF cell cycle progression that may underlie the development of cardiac fibrosis.

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