scholarly journals Formation of mast cell granules in cell cycle mutants of an undifferentiated mastocytoma line: evidence for two different states of reversible proliferative quiescence.

1983 ◽  
Vol 96 (6) ◽  
pp. 1756-1760 ◽  
Author(s):  
A Zimmermann ◽  
J C Schaer ◽  
D E Muller ◽  
J Schneider ◽  
N M Miodonski-Maculewicz ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mast Cell ◽  
Mast Cells ◽  
The State ◽  
Nonpermissive Temperature ◽  
Wild Type ◽  
Differentiated Cells ◽  
Cycle Arrest ◽  
Intact Organism ◽  
Cold Sensitive

A heat-sensitive (hs, arrested at 39.5 degrees C, multiplying at 33 degrees C) and a cold-sensitive (cs, arrested at 33 degrees C, multiplying at 39.5 degrees C) cell cycle variant were isolated from an undifferentiated P-815 murine mastocytoma line. At the respective nonpermissive temperature, both the hs and the cs variant cells were reversibly arrested with a DNA content, typical of G1 phase. The cells of two cs variant subclones, when exposed to the nonpermissive temperature of 33 degrees C, formed metachromatically staining granules with an ultrastructure resembling that of mature mast cells. In addition, the cellular 5-hydroxytryptamine content underwent a marked increase, and the cells responded to compound 48/80 by degranulation as described for normal mast cells. On the other hand, in cells of two hs variant subclones, essentially no mast cell granules were detectable at either 33 or 39.5 degrees C. As previously reported, the cs cell cycle variant phenotype is expressed dominantly in heterokaryons obtained by fusing cs with wild-type cells, whereas hs cell cycle variant cells, similar to other hs mutants, were found to behave recessively under these conditions. Thus the state of proliferative quiescence induced in the cs cells at 33 degrees C is qualitatively different from the state of cell cycle arrest observed in hs cells at 39.5 degrees C and may represent a model for proliferative quiescence of differentiated cells in the intact organism.

scholarly journals The Anti-Tumor Activity of the NEDD8 Inhibitor Pevonedistat in Neuroblastoma

2021 ◽  
Vol 22 (12) ◽  
pp. 6565
Author(s):  
Jennifer H. Foster ◽  
Eveline Barbieri ◽  
Linna Zhang ◽  
Kathleen A. Scorsone ◽  
Myrthala Moreno-Smith ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Neuroblastoma Cell ◽  
Wild Type ◽  
Tumor Weight ◽  
Cycle Arrest ◽  
P53 Status ◽  
Neuroblastoma Cell Lines ◽  
Anti Tumor Activity

Pevonedistat is a neddylation inhibitor that blocks proteasomal degradation of cullin–RING ligase (CRL) proteins involved in the degradation of short-lived regulatory proteins, including those involved with cell-cycle regulation. We determined the sensitivity and mechanism of action of pevonedistat cytotoxicity in neuroblastoma. Pevonedistat cytotoxicity was assessed using cell viability assays and apoptosis. We examined mechanisms of action using flow cytometry, bromodeoxyuridine (BrDU) and immunoblots. Orthotopic mouse xenografts of human neuroblastoma were generated to assess in vivo anti-tumor activity. Neuroblastoma cell lines were very sensitive to pevonedistat (IC50 136–400 nM). The mechanism of pevonedistat cytotoxicity depended on p53 status. Neuroblastoma cells with mutant (p53MUT) or reduced levels of wild-type p53 (p53si-p53) underwent G2-M cell-cycle arrest with rereplication, whereas p53 wild-type (p53WT) cell lines underwent G0-G1 cell-cycle arrest and apoptosis. In orthotopic neuroblastoma models, pevonedistat decreased tumor weight independent of p53 status. Control mice had an average tumor weight of 1.6 mg + 0.8 mg versus 0.5 mg + 0.4 mg (p < 0.05) in mice treated with pevonedistat. The mechanism of action of pevonedistat in neuroblastoma cell lines in vitro appears p53 dependent. However, in vivo studies using mouse neuroblastoma orthotopic models showed a significant decrease in tumor weight following pevonedistat treatment independent of the p53 status. Novel chemotherapy agents, such as the NEDD8-activating enzyme (NAE) inhibitor pevonedistat, deserve further study in the treatment of neuroblastoma.

Sequential cold-sensitive mutations in Aspergillus fumigatus

1978 ◽  
Vol 24 (2) ◽  
pp. 84-88 ◽  
Author(s):  
Ole Nielsen ◽  
Kenneth F. Gregory
Keyword(s):  
Aspergillus Fumigatus ◽  
Type A ◽  
Maximum Growth ◽  
Cold Sensitivity ◽  
Nonpermissive Temperature ◽  
Wild Type ◽  
Cold Sensitive ◽  
Wild Type Parent ◽  
Thermotolerant Fungus

Mutants of the thermotolerant fungus Aspergillus fumigatus I-21 (ATCC 32722) unable to grow at 37 °C were sought. Cold-sensitive mutants were enriched from progeny spores of γ-irradiated conidia by two or more incubations at various nonpermissive temperatures alternating with filtrations through cheesecloth. The approximate minimum, optimum, and maximum growth temperatures of the parent were 12, 40, and 50 °C, respectively. Mutants unable to grow at 37 °C were not successfully isolated directly from the wild type. A mutant unable to grow at 25 °C was isolated and mutations further increasing the cold sensitivity by increments of 3–5 °C were found to occur. Mutants completely unable to grow at 37 °C were obtained by five sequential mutations. All mutants grew as fast as the wild-type parent at 45 °C and higher. Each mutant produced revenants able to grow not only at the nonpermissive temperature used for its isolation but also at lower temperatures.

YakA, a protein kinase required for the transition from growth to development in Dictyostelium

Development ◽  
1998 ◽  
Vol 125 (12) ◽  
pp. 2291-2302 ◽  
Author(s):  
G.M. Souza ◽  
S. Lu ◽  
A. Kuspa
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Basic Protein ◽  
Mrna Levels ◽  
Wild Type ◽  
E Coli ◽  
Cycle Arrest ◽  
Expression Of Genes ◽  
Extracellular Signal ◽  
Nutrient Rich Medium

When Dictyostelium cells starve they arrest their growth and induce the expression of genes necessary for development. We have identified and characterized a protein kinase, YakA, that is essential for the proper regulation of both events. Amino acid sequence and functional similarities indicate that YakA is a homolog of Yak1p, a growth-regulating protein kinase in S. cerevisiae. Purified YakA expressed in E. coli is able to phosphorylate myelin basic protein. YakA-null cells are smaller and their cell cycle is accelerated relative to wild-type cells. When starved, YakA-null cells fail to decrease the expression of the growth-stage gene cprD, and do not induce the expression of genes required for the earliest stages of development. YakA mRNA levels increase during exponential growth and reach a maximum at the point of starvation, consistent with a role in mediating starvation responses. YakA mRNA also accumulates when cells are grown in medium conditioned by cells grown to high density, suggesting that yakA expression is under the control of an extracellular signal that accumulates during growth. Expression of yakA from a conditional promoter causes cell-cycle arrest in nutrient-rich medium and promotes developmental events, such as the expression of genes required for cAMP signaling. YakA appears to regulate the transition from growth to development in Dictyostelium.

scholarly journals Effect of Piceatannol on Cell Cycle Progression in Prostate Cancer Cells (P05-005-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Larissa Kido ◽  
Eun-Ryeong Hahm ◽  
Valeria Cagnon ◽  
Mário Maróstica ◽  
Shivendra Singh
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Cell Cycle Distribution ◽  
Mutant P53 ◽  
Wild Type ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract Objectives Piceatannol (PIC) is a polyphenolic and resveratrol analog that is found in many vegetables consumed by humans. Like resveratrol, PIC has beneficial effects on health due to its anti-inflammatory, anti-oxidative and anti-proliferative features. However, the molecular targets of PIC in prostate cancer (PCa), which is the second most common cancer in men worldwide, are still poorly understood. Preventing cancer through dietary sources is a promising strategy to control diseases. Therefore, the aim of present study was to investigate the molecular mechanistic of actions of PIC in PCa cell lines with different genetic background common to human prostate cancer. Methods Human PCa cell lines (PC-3, 22Rv1, LNCaP, and VCaP) were treated with different doses of PIC (5–40 µM) and used for cell viability assay, measurement of total free fatty acids (FFA) and lactate, and cell cycle distribution. Results PIC treatment dose- and time-dependently reduced viability in PC-3 (androgen-independent, PTEN null, p53 null) and VCaP cells (androgen-responsive, wild-type PTEN, mutant p53). Because metabolic alterations, such as increased glucose and lipid metabolism are implicated in pathogenesis of in PCa, we tested if PIC could affect these pathways. Results from lactate and total free fatty acid assays in VCaP, 22Rv1 (castration-resistant, wild-type PTEN, mutant p53), and LNCaP (androgen-responsive, PTEN null, wild-type p53) revealed no effect of PIC on these metabolisms. However, PIC treatment delayed cell cycle progression in G0/G1 phase concomitant with the induction of apoptosis in both LNCaP and 22Rv1 cells, suggesting that growth inhibitory effect of PIC in PCa is associated with cell cycle arrest and apoptotic cell death at least LNCaP and 22Rv1 cells. Conclusions While PIC treatment does not alter lipid or glucose metabolism, cell cycle arrest and apoptosis induction are likely important in anti-cancer effects of PIC. Funding Sources São Paulo Research Foundation (2018/09793-7).

scholarly journals Co-expression of murine double minute 2 siRNA and wild-type p53 induces G1 cell cycle arrest in H1299 cells

2017 ◽  
Vol 16 (6) ◽  
pp. 9137-9142
Author(s):  
Long Liu ◽  
Ping Zhang ◽  
Hua Guo ◽  
Xinyu Tang ◽  
Lianqin Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Wild Type ◽  
Cycle Arrest ◽  
Double Minute ◽  
G1 Cell Cycle Arrest ◽  
Murine Double Minute ◽  
Wild Type P53

scholarly journals The Fanconi anemia complementation group C protein corrects DNA interstrand cross-link-specific apoptosis in HSC536N cells

Blood ◽  
1996 ◽  
Vol 88 (6) ◽  
pp. 2298-2305 ◽  
Author(s):  
UK Marathi ◽  
SR Howell ◽  
RA Ashmun ◽  
TP Brent
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Fanconi Anemia ◽  
Complementation Group ◽  
Cross Linking ◽  
Wild Type ◽  
Cross Link ◽  
Cycle Arrest ◽  
Protein Functions ◽  
Induced Apoptosis

Fanconi anemia (FA) cells are hypersensitive to cytotoxicity, cell cycle arrest, and chromosomal aberrations induced by DNA cross-linking agents, such as mitomycin C (MMC) and nitrogen mustard (HN2). Although MMC hypersensitivity is complemented in a subset of FA cells (complementation group C [FA-C]) by wild-type FAC cDNA, the cytoprotective mechanism is unknown. In the current study, we tested the hypothesis that FAC protein functions in the suppression of DNA interstand cross-link (ISC)-induced cell cycle arrest and apoptosis. Comparison of HN2-induced cell cycle arrest and apoptosis with those of its non-cross-linking analogs, diethylaminoethyl chloride and 2- dimethylaminoethyl chloride, delineated the DNA ISC specificity of FAC- mediated cytoprotection. Overexpression of wild-type FAC cDNA in FA-C lymphoblasts (HSC536N cell line) prevented HN2-induced growth inhibition, G2 arrest, and DNA fragmentation that is characteristic of apoptosis. In contrast cytoprotection was not conferred against the effects of the non-cross-linking mustards. Our data show that DNA ISCs induce apoptosis more potently than do DNA monoadducts and suggest that FAC suppresses specifically DNA ISC-induced apoptosis in the G2 phase of the cell cycle.

scholarly journals Pathogenic role of mast cells in experimental eosinophilic esophagitis

2013 ◽  
Vol 304 (12) ◽  
pp. G1087-G1094 ◽  
Author(s):  
Rituraj Niranjan ◽  
Parm Mavi ◽  
Madhavi Rayapudi ◽  
Scott Dynda ◽  
Anil Mishra
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Muscle Cell ◽  
Significant Role ◽  
Eosinophilic Esophagitis ◽  
Brdu Incorporation ◽  
Dependent Manner ◽  
Wild Type ◽  
Cell Hyperplasia ◽  
Cell Accumulation

Eosinophilic esophagitis (EoE) is a chronic allergic disease characterized by esophageal intraepithelial eosinophils, extracellular eosinophil granule deposition, induced mast cell accumulation, and epithelial cell hyperplasia. However, the processes involved in the development of a number of these characteristics are largely unknown. Herein, we tested the hypothesis whether induced mast cell accumulation in the esophagus has a role in promoting EoE pathogenesis. Accordingly, we induced experimental EoE in wild-type mice, mast cell-deficient WWv mice, and mast cell-reconstituted WWv mice. We report that esophageal mast cell numbers increase in parallel with eosinophils in a dose- and time-dependent manner following the induction of allergen-induced EoE. The induced mast cells are localized in the esophageal lamina propria and muscular mucosa but have no influence on promoting esophageal eosinophilia. The 5′-bromodeoxyuridine (BrdU) incorporation analysis indicated that mast cells have a significant role in muscle cell hyperplasia and hypertrophy. In addition, the wild-type and mast cell-reconstituted WWv mice showed a comparable number of BrdU+ cells in the esophageal muscular mucosa following allergen-induced EoE. In conclusion, we provide for the first time direct evidence that mast cell promotes muscle cell hyperplasia and hypertrophy and may have a significant role in promoting esophageal functional abnormalities in EoE.

Thrombopoietin Regulates Proliferation and Maturation of Murine Mast Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1707-1707
Author(s):  
Giovanni Migliaccio ◽  
Barbara Ghinassi ◽  
Lucia Centurione ◽  
Maria Zingariello ◽  
Lucia Bianchi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Cell Differentiation ◽  
Growth Factor ◽  
Mast Cells ◽  
Wild Type ◽  
Connective Tissues ◽  
Immature Cells

Abstract Megakaryocytopoiesis is regulated by extrinsic (interaction of the growth factor thrombopoietin, TPO with its receptor Mpl) and intrinsic (interaction between the trascription factors GATA-1 and Fog-1) factors. The observation that mice impaired for GATA-1 expression (i.e. harbouring the GATA-1low mutation) are defective not only in megakaryocyte maturation but also in mast cell differentiation (Migliaccio et al. J Exp Med197:281, 2003), led us to investigate whether TPO might control mast cell differentiation as well. We first observed that mice genetically unable to responde to TPO (Mplnull mice) express in the connective tissues 5 times more mast cells than their normal littermates. Then, we analysed the effects on mast cell differentiation of in vivo treatment with TPO. Normal mice, and their GATA-1low littermates, were injected i.p. with TPO (100 μg/kg/day per 5 days, kindly provided by Kirin Brewery, Japan) and the number of immature (Toluidinepos) and mature (AlcianBlue/Saphraninepos) mast cells present in the connective tissues of the animals, as well as the frequency of GATA-1pos and TUNELpos mast cells, was evaluated 14 days after treatment. In wild-type animals, TPO reduced the presence of GATA-1 in mast cells (by immuno-histochemistry) and increased the number of immature cells (from 320±28 to 852±60) and of those undergoing apoptosis (from 16±1 to 600±43). In contrast, in GATA-1low animals, TPO-treatment induced the expression of GATA-1 in mast cells while decreased the number of immature cells (from 1100±72 to 427±29) as well as that of apoptotic cells (from 600±45 to 60±2). The role of TPO on mast cell differentiation were further confirmed by the analysis of the effects exerted by the growth factor on in vitro differentiation of bone marrow derived mast cells (BMMC). In these experiments, wild type bone marrow and spleen cells were cultured for 21 days with SCF and IL-3 with or without TPO and BMMC differentiation measured on the basis of the number of cells expressing the phenotype c-kithigh/CD34high and FcεRIpos. In cultures stimulated with SCF and IL-3, all the cells expressed the phenotype c-kithigh/CD34high and FcεRIpos. In contrast, in cultures supplemented also with SCF, IL-3 and TPO, only 25% of the cells were c-kithigh/CD34high and none of them was FcεRIpos. These results establish a role for TPO in the control of mast cell differentiation (possibly by modulating the GATA-1 content of the cells) and unveil further similarities between the mechanism(s) controlling megakaryocyte and mast cell differentiation.

Effects of AMN107, a Novel Aminopyrimidine Tyrosine Kinase Inhibitor, on Human Mast Cells Bearing Wild-Type or Mutated Codon 816 c-kit.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3528-3528 ◽  
Author(s):  
Srdan Verstovsek ◽  
Cem Akin ◽  
Giles J. Francis ◽  
Manshouri Taghi ◽  
Ly Huynh ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cell Line ◽  
Cell Lines ◽  
Cellular Proliferation ◽  
Kinase Inhibitor ◽  
Wild Type ◽  
Kit Mutation

Abstract Background. Majority of adult patients with systemic mastocytosis (SM) have activating mutation in codon 816 of c-kit (CD117), a receptor on the surface of mast cells. This abnormality is responsible for the pathogenesis of the disease. Methods. We investigated the effects of a newly designed tyrosine kinase inhibitor, AMN107, by comparing its in vitro inhibitory potency on c-kit mutated mast cell lines and patient samples with that of imatinib mesylate, another tyrosine kinase inhibitor, effective in some patients with SM. Two cell lines, subclones of HMC-1 cells, were used: HMC-1560 carrying juxtamembrane domain mutation in codon 560 of c-kit, and HMC-1560, 816 carrying both codon 560 mutation and tyrosine kinase domain mutation in codon 816 of c-kit. Results. In HMC-1560 mast cell line carrying wild-type codon 816, AMN107 was as potent as imatinib in inhibiting cellular proliferation, with IC50 values of 108 and 74 nM respectively, while in HMC-1560, 816 cell line carrying 816 mutation, neither medication had an effect. AMN107 was also as effective as imatinib in inhibiting phosphorylation of c-kit tyrosine kinase in HMC-1560 cells. The inhibition of cellular proliferation was associated with induction of apoptosis in HMC-1560 cells. AMN107 in concentrations up to 1 uM had no effect on bone marrow mast cells carrying D816V c-kit mutation obtained from patients with mastocytosis. Conclusions. Our results suggest similar potency of AMN107 and imatinib in mast cells that carry wild-type codon 816, but no activity against codon 816 mutation carrying cells.

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