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1.
Cell Mol Life Sci ; 77(2): 231-242, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31420702

RESUMO

Regulation of cell division is orchestrated by cyclins, which bind and activate their catalytic workmates, the cyclin-dependent kinases (CDKs). Cyclins have been traditionally defined by an oscillating (cyclic) pattern of expression and by the presence of a characteristic "cyclin box" that determines binding to the CDKs. Noteworthy, the Human Genome Sequence Project unveiled the existence of several other proteins containing the "cyclin box" domain. These potential "cyclins" have been named new, orphan or atypical, creating a conundrum in cyclins nomenclature. Moreover, although many years have passed after their discovery, the scarcity of information regarding these possible members of the family has hampered the establishment of criteria for systematization. Here, we discuss the criteria that define cyclins and we propose a classification and nomenclature update based on structural features, interactors, and phylogenetic information. The application of these criteria allows to systematically define, for the first time, the subfamily of atypical cyclins and enables the use of a common nomenclature for this extended family.


Assuntos
Ciclinas/genética , Animais , Divisão Celular/genética , Quinases Ciclina-Dependentes/genética , Genoma Humano/genética , Humanos , Filogenia
2.
World Neurosurg ; 133: e165-e172, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31476465

RESUMO

BACKGROUND: Cartilaginous endplate (CEP), a thin layer of hyaline cartilage located between the vertebral endplate and nucleus pulposus, transports the nutrient into the disc. The objective of this study was to evaluate the influence of T140 (polyphemusin II-derived peptide) on the CEP cell growth, apoptosis, and the matrix formation via the stromal cell-derived factor-1 (SDF-1)/cysteine X cysteine (CXC) receptor-4 (CXCR4) signaling pathway. METHODS: Sprague-Dawley rats were euthanized by cervical dislocation and dissected for the isolation and the appraisal of CEP cells that were extracted from the endplate in rat intervertebral discs and were then added with different concentrations of reagents (SDF-1 and T140). The effect of T140 on CEP cell proliferation and apoptosis were analyzed. The messenger RNA (mRNA) and protein expressions of CXCR4, prominin-1, proteoglycans, type II collagen, B-cell lymphoma-2 (Bcl-2), and Bcl-2 associated X protein were analyzed by reverse transcription quantitative polymerase chain reaction and Western blot analysis. RESULTS: T140 promoted the proliferation of CEP cells and inhibited the apoptosis of CEP cells. Additionally, T140 suppressed the mRNA and protein expression of CXCR4, prominin-1, and Bcl-2 associated X protein, and increased the mRNA and protein expression of proteoglycans, type II collagen, and Bcl-2. CONCLUSIONS: T140 promotes the proliferation and matrix formation and inhibits the apoptosis of CEP cells by blocking the SDF-1/CXCR4 signaling pathway in vitro, which provides a certain therapeutic effect on the degeneration of intervertebral discs.


Assuntos
Apoptose/efeitos dos fármacos , Quimiocina CXCL12/fisiologia , Condrócitos/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Cartilagem Hialina/citologia , Disco Intervertebral/citologia , Oligopeptídeos/farmacologia , Receptores CXCR4/fisiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Divisão Celular/efeitos dos fármacos , Proteínas da Matriz Extracelular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Disco Intervertebral/efeitos dos fármacos , Masculino , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley
3.
Science ; 366(6471): 1315-1316, 2019 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-31831659
4.
Exp Hematol ; 80: 16-20, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31874780

RESUMO

Serum albumin has long been an essential supplement for ex vivo hematopoietic and immune cell cultures. However, serum albumin medium supplements represent a major source of biological contamination in cell cultures and often cause loss of cellular function. As serum albumin exhibits significant batch-to-batch variability, it has also been blamed for causing major issues in experimental reproducibility. We recently discovered the synthetic polymer polyvinyl alcohol (PVA) as an inexpensive, Good Manufacturing Practice-compatible, and biologically inert serum albumin replacement for ex vivo hematopoietic stem cell cultures. Importantly, PVA is free of the biological contaminants that have plagued serum albumin-based media. Here, we describe that PVA can replace serum albumin in a range of blood and immune cell cultures including cell lines, primary leukemia samples, and human T lymphocytes. PVA can even replace human serum in the generation and expansion of functional chimeric antigen receptor (CAR) T cells, offering a potentially safer and more cost-efficient approach for this clinical cell therapy. In summary, PVA represents a chemically defined, biologically inert, and inexpensive alternative to serum albumin for a range of cell cultures in hematology and immunology.


Assuntos
Imunoterapia Adotiva/métodos , Álcool de Polivinil/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Técnicas de Cultura de Células , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Citotoxicidade Imunológica , Humanos , Células K562 , Leucemia Mieloide Aguda/patologia , Camundongos , Receptores de Antígenos Quiméricos , Albumina Sérica , Linfócitos T/citologia , Linfócitos T/metabolismo , Células Tumorais Cultivadas
5.
Phys Rev Lett ; 123(18): 188101, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31763902

RESUMO

The cell cortex, a thin film of active material assembled below the cell membrane, plays a key role in cellular symmetry-breaking processes such as cell polarity establishment and cell division. Here, we present a minimal model of the self-organization of the cell cortex that is based on a hydrodynamic theory of curved active surfaces. Active stresses on this surface are regulated by a diffusing molecular species. We show that coupling of the active surface to a passive bulk fluid enables spontaneous polarization and the formation of a contractile ring on the surface via mechanochemical instabilities. We discuss the role of external fields in guiding such pattern formation. Our work reveals that key features of cellular symmetry breaking and cell division can emerge in a minimal model via general dynamic instabilities.


Assuntos
Forma Celular/fisiologia , Estruturas Celulares/citologia , Modelos Biológicos , Fenômenos Biomecânicos , Divisão Celular/fisiologia , Polaridade Celular/fisiologia , Viscosidade
6.
Life Sci ; 239: 117008, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31669240

RESUMO

OBJECTIVE: We aimed to explore the expression level and biological function of miR-145-5p in preeclampsia (PE). METHODS: The differentially expressed miRNA/mRNA between normal placentas and PE placentas were screened using the GSE84260 and GSE73374 datasets from the Gene Expression Omnibus Database. The expression of miR-145-5p in PE placentas was detected by qRT-PCR. The CCK-8 assay, wound healing and transwell were carried out to determine the cell growth, migration and invasion when miR-145-5p was overexpressed or inhibited. The real-time quantitative PCR (qRT-PCR), Western Blot and dual-luciferase reporter assays were conducted to preliminarily explore possible mechanisms. RESULTS: A total of 33 miRNAs were found significantly differentially expressed in PE patients, 19 were significantly upregulated and 14 were significantly downregulated. The relative miR-145-5p expression was lower in PE placentas than normal placentas. The viability and invasion were suppressed when miR-145-5p was inhibited in trophoblasts cells, while miR-145-5p overexpression promoted the effectiveness. In addition, mRNA and protein expression of FLT1 in HTR-8/SVneo cell was also downregulated with miR-145-5p overexpression, suggesting that FLT1 is the target gene of miR-145-5p. Consistent with miR-145-5p overexpression, the mRNA and protein expression of FLT1 also were upregulated with miR-145-5p interference. Furthermore, the expression of miR-145-5p was regulated by the Hypoxic conditions. CONCLUSIONS: In conclusion, the results showed miR-145-5p may participate in PE development by affecting the proliferation and invasion of trophoblast cells. This is a new perspective to understand the etiology and pathogenesis of PE, which may provide a new breakthrough for the early prediction and diagnosis of PE.


Assuntos
MicroRNAs/genética , Trofoblastos , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Adulto , Divisão Celular , Hipóxia Celular , Movimento Celular , Células Cultivadas , Bases de Dados Genéticas , Feminino , Redes Reguladoras de Genes , Marcação de Genes , Humanos , Placenta/metabolismo , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Gravidez
8.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(4): 546-550, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31642233

RESUMO

OBJECTIVE: To investigate the expression of stearoyl-CoA desaturase-1 (SCD1) in breast cancer cell lines. To analyze the effect of inhibiting SCD1 activity on the proliferation and cell cycle of MCF-7 breast cancer cell and its mechanism. METHODS: The expression of SCD1 protein were detected by Western blot techniques in breast cancer cell lines and humanskin fibroblasts.Cell viability of MCF-7 cells treated with MF-438 was measured using MTS assay and IC50 value was calculated.The distribution of cell cycle was determined by PI staining using flow cytometry.The expression of Cyclin D1 was detected by Western blot. The expression of Akt, pAkt, pAMPK and pACC were also detected by Western blot. RESULTS: The expression level of SCD1 in MCF-7 and MDA-MB-231 cells was significantly higher than that in HSF cells (P < 0.05).MF-438 showed a significant dose-dependent proliferation inhibition effect on MCF-7 cells cultured in low serum at a concentration ranging from 100 nmol/L to 100 µmol/L with an IC50 value of (3.9±0.45) µmol/L. After intervention of 5 µmol/L MF-438 in MCF-7 cells, the proportion of cells in S phase and G2/M phase was significantly decreased (P < 0.01), the proportion of cells in G0/G1 phase increased (P < 0.01), and the expression of Cyclin D1 was significantly decreased (P < 0.05); Meanwhile, the expression of pAkt and pAkt/Akt value were significantly decreased (P < 0.05) and the expression of pAMPK and pACC levels were significantly increased (P < 0.05). CONCLUSIONS: SCD1 plays an important role in the occurrence and development of breast cancer. Inhibition of SCD1 activity can inhibit cell cycle progression and impair cell proliferation by down-regulating the Akt pathway and activating the AMPK pathway. Further research on SCD1 is expected to provide a new target for molecular targeted therapy of breast cancer.


Assuntos
Neoplasias da Mama/patologia , Ciclo Celular , Proliferação de Células , Estearoil-CoA Dessaturase/genética , Divisão Celular , Ciclina D1/metabolismo , Humanos , Células MCF-7 , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estearoil-CoA Dessaturase/antagonistas & inibidores
9.
Ann Hematol ; 98(11): 2569-2578, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31628518

RESUMO

Treatment results for multiple myeloma and plasma cell leukemia have considerably improved, but cure remains elusive and establishing new therapeutic approaches constitutes a major unmet clinical need. We analyzed the anti-myeloma properties of the aza-anthracenedione pixantrone which has been successfully used in a phase III study for the treatment of patients with aggressive non-Hodgkin's lymphoma as monotherapy as well as in combination regimes in vitro and in an adapted in vivo model (ex ovo chicken chorioallantoic membrane (CAM) assay). Pixantrone significantly inhibited proliferation and metabolic activity of all investigated myeloma cell lines. Importantly, anti-myeloma effects were more pronounced in tumor cell lines than in stromal cells, mesenchymal stem cells, and peripheral blood mononuclear cells of healthy controls. Apoptosis of myeloma cell lines was observed only after a 7-day incubation period, indicating a fast cytostatic and a slower cytotoxic effect of this drug. Pixantrone reduced the viability of primary plasma cells of patients and induced downregulation of myeloma-cell growth in the CAM assay. Additionally, we demonstrate in vitro synergism between pixantrone and the histone deacetylase inhibitor panobinostat with respect to its anti-proliferative features. From these data, we conclude that systematic investigations of the clinical usefulness of pixantrone in the framework of controlled clinical trials are clearly indicated (e.g., in penta-refractory patients).


Assuntos
Antineoplásicos/uso terapêutico , Isoquinolinas/uso terapêutico , Leucemia Plasmocitária/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Embrião de Galinha , Membrana Corioalantoide/efeitos dos fármacos , Ensaios Clínicos como Assunto , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Panobinostat/farmacologia , Estudos Retrospectivos
10.
BMC Bioinformatics ; 20(1): 536, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664894

RESUMO

BACKGROUND: Analysis of high-throughput multi-'omics interactions across the hierarchy of expression has wide interest in making inferences with regard to biological function and biomarker discovery. Expression levels across different scales are determined by robust synthesis, regulation and degradation processes, and hence transcript (mRNA) measurements made by microarray/RNA-Seq only show modest correlation with corresponding protein levels. RESULTS: In this work we are interested in quantitative modelling of correlation across such gene products. Building on recent work, we develop computational models spanning transcript, translation and protein levels at different stages of the H. sapiens cell cycle. We enhance this analysis by incorporating 25+ sequence-derived features which are likely determinants of cellular protein concentration and quantitatively select for relevant features, producing a vast dataset with thousands of genes. We reveal insights into the complex interplay between expression levels across time, using machine learning methods to highlight outliers with respect to such models as proteins associated with post-translationally regulated modes of action. CONCLUSIONS: We uncover quantitative separation between modified and degraded proteins that have roles in cell cycle regulation, chromatin remodelling and protein catabolism according to Gene Ontology; and highlight the opportunities for providing biological insights in future model systems.


Assuntos
Divisão Celular , Perfilação da Expressão Gênica/métodos , Genômica , Humanos , Biossíntese de Proteínas , Proteínas/genética , Controle Social Formal
11.
Results Probl Cell Differ ; 68: 127-154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31598855

RESUMO

Cells are arranged into species-specific patterns during early embryogenesis. Such cell division patterns are important since they often reflect the distribution of localized cortical factors from eggs/fertilized eggs to specific cells as well as the emergence of organismal form. However, it has proven difficult to reveal the mechanisms that underlie the emergence of cell positioning patterns that underlie embryonic shape, likely because a systems-level approach is required that integrates cell biological, genetic, developmental, and mechanical parameters. The choice of organism to address such questions is also important. Because ascidians display the most extreme form of invariant cleavage pattern among the metazoans, we have been analyzing the cell biological mechanisms that underpin three aspects of cell division (unequal cell division (UCD), oriented cell division (OCD), and asynchronous cell cycles) which affect the overall shape of the blastula-stage ascidian embryo composed of 64 cells. In ascidians, UCD creates two small cells at the 16-cell stage that in turn undergo two further successive rounds of UCD. Starting at the 16-cell stage, the cell cycle becomes asynchronous, whereby the vegetal half divides before the animal half, thus creating 24-, 32-, 44-, and then 64-cell stages. Perturbing either UCD or the alternate cell division rhythm perturbs cell position. We propose that dynamic cell shape changes propagate throughout the embryo via cell-cell contacts to create the ascidian-specific invariant cleavage pattern.


Assuntos
Padronização Corporal , Divisão Celular , Embrião não Mamífero/citologia , Embrião não Mamífero/embriologia , Urocordados/citologia , Urocordados/embriologia , Animais , Fertilização
12.
Results Probl Cell Differ ; 68: 217-230, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31598858

RESUMO

Creophilus maxillosus (Staphylinidae, Coleoptera, Polyphaga) has a meroistic-telotrophic ovary composed of tropharium, which contains trophocytes (nurse cells) and vitellarium, which contains growing oocytes. The trophocytes are connected to the oocytes by cytoplasmic nutritive cords, which deliver nutrients to the oocytes. The formation/differentiation of the oocytes and trophocytes takes place in the pupal ovary within linear chains of sibling cells. Each chain is composed of a single oocyte connected to a linear chain of sister trophocytes. The nuclei of the oocytes contain an extrachromosomal DNA body (extra DNA body) consisting of amplified ribosomal DNA (rDNA). During oogenesis, the prospective oocyte, located at the base (posterior) of each chain, is the only cell within the chain that amplifies rDNA and retains permanent contact with the somatic pre-follicular cells. The oogonial divisions leading to the formation of the oocyte/trophocytes chain are asymmetric, and during consecutive divisions, the rDNA body always segregates basally (posteriorly) to the prospective oocyte abutted on the somatic cells. However, the segregation of rDNA is imperfect, and within each oocyte/trophocytes chain, there is a gradient of rDNA: the prospective oocyte has the highest amount of rDNA and the trophocyte that is most distant (most anterior) from the oocyte has no or the lowest amount of rDNA. In addition, the divisions within each chain are parasynchronous, with the pro-oocyte being the most mitotically advanced cell in the chain. These observations indicate the presence of a signaling gradient emanating from the somatic cells and/or oocyte; this gradient diminishes in strength with the increasing distance from its source, i.e., the oocyte/somatic cells. Because of this phenomenon, C. maxillosus is the perfect model in which to study the germ-somatic cell interactions and signaling. This chapter describes the methods for the collection and laboratory culture of C. maxillosus and the analysis of divisions and signaling in the C. maxillosus ovary.


Assuntos
Diferenciação Celular , Divisão Celular , Besouros/citologia , Modelos Animais , Oócitos/citologia , Transdução de Sinais , Animais , Feminino , Ovário/citologia
13.
Gen Physiol Biophys ; 38(6): 473-484, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31588915

RESUMO

Isorhamnetin is a 3'-O-methylated metabolite of quercetin that is found predominantly in a variety of medicinal plants. Although many previous studies have reported that this flavonol has diverse health-promoting effects, evidence for the underlying molecular mechanism of anti-cancer efficacy is still lacking. In this study, it was examined the anti-proliferative effect of isorhamnetin on human hepatocarcinoma Hep3B cells, and found that isorhamnetin induced cell cycle arrest at G2/M phase and apoptosis. Isorhamnetin-induced G2/M arrest was associated with decreased expression of proliferating cell nuclear antigen as well as cyclin A and cyclin B1. However, isorhamnetin increased expression of p21WAF1/CIP1, a cyclin-dependent kinase (Cdk) inhibitor, and increased p21 complexed with Cdk2 and Cdc2. In addition, Isorhamnetin-induced apoptosis was associated with increased expression of Fas/Fas ligand, reduced ratio of Bcl-2/Bax expression, truncation of Bid, cytosolic release of cytochrome c, and activation of caspase-8, -9 and -3. Isorhamnetin also enhanced intracellular levels of reactive oxygen species (ROS), while the addition of N-acetyl cysteine (NAC), a ROS inhibitor, significantly diminished isorhamnetin-induced mitochondrial dysfunction. Furthermore, the interruption of ROS generation using NAC significantly attenuated isorhamnetin-mediated G2/M arrest and apoptosis. Collectively, this is the first report to show that isorhamnetin inhibited the proliferation of human hepatocarcinoma cells by ROS-dependent arrest of the cell cycle at the G2/M phase and induction of apoptosis.


Assuntos
Apoptose , Neoplasias Hepáticas , Divisão Celular , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Quercetina/análogos & derivados , Espécies Reativas de Oxigênio
14.
Rinsho Ketsueki ; 60(9): 1027-1032, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597824

RESUMO

Cellular senescence is a state of durable cell cycle arrest after a defined number of cell divisions. The number of population doublings of normal cells in culture depends on the species but not on the types of cells used to establish the culture, showing a positive correlation with the life span of the animals. Therefore, the results suggest a physiological link between a limited proliferative capacity in cell culture and the processes observed in organismal aging. The pivotal role of senescence in organismal aging and the onset of age-related disorders, such as atherosclerosis, type II diabetes, and Alzheimer's disease, is supported by the observation that the clearance of p16-positive senescent cells delays various age-associated disorders and extends healthy lifespan. In this review, I provide an overview of recent advances in understanding the mechanisms underlying the induction of senescence and maintenance of the specific phenotypes, such as senescence associated secretory phenotypes (SASP).


Assuntos
Envelhecimento , Senescência Celular , Doença de Alzheimer , Animais , Aterosclerose , Divisão Celular , Diabetes Mellitus Tipo 2 , Humanos , Fenótipo
15.
mBio ; 10(5)2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31662459

RESUMO

Bacillus subtilis cells can mount a number of responses to nutritional deprivation but ultimately either form dormant spores or enter a metabolically quiescent state. In a recent article (mBio 10:e01414-19, https://doi.org/10.1128/mBio.01414-19, 2019), R. Hashuel and S. Ben-Yehuda report on a novel means by which nutrient-starved B. subtilis cells escape from aging (days-old) colonies by accumulating mutations enabling them to continue growth under nutrient-limited conditions. They postulate that such a strategy may be a major factor determining the dynamics of bacterial populations in natural environments.


Assuntos
Bacillus subtilis , Proteínas de Bactérias/genética , Divisão Celular , Mutação
16.
Nat Commun ; 10(1): 4200, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519880

RESUMO

The vimentin network displays remarkable plasticity to support basic cellular functions and reorganizes during cell division. Here, we show that in several cell types vimentin filaments redistribute to the cell cortex during mitosis, forming a robust framework interwoven with cortical actin and affecting its organization. Importantly, the intrinsically disordered tail domain of vimentin is essential for this redistribution, which allows normal mitotic progression. A tailless vimentin mutant forms curly bundles, which remain entangled with dividing chromosomes leading to mitotic catastrophes or asymmetric partitions. Serial deletions of vimentin tail domain gradually impair cortical association and mitosis progression. Disruption of f-actin, but not of microtubules, causes vimentin bundling near the chromosomes. Pathophysiological stimuli, including HIV-protease and lipoxidation, induce similar alterations. Interestingly, full filament formation is dispensable for cortical association, which also occurs in vimentin particles. These results unveil implications of vimentin dynamics in cell division through its interplay with the actin cortex.


Assuntos
Actinas/metabolismo , Vimentina/metabolismo , Western Blotting , Divisão Celular/fisiologia , Linhagem Celular Tumoral , Humanos , Filamentos Intermediários/metabolismo , Microscopia de Fluorescência , Mitose/fisiologia
17.
BMC Bioinformatics ; 20(1): 470, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31521111

RESUMO

BACKGROUND: Neurogenesis in the murine cerebral cortex involves the coordinated divisions of two main types of progenitor cells, whose numbers, division modes and cell cycle durations set up the final neuronal output. To understand the respective roles of these factors in the neurogenesis process, we combine experimental in vivo studies with mathematical modeling and numerical simulations of the dynamics of neural progenitor cells. A special focus is put on the population of intermediate progenitors (IPs), a transit amplifying progenitor type critically involved in the size of the final neuron pool. RESULTS: A multiscale formalism describing IP dynamics allows one to track the progression of cells along the subsequent phases of the cell cycle, as well as the temporal evolution of the different cell numbers. Our model takes into account the dividing apical progenitors (AP) engaged into neurogenesis, both neurogenic and proliferative IPs, and the newborn neurons. The transfer rates from one population to another are subject to the mode of division (proliferative, or neurogenic) and may be time-varying. The model outputs are successfully fitted to experimental cell numbers from mouse embryos at different stages of cortical development, taking into account IPs and neurons, in order to adjust the numerical parameters. We provide additional information on cell kinetics, such as the mitotic and S phase indexes, and neurogenic fraction. CONCLUSIONS: Applying the model to a mouse mutant for Ftm/Rpgrip1l, a gene involved in human ciliopathies with severe brain abnormalities, reveals a shortening of the neurogenic period associated with an increased influx of newborn IPs from apical progenitors at mid-neurogenesis. Our model can be used to study other mouse mutants with cortical neurogenesis defects and can be adapted to study the importance of progenitor dynamics in cortical evolution and human diseases.


Assuntos
Córtex Cerebral/crescimento & desenvolvimento , Modelos Biológicos , Neurogênese , Animais , Ciclo Celular , Divisão Celular , Córtex Cerebral/fisiopatologia , Proteínas do Citoesqueleto , Modelos Animais de Doenças , Humanos , Camundongos , Mutação , Células-Tronco Neurais/fisiologia , Neurônios/fisiologia , Proteínas/genética
18.
Int J Mycobacteriol ; 8(3): 281-286, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31512605

RESUMO

Background: Bacterial cytokinesis is orchestrated by a complex of dozen of proteins called 'divisome' at the mid-cell site. FtsZ, the eukaryotic tubulin homolog, localizes to the mid-cell site where it polymerizes and forms a cytokinetic Z-ring. The Z-ring acts as a docking platform for other proteins to localize. In model organisms, Escherichia coli and Bacillus subtilis, FtsZ is known to interact with several proteins. The role of few of these interactions is known, while of others is yet to be studied. In Mycobacterium tuberculosis, the cell division and its regulation are poorly studied. Although, most of the divisome proteins are conserved in M. tuberculosis, surprisingly the homologues of the protein factors required for membrane association of Z-ring and its stabilization are absent. In E. coli FtsE and FtsX, the constituent ATPase and membrane domains of the ABC transporter complex, localize to the Z-ring immediately after Z-ring stabilizing proteins, ZipA and FtsA. Therefore, investigation of the interaction between MtFtsX and MtFtsZ is demanding. Methods: Bacterial two-hybrid system was used to identify the interaction between MtFtsE and MtFtsZ. This interaction was further confirmed by biochemical methods of Ni2+-NTA agarose pull-down and coimmunoprecipitation. Results and Conclusion: Here, we demonstrated that MtFtsX interacts with MtFtsZ in vivo and ex-vivo. Further, we showed that self-interacting MtFtsX interacts with MtFtsE. However, we did not find any interaction between MtFtsE and MtFtsZ. These results suggest that the membrane domain MtFtsX of the ABC transporter complex 'MtFtsEX' might be the membrane-tethering and stabilizing factor for Z-ring in M. tuberculosis.


Assuntos
Proteínas de Bactérias/metabolismo , Proteínas de Ciclo Celular/metabolismo , Divisão Celular , Proteínas do Citoesqueleto/metabolismo , Mycobacterium tuberculosis/genética , Proteínas de Bactérias/genética , Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/genética , Mycobacterium tuberculosis/metabolismo , Ligação Proteica , Técnicas do Sistema de Duplo-Híbrido
19.
Endocrinology ; 160(11): 2573-2586, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504408

RESUMO

Ciliated bronchial epithelium 1 (CBE1) is a microtubule-associated protein localized to the manchette and developing flagellum during spermiogenesis and is associated with sperm maturation arrest in humans. It was hypothesized that CBE1 functions in microtubule-mediated transport mechanisms and sperm tail formation. To test this hypothesis, we analyzed Cbe1 expression and localization during spermiogenesis, and in mouse inner medullary collecting duct-3 (IMCD3) cells as a model of ciliogenesis. Furthermore, we generated and analyzed the fertility of a Cbe1 mutant mouse line. Mice containing a homozygous deletion in the long forms of Cbe1 were born at a lower frequency than predicted by Mendelian inheritance; however, adult male mice were fertile. An in-depth analysis of the Cbe1 gene revealed alternative transcript variants, which were not affected by the exon 2 mutation. To assess whether short variants compensate for the loss of long variants, exons 2 and 4 (which affect all variants) were individually mutated in IMCD3 cells and the effects on cell proliferation and ciliogenesis were analyzed. In wild-type IMCD3 cells, both variants were upregulated during cilia assembly. CBE1 protein was not a structural component of cilia; rather, CBE1 localized to the mitochondria and the contractile ring of dividing IMCD3 cells. Although IMCD3 cells carrying the mutation in long variants showed no phenotypic alterations, the mutation in exon 4 resulted in a significantly decreased proliferation rate. This study reveals that long isoforms of CBE1 are not essential for male fertility. Data, however, suggest that CBE1 is associated with intramanchette transport and midpiece formation of the sperm tail.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Espermátides/metabolismo , Espermatogênese , Animais , Divisão Celular , Linhagem Celular , Proteínas do Citoesqueleto/genética , Fertilidade , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Isoformas de Proteínas/metabolismo
20.
Environ Pollut ; 255(Pt 2): 113228, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31563769

RESUMO

Tamoxifen has been applied widely in the treatment of estrogen receptor (ER)-positive breast cancer. The impact of low concentrations of 17ß-estradiol (E2) (a pervasive environmental pollutant) on its effectiveness was studied in vitro using an MCF-7 cell line. Cell proliferation, migration, invasion, and apoptosis were studied along with cell cycle progression, reactive oxygen species generation and mitochondrial membrane potentials repression. The signaling pathways involved were identified. Typical concentrations of E2 in the environment (10-10 to 10-8 M) were observed to promote cell growth and protect MCF-7 cells from tamoxifen's cytotoxicity. Cell migration, invasion, cell cycle progression and apoptosis all involved in reducing tamoxifen's cytotoxicity. E2 at environmental concentrations induced PI3K/Akt and MAPK/ERK signal transduction through the estrogen receptor pathways to affect cell proliferation. Taken together, the results explain how E2 in the environment may attenuate the efficacy of tamoxifen in ER-positive breast cancer therapy. They provide considerable support for E2's adverse effects on human health and cancer management.


Assuntos
Neoplasias da Mama/metabolismo , Estradiol/toxicidade , Tamoxifeno/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Fosfatidilinositol 3-Quinases/metabolismo , Receptores Estrogênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos
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