scholarly journals Diverse mitotic functions of the cytoskeletal cross-linking protein Shortstop suggest a role in Dynein/Dynactin activity

2017 ◽  
Vol 28 (19) ◽  
pp. 2555-2568 ◽  
Author(s):  
Evan B. Dewey ◽  
Christopher A. Johnston
Keyword(s):  
Cell Fate ◽  
Mitotic Spindle ◽  
Cell Cycle Progression ◽  
Epithelial Mesenchymal Transition ◽  
Spindle Pole ◽  
Actin Binding ◽  
Epithelial Tissue ◽  
Mesenchymal Transition ◽  
Underlying Mechanisms ◽  
Dynactin Complex

Proper assembly and orientation of the bipolar mitotic spindle is critical to the fidelity of cell division. Mitotic precision fundamentally contributes to cell fate specification, tissue development and homeostasis, and chromosome distribution within daughter cells. Defects in these events are thought to contribute to several human diseases. The underlying mechanisms that function in spindle morphogenesis and positioning remain incompletely defined, however. Here we describe diverse roles for the actin-microtubule cross-linker Shortstop (Shot) in mitotic spindle function in Drosophila. Shot localizes to mitotic spindle poles, and its knockdown results in an unfocused spindle pole morphology and a disruption of proper spindle orientation. Loss of Shot also leads to chromosome congression defects, cell cycle progression delay, and defective chromosome segregation during anaphase. These mitotic errors trigger apoptosis in Drosophila epithelial tissue, and blocking this apoptotic response results in a marked induction of the epithelial–mesenchymal transition marker MMP-1. The actin-binding domain of Shot directly interacts with Actin-related protein-1 (Arp-1), a key component of the Dynein/Dynactin complex. Knockdown of Arp-1 phenocopies Shot loss universally, whereas chemical disruption of F-actin does so selectively. Our work highlights novel roles for Shot in mitosis and suggests a mechanism involving Dynein/Dynactin activation.

scholarly journals Transcription Factor AP4 Mediates Cell Fate Decisions: To Divide, Age, or Die

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 676
Author(s):  
Matthew Man-Kin Wong ◽  
Sancy Mary Joyson ◽  
Heiko Hermeking ◽  
Sung Kay Chiu
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Leucine Zipper ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Ex Vivo ◽  
Mesenchymal Transition ◽  
Multiple Tumor ◽  
Cell Fate Decisions

Activating Enhancer-Binding Protein 4 (AP4)/transcription factor AP4 (TFAP4) is a basic-helix-loop-helix-leucine-zipper transcription factor that was first identified as a protein bound to SV40 promoters more than 30 years ago. Almost 15 years later, AP4 was characterized as a target of the c-Myc transcription factor, which is the product of a prototypic oncogene that is activated in the majority of tumors. Interestingly, AP4 seems to represent a central hub downstream of c-Myc and N-Myc that mediates some of their functions, such as proliferation and epithelial-mesenchymal transition (EMT). Elevated AP4 expression is associated with progression of cancer and poor patient prognosis in multiple tumor types. Deletion of AP4 in mice points to roles of AP4 in the control of stemness, tumor initiation and adaptive immunity. Interestingly, ex vivo AP4 inactivation results in increased DNA damage, senescence, and apoptosis, which may be caused by defective cell cycle progression. Here, we will summarize the roles of AP4 as a transcriptional repressor and activator of target genes and the contribution of protein and non-coding RNAs encoded by these genes, in regulating the above mentioned processes. In addition, proteins interacting with or regulating AP4 and the cellular signaling pathways altered after AP4 dysregulation in tumor cells will be discussed.

scholarly journals Modulating Tumor Cell Functions by Tunable Nanopatterned Ligand Presentation

Nanomaterials ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 212
Author(s):  
Katharina Amschler ◽  
Michael P. Schön
Keyword(s):  
Extracellular Matrix ◽  
Tumor Cell ◽  
Cell Fate ◽  
Epithelial Mesenchymal Transition ◽  
Model Systems ◽  
Cellular Functions ◽  
Biophysical Parameters ◽  
Ligand Density ◽  
Mesenchymal Transition ◽  
Cell Functions

Cancer comprises a large group of complex diseases which arise from the misrouted interplay of mutated cells with other cells and the extracellular matrix. The extracellular matrix is a highly dynamic structure providing biochemical and biophysical cues that regulate tumor cell behavior. While the relevance of biochemical signals has been appreciated, the complex input of biophysical properties like the variation of ligand density and distribution is a relatively new field in cancer research. Nanotechnology has become a very promising tool to mimic the physiological dimension of biophysical signals and their positive (i.e., growth-promoting) and negative (i.e., anti-tumoral or cytotoxic) effects on cellular functions. Here, we review tumor-associated cellular functions such as proliferation, epithelial-mesenchymal transition (EMT), invasion, and phenotype switch that are regulated by biophysical parameters such as ligand density or substrate elasticity. We also address the question of how such factors exert inhibitory or even toxic effects upon tumor cells. We describe three principles of nanostructured model systems based on block copolymer nanolithography, electron beam lithography, and DNA origami that have contributed to our understanding of how biophysical signals direct cancer cell fate.

scholarly journals CENP-A overexpression promotes distinct fates in human cells, depending on p53 status

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Daniel Jeffery ◽  
Alberto Gatto ◽  
Katrina Podsypanina ◽  
Charlène Renaud-Pageot ◽  
Rebeca Ponce Landete ◽  
...  
Keyword(s):  
Cell Fate ◽  
Epithelial Mesenchymal Transition ◽  
Clonogenic Survival ◽  
Response To Therapy ◽  
Epigenetic Mark ◽  
Mammalian Development ◽  
Mesenchymal Transition ◽  
Histone H3 Variant ◽  
Tumour Cell Invasion ◽  
P53 Status

AbstractTumour evolution is driven by both genetic and epigenetic changes. CENP-A, the centromeric histone H3 variant, is an epigenetic mark that directly perturbs genetic stability and chromatin when overexpressed. Although CENP-A overexpression is a common feature of many cancers, how this impacts cell fate and response to therapy remains unclear. Here, we established a tunable system of inducible and reversible CENP-A overexpression combined with a switch in p53 status in human cell lines. Through clonogenic survival assays, single-cell RNA-sequencing and cell trajectory analysis, we uncover the tumour suppressor p53 as a key determinant of how CENP-A impacts cell state, cell identity and therapeutic response. If p53 is functional, CENP-A overexpression promotes senescence and radiosensitivity. Surprisingly, when we inactivate p53, CENP-A overexpression instead promotes epithelial-mesenchymal transition, an essential process in mammalian development but also a precursor for tumour cell invasion and metastasis. Thus, we uncover an unanticipated function of CENP-A overexpression to promote cell fate reprogramming, with important implications for development and tumour evolution.

scholarly journals The Role of microRNAs in Cholangiocarcinoma

2021 ◽  
Vol 22 (14) ◽  
pp. 7627
Author(s):  
Tingting Shi ◽  
Asahiro Morishita ◽  
Hideki Kobara ◽  
Tsutomu Masaki
Keyword(s):  
Cell Cycle Progression ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Survival Rates ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Mesenchymal Transition ◽  
Diagnosis And Prognosis ◽  
Related Risk

Cholangiocarcinoma (CCA), an aggressive malignancy, is typically diagnosed at an advanced stage. It is associated with dismal 5-year postoperative survival rates, generating an urgent need for prognostic and diagnostic biomarkers. MicroRNAs (miRNAs) are a class of non-coding RNAs that are associated with cancer regulation, including modulation of cell cycle progression, apoptosis, metastasis, angiogenesis, autophagy, therapy resistance, and epithelial–mesenchymal transition. Several miRNAs have been found to be dysregulated in CCA and are associated with CCA-related risk factors. Accumulating studies have indicated that the expression of altered miRNAs could act as oncogenic or suppressor miRNAs in the development and progression of CCA and contribute to clinical diagnosis and prognosis prediction as potential biomarkers. Furthermore, miRNAs and their target genes also contribute to targeted therapy development and aid in the determination of drug resistance mechanisms. This review aims to summarize the roles of miRNAs in the pathogenesis of CCA, their potential use as biomarkers of diagnosis and prognosis, and their utilization as novel therapeutic targets in CCA.

Molecular Mechanism and Prediction of Sorafenib Chemoresistance in Human Hepatocellular Carcinoma

2015 ◽  
Vol 33 (6) ◽  
pp. 771-779 ◽  
Author(s):  
Naoshi Nishida ◽  
Masayuki Kitano ◽  
Toshiharu Sakurai ◽  
Masatoshi Kudo
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Kinase Inhibitor ◽  
Epithelial Mesenchymal Transition ◽  
Growth Factor Receptor ◽  
Stem Cell Markers ◽  
Mesenchymal Transition ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Underlying Mechanisms

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, and prognosis remains unsatisfactory when the disease is diagnosed at an advanced stage. Many molecular targeted agents are being developed for the treatment of advanced HCC; however, the only promising drug to have been developed is sorafenib, which acts as a multi-kinase inhibitor. Unfortunately, a subgroup of HCC is resistant to sorafenib, and the majority of these HCC patients show disease progression even after an initial satisfactory response. To date, a number of studies have examined the underlying mechanisms involved in the response to sorafenib, and trials have been performed to overcome the acquisition of drug resistance. The anti-tumor activity of sorafenib is largely attributed to the blockade of the signals from growth factors, such as vascular endothelial growth factor receptor and platelet-derived growth factor receptor, and the downstream RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade. The activation of an escape pathway from RAF/MEK/ERK possibly results in chemoresistance. In addition, there are several features of HCCs indicating sorafenib resistance, such as epithelial-mesenchymal transition and positive stem cell markers. Here, we review the recent reports and focus on the mechanism and prediction of chemoresistance to sorafenib in HCC.

scholarly journals Cytoplasmic NOTCH and membrane-derived β-catenin link cell fate choice to epithelial-mesenchymal transition during myogenesis

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Daniel Sieiro ◽  
Anne C Rios ◽  
Claire E Hirst ◽  
Christophe Marcelle
Keyword(s):  
Cell Fate ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Epithelial Plasticity ◽  
Cellular Environment ◽  
Muscle Formation ◽  
Fate Decision ◽  
Gsk 3Β ◽  
Coupling Cell

How cells in the embryo coordinate epithelial plasticity with cell fate decision in a fast changing cellular environment is largely unknown. In chick embryos, skeletal muscle formation is initiated by migrating Delta1-expressing neural crest cells that trigger NOTCH signaling and myogenesis in selected epithelial somite progenitor cells, which rapidly translocate into the nascent muscle to differentiate. Here, we uncovered at the heart of this response a signaling module encompassing NOTCH, GSK-3β, SNAI1 and β-catenin. Independent of its transcriptional function, NOTCH profoundly inhibits GSK-3β activity. As a result SNAI1 is stabilized, triggering an epithelial to mesenchymal transition. This allows the recruitment of β-catenin from the membrane, which acts as a transcriptional co-factor to activate myogenesis, independently of WNT ligand. Our results intimately associate the initiation of myogenesis to a change in cell adhesion and may reveal a general principle for coupling cell fate changes to EMT in many developmental and pathological processes.

scholarly journals Circular RNA CDR1as Inhibits the Metastasis of Gastric Cancer through Targeting miR-876-5p/GNG7 Axis

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Jiajia Jiang ◽  
Rong Li ◽  
Junyi Wang ◽  
Jie Hou ◽  
Hui Qian ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Circular Rna ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Luciferase Reporter Gene ◽  
Mesenchymal Transition ◽  
Underlying Mechanisms

Circular RNA CDR1as has been demonstrated to participate in various cancer progressions as miRNA sponges. The exact underlying mechanisms of CDR1as on gastric cancer (GC) metastasis remain unknown. Here, we found that CDR1as knockdown facilitated GC cell migration and invasion while its overexpression inhibited the migration and invasion abilities of GC cells in vitro and in vivo. Moreover, epithelial-mesenchymal transition- (EMT-) associated proteins and MMP2 and MMP9 were downregulated by CDR1as. Bioinformatics analysis combined with dual-luciferase reporter gene assays, western blot, RT-qPCR analysis, and functional rescue experiments demonstrated that CDR1as served as a miR-876-5p sponge and upregulated the target gene GNG7 expression to suppress GC metastasis. In summary, our findings indicate that CDR1as suppresses GC metastasis through the CDR1as/miR-876-5p/GNG7 axis.

Rosehip Oil Promotes Excisional Wound Healing by Accelerating the Phenotypic Transition of Macrophages

Planta Medica ◽  
2018 ◽  
Vol 85 (07) ◽  
pp. 563-569 ◽  
Author(s):  
Zhiyong Lei ◽  
Zhijian Cao ◽  
Zaiwang Yang ◽  
Mingzhang Ao ◽  
Wenwen Jin ◽  
...  
Keyword(s):  
Wound Healing ◽  
Epithelial Mesenchymal Transition ◽  
New Drugs ◽  
Mesenchymal Transition ◽  
Excisional Wound ◽  
Macrophage Phenotypes ◽  
Immunohistological Staining ◽  
Underlying Mechanisms ◽  
Global Threat ◽  
Phenotypic Transition

AbstractPoor wound healing is a major and global threat to public health. Efforts have been made to better understand the underlying mechanisms and develop effective remedies, though the advancements that have been made are still limited. As there are no effective and generally applicable therapies available for skin injuries and fibrosis, it is urgent to develop new drugs and therapies that facilitate wound healing and effectively improve scars. In this study, GC-MS analysis was performed to identify the chemical composition of rosehip oil. The excisional wound healing model and the carrageenan-induced paw edema method were respectively applied to evaluate the wound healing activity and anti-inflammatory activity of rosehip oil. Hematoxylin and eosin staining was used to assess the pathological changes of sections, and Sirius-red staining was performed to analyze the ratio of collagen I/III in wound tissues. Immunohistological staining for CD68, CCR7 (CD197), CD163, TGF-β1, and α-SMA was applied to determine the macrophage phenotypes transition (M1-to-M2) and demonstrate the scar-improving efficacy of rosehip oil on wound healing. Results showed that rosehip oil significantly promoted wound healing and effectively improved scars. This efficacy might be exerted by accelerating the macrophage phenotypes transition and inhibiting the process of epithelial-mesenchymal transition.

The role of gamma-tubulin in mitotic spindle formation and cell cycle progression in Aspergillus nidulans

1997 ◽  
Vol 110 (5) ◽  
pp. 623-633 ◽  
Author(s):  
M.A. Martin ◽  
S.A. Osmani ◽  
B.R. Oakley
Keyword(s):  
Cell Cycle ◽  
Mitotic Spindle ◽  
Cell Cycle Progression ◽  
Spindle Pole ◽  
Microtubule Assembly ◽  
Cytoplasmic Microtubule ◽  
Cycle Progression ◽  
Spindle Microtubules ◽  
Gamma Tubulin

gamma-Tubulin has been hypothesized to be essential for the nucleation of the assembly of mitotic spindle microtubules, but some recent results suggest that this may not be the case. To clarify the role of gamma-tubulin in microtubule assembly and cell-cycle progression, we have developed a novel variation of the gene disruption/heterokaryon rescue technique of Aspergillus nidulans. We have used temperature-sensitive cell-cycle mutations to synchronize germlings carrying a gamma-tubulin disruption and observe the phenotypes caused by the disruption in the first cell cycle after germination. Our results indicate that gamma-tubulin is absolutely required for the assembly of mitotic spindle microtubules, a finding that supports the hypothesis that gamma-tubulin is involved in spindle microtubule nucleation. In the absence of functional gamma-tubulin, nuclei are blocked with condensed chromosomes for about the length of one cell cycle before chromatin decondenses without nuclear division. Our results indicate that gamma-tubulin is not essential for progression from G1 to G2, for entry into mitosis nor for spindle pole body replication. It is also not required for reactivity of spindle pole bodies with the MPM-2 antibody which recognizes a phosphoepitope important to mitotic spindle formation. Finally, it does not appear to be absolutely required for cytoplasmic microtubule assembly but may play a role in the formation of normal cytoplasmic microtubule arrays.

scholarly journals Keratin 17 Suppresses Cell Proliferation and Epithelial-Mesenchymal Transition in Pancreatic Cancer

2020 ◽  
Vol 7 ◽  
Author(s):  
Yong Zeng ◽  
Min Zou ◽  
Yan Liu ◽  
Keting Que ◽  
Yunbing Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
Cell Cycle Progression ◽  
Pancreatic Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Cancer Cell Proliferation ◽  
Cycle Progression ◽  
Mesenchymal Transition

Keratin 17 (K17), a member of type I acidic epithelial keratin family, has been reported to be upregulated in many malignant tumors and to be involved in promoting the development of tumors. However, the precise role of K17 in progression of pancreatic cancer is still unknown. In this study, we found that K17 expression was highly expressed in pancreatic cancer tissues and cell lines and that upregulated expression was associated with the pathological grade and poor prognosis. K17 expression served as an independent predictor of pancreatic cancer survival. Meanwhile, we showed that knocking down K17 induced pancreatic cancer cell proliferation, colony formation and tumor growth in xenografts in mice. However, K17 upregulation inhibited pancreatic cancer cell proliferation and colony formation. Further mechanistic study revealed that K17 knockdown promoted cell cycle progression by upregulating CyclinD1 expression and repressed cell apoptosis. However, K17 upregulation suppressed cell cycle progression by decreasing CyclinD1 expression, and induced apoptosis by increasing the levels of cleaved Caspase3. In addition, K17 knockdown promoted pancreatic cancer cell migration and invasion, but K17 upregulation suppressed cell migration and invasion. Moreover, knocking down K17 promoted epithelial-mesenchymal transition (EMT) in pancreatic cancer cell by inhibiting E-cadherin expression and inducing Vimentin expression, and the effects of K17 upregulation were opposite to that of K17downregulation. Taken together, our findings suggest that K17 functions as a potential tumor suppressor, even though it is upregulated in pancreatic cancer.

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