scholarly journals BMSC-Derived Small Extracellular Vesicles Induce Cartilage Reconstruction of Temporomandibular Joint Osteoarthritis via Autotaxin–YAP Signaling Axis

2021 ◽  
Vol 9 ◽  
Author(s):  
Yingnan Wang ◽  
Miaomiao Zhao ◽  
Wen Li ◽  
Yuzhi Yang ◽  
Zhenliang Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Temporomandibular Joint ◽  
Hippo Pathway ◽  
Key Factors ◽  
Related Factors ◽  
Cartilage Reconstruction ◽  
Temporomandibular Joint Osteoarthritis ◽  
Signaling Axis ◽  
Cartilage Cells ◽  
The Hippo Pathway

Background: Temporomandibular joint osteoarthritis (TMJOA) seriously affects the health of patients, and the current treatments are invasive and only used for advanced cases. Bone marrow mesenchymal stem cell (BMSC)-derived small extracellular vesicles (BMSC-sEVs) may represent a safer and more effective treatment, but their role in TMJOA has not been elucidated. This study attempted to analyze the cartilage reconstruction effect of BMSC-sEVs on TMJOA and the mechanism underlying this effect.Methods: BMSC-sEVs were isolated and purified by microfiltration and ultrafiltration and were subsequently characterized by nanoparticle tracking analysis, electron microscopy, and immunoblotting. TMJOA models were established in vivo and in vitro, and hematoxylin–eosin staining, immunohistochemistry, and histological scoring were performed to analyze the histological changes in TMJOA cartilage tissues treated with BMSC-sEVs. The proliferation, migratory capacity, and cell cycle distribution of TMJOA cartilage cells treated with BMSC-sEVs were detected. Furthermore, the related mechanisms were studied by bioinformatic analysis, immunoblotting, and quantitative PCR, and they were further analyzed by knockdown and inhibitor techniques.Results: The acquisition and identification of BMSC-sEVs were efficient and satisfactory. Compared with the osteoarthritis (OA) group, the condylar tissue of the OA group treated with BMSC-sEV (OAsEV) showed an increase in cartilage lacuna and hypertrophic cartilage cells in the deep area of the bone under the cartilage. Significantly upregulated expression of proliferating cell nuclear antigen and cartilage-forming factors and downregulated expression of cartilage inflammation-related factors in OAsEV were observed. In addition, we found higher rates of cell proliferation and migratory activity and alleviated G1 stagnation of the cell cycle of OAsEV. Autotaxin was found in the BMSC-sEVs, and key factors of the Hippo pathway, Yes-associated protein (YAP), phosphorylated Yes-associated protein (p-YAP), etc. were upregulated in the OAsEV group. Treatment with BMSC-sEVs after autotaxin knockdown or inhibition no longer resulted in expression changes in cartilage-forming and inflammation-related factors and key factors of the Hippo pathway.Conclusions: These results suggest that the autotaxin–YAP signaling axis plays an important role in the mechanism by which BMSC-sEVs promote cartilage reconstruction in TMJOA, which may provide guidance regarding their therapeutic applications as early and minimally invasive therapies for TMJOA, and provide insight into the internal mechanisms of TMJOA.

Abstract 396: Regulation of Cardiomyocyte Proliferation by the Hippo Pathway and Dystrophin Complex

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Yuka Morikawa ◽  
John Leach ◽  
Todd Heallen ◽  
Ge Tao ◽  
James F Martin
Keyword(s):  
Cell Cycle ◽  
Muscular Dystrophy ◽  
Dna Synthesis ◽  
De Novo ◽  
Hippo Pathway ◽  
Myocardial Damage ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Heart Repair ◽  
The Hippo Pathway

Regeneration in mammalian hearts is limited due to the extremely low renewal rate of cardiomyocytes and their inability to reenter the cell cycle. In rodent hearts, endogenous regenerative capacity exists during development but is rapidly repressed after birth, at which time growth is by hypertrophy. During the developmental and neonatal periods, heart regeneration occurs through proliferation of pre-existing cardiomyocytes. Our approach of activating heart regeneration is to uncover the mechanisms responsible for repression of cardiomyocyte proliferation. The Hippo pathway controls heart size by repressing cardiomyocyte proliferation during development. By deleting Salv , a modulator of the Hippo pathway, we found that myocardial damage in postnatal and adult hearts was repaired both anatomically and functionally. This heart repair occurred primary through proliferation of preexisting cardiomyocytes. During repair, cardiomyocytes reenter the cell cycle; de novo DNA synthesis, karyokinesis, and cytokinesis all take place. The dystrophin glycoprotein complex (DGC) is essential for muscle maintenance by anchoring the cytoskeleton and extracellular matrix. Disruption of the DGC results in muscular dystrophies, including Duchenne muscular dystrophy, resulting in both skeletal and cardiac myopathies. Recently the DGC was shown to regulate cardiomyocyte proliferation and we found that the DGC and the Hippo pathway components directly interact. To address if the DGC and the Hippo pathway coordinately regulate cardiomyocyte proliferation, we conditionally deleted Salv in the mouse model of muscular dystrophy, the mdx line. We found that simultaneous disruption of both the DGC and Hippo pathway leads an increased de novo DNA synthesis and cytokinesis in cardiomyocytes after heart damage. Our findings provide new insights into the mechanisms leading to heart repair through proliferation of endogenous cardiomyocytes.

scholarly journals The NDR Kinase DBF-2 Is Involved in Regulation of Mitosis, Conidial Development, and Glycogen Metabolism in Neurospora crassa

2009 ◽  
Vol 9 (4) ◽  
pp. 502-513 ◽  
Author(s):  
Efrat Dvash ◽  
Galia Kra-Oz ◽  
Carmit Ziv ◽  
Shmuel Carmeli ◽  
Oded Yarden
Keyword(s):  
Cell Cycle ◽  
Neurospora Crassa ◽  
Filamentous Fungus ◽  
Hippo Pathway ◽  
Glycogen Metabolism ◽  
Content Type ◽  
Protein Levels ◽  
Carbon Nitrogen Ratio ◽  
Cdc 2 ◽  
The Hippo Pathway

ABSTRACT Neurospora crassa dbf-2 encodes an NDR (nuclear Dbf2-related) protein kinase, homologous to LATS1, a core component of the Hippo pathway. This pathway plays important roles in restraining cell proliferation and promoting apoptosis in differentiating cells. Here, we demonstrate that DBF-2 is involved in three fundamental processes in a filamentous fungus: cell cycle regulation, glycogen biosynthesis, and conidiation. DBF-2 is predominantly localized to the nucleus, and most (approximately 60%) dbf-2 null mutant nuclei are delayed in mitosis, indicating that DBF-2 activity is required for properly completing the cell cycle. The dbf-2 mutant exhibits reduced basal hyphal extension rates accompanied by a carbon/nitrogen ratio-dependent bursting of hyphal tips, vast glycogen leakage, defects in aerial hypha formation, and impairment of all three asexual conidiation pathways in N. crassa. Our findings also indicate that DBF-2 is essential for sexual reproduction in a filamentous fungus. Defects in other Hippo and glycogen metabolism pathway components (mob-1, ccr-4, mst-1, and gsk-3) share similar phenotypes such as mitotic delay and decreased CDC-2 (cell division cycle 2) protein levels, massive hyphal swellings, hyphal tip bursting, glycogen leakage, and impaired conidiation. We propose that DBF-2 functions as a link between Hippo and glycogen metabolism pathways.

scholarly journals Hippo signaling in the kidney: the good and the bad

2016 ◽  
Vol 311 (2) ◽  
pp. F241-F248 ◽  
Author(s):  
Jenny S. Wong ◽  
Kristin Meliambro ◽  
Justina Ray ◽  
Kirk N. Campbell
Keyword(s):  
Embryonic Development ◽  
Current Knowledge ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Filtration Barrier ◽  
Signaling Axis ◽  
Kinase Cascade ◽  
Barrier Regulation ◽  
Renal Tubular ◽  
The Hippo Pathway

The Hippo signaling pathway is an evolutionarily conserved kinase cascade, playing multiple roles in embryonic development that controls organ size, cell proliferation, and apoptosis. At the center of this network lie the Hippo kinase target and downstream pathway effector Yes-associated protein (YAP) and its paralog TAZ. In its phosphorylated form, cytoplasmic YAP is sequestered in an inactive state. When it is dephosphorylated, YAP, a potent oncogene, is activated and relocates to the nucleus to interact with a number of transcription factors and signaling regulators that promote cell growth, differentiation, and survival. The identification of YAP activation in human cancers has made it an attractive target for chemotherapeutic drug development. Little is known to date about the function of the Hippo pathway in the kidney, but that is rapidly changing. Recent studies have shed light on the role of Hippo-YAP signaling in glomerular and lower urinary tract embryonic development, maintenance of podocyte homeostasis, the integrity of the glomerular filtration barrier, regulation of renal tubular cyst growth, renal epithelial injury in diabetes, and renal fibrogenesis. This review summarizes the current knowledge of the Hippo-YAP signaling axis in the kidney under normal and disease conditions.

Abstract 78: Hippo Pathway and Dystrophin Glycoprotein Complex Regulate Cardiomyocyte Proliferation

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Yuka Morikawa ◽  
Todd Heallen ◽  
John Leach ◽  
Yang Xiao ◽  
James Martin
Keyword(s):  
Cell Cycle ◽  
Muscular Dystrophy ◽  
Hippo Pathway ◽  
Myocardial Damage ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
The Hippo Pathway ◽  
Dystrophin Glycoprotein

Regeneration of mammalian heart is limited due to the extremely low renewal rate of cardiomyocytes and their inability to reenter the cell cycle. The Hippo pathway controls heart size during development and represses postnatal heart regeneration by repressing cardiomyocyte proliferation. Our approach for activating adult heart regeneration is to uncover the mechanisms responsible for repression of cardiomyocyte proliferation. We have previously found that deletion of Salv, a modulator of the Hippo pathway, results in myocardial damage repair in postnatal and adult hearts. Deletion of Salv results in activation of the transcription factor, Yap, which positively regulates cytoskeleton and cell cycle genes. We also found that the components of dystrophin glycoprotein complex (DGC) are the target of Yap and DGC regulates heart regeneration. The dystrophin glycoprotein complex (DGC) is essential for muscle maintenance by anchoring the cytoskeleton and extracellular matrix. Disruption of the DGC results in muscular dystrophies, including Duchenne muscular dystrophy, resulting in both skeletal and cardiac myopathies. To explore the connection between DGC and the Hippo pathway, we conditionally deleted Salv in the mdx background, a mouse model of muscular dystrophy. We found that simultaneous disruption of the DGC and the Hippo pathway leads an increased cardiomyocyte proliferation after heart damage. This is associated with increased activity of Yap, suggesting DGC negatively regulate Yap to repress proliferation. We also found that one of the components DGC, dystroglycan directly binds Yap and anchors to the membrane. Our findings provide new insights into the mechanisms leading to heart repair through proliferation of endogenous cardiomyocytes.

scholarly journals Roles for B[a]P and FICZ in subchondral bone metabolism and experimental temporomandibular joint osteoarthritis via the AhR/Cyp1a1 signaling axis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yuri Yoshikawa ◽  
Takashi Izawa ◽  
Yusaku Hamada ◽  
Hiroko Takenaga ◽  
Ziyi Wang ◽  
...  
Keyword(s):  
Bone Loss ◽  
Mouse Model ◽  
Bone Metabolism ◽  
Temporomandibular Joint ◽  
Subchondral Bone ◽  
Dependent Manner ◽  
Bone Homeostasis ◽  
Wild Type ◽  
Temporomandibular Joint Osteoarthritis ◽  
Signaling Axis

AbstractBone loss due to smoking represents a major risk factor for fractures and bone osteoporosis. Signaling through the aryl hydrocarbon receptor (AhR) and its ligands contributes to both bone homeostasis and inflammatory diseases. It remains unclear whether the same AhR signaling axis affects the temporomandibular joint (TMJ). The aim of this study was to investigate possible mechanisms which mediate bone loss in the TMJ due to smoking. In particular, whether benzo[a]pyrene (B[a]P), a carcinogen of tobacco smoke, induces expression of the AhR target gene, Cyp1a1, in mandibular condyles. Possible functions of an endogenous ligand of FICZ, were also investigated in a TMJ-osteoarthritis (OA) mouse model. B[a]P was administered orally to wild-type and AhR−/− mice and bone metabolism was subsequently examined. TMJ-OA was induced in wild-type mice with forceful opening of the mouth. Therapeutic functions of FICZ were detected with μCT and histology. Exposure to B[a]P accelerated bone loss in the mandibular subchondral bone. This bone loss manifested with osteoclastic bone resorption and upregulated expression of Cyp1a1 in an AhR-dependent manner. In a mouse model of TMJ-OA, FICZ exhibited a dose-dependent rescue of mandibular subchondral bone loss by repressing osteoclast activity. Meanwhile, in vitro, pre-treatment with FICZ reduced RANKL-mediated osteoclastogenesis. B[a]P regulates mandibular subchondral bone metabolism via the Cyp1a1. The AhR ligand, FICZ, can prevent TMJ-OA by regulating osteoclast differentiation.

Phospho-regulation of KIBRA by CDK1 and CDC14 phosphatase controls cell-cycle progression

2012 ◽  
Vol 447 (1) ◽  
pp. 93-102 ◽  
Author(s):  
Ming Ji ◽  
Shuping Yang ◽  
Yuanhong Chen ◽  
Ling Xiao ◽  
Lin Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Memory Performance ◽  
Hippo Pathway ◽  
Tissue Growth ◽  
Cycle Progression ◽  
Mitotic Kinases ◽  
The Hippo Pathway

KIBRA (kidney- and brain-expressed protein) is a novel regulator of the Hippo pathway, which controls tissue growth and tumorigenesis by regulating both cell proliferation and apoptosis. In mammals, KIBRA is associated with memory performance. The physiological function and regulation of KIBRA in non-neuronal cells remain largely unclear. We reported recently that KIBRA is phosphorylated by the mitotic kinases Aurora-A and -B. In the present study, we have expanded our analysis of KIBRA's role in cell-cycle progression. We show that KIBRA is also phosphorylated by CDK1 (cyclin-dependent kinase 1) in response to spindle damage stress. We have identified KIBRA Ser542 and Ser931 as main phosphorylation sites for CDK1 both in vitro and in vivo. Moreover, we found that the CDC (cell division cycle) 14A/B phosphatases associate with KIBRA, and CDK1-non-phosphorylatable KIBRA has greatly reduced interaction with CDC14B. CDC14A/B dephosphorylate CDK1-phosphorylated KIBRA in vitro and in cells. By using inducible-expression cell lines, we show further that phospho-regulation of KIBRA by CDK1 and CDC14 is involved in mitotic exit under spindle stress. Our results reveal a new mechanism through which KIBRA regulates cell-cycle progression.

scholarly journals The miRNA bantam regulates growth and tumorigenesis by repressing the cell cycle regulator tribbles

2019 ◽  
Vol 2 (4) ◽  
pp. e201900381 ◽  
Author(s):  
Stephan U Gerlach ◽  
Moritz Sander ◽  
Shilin Song ◽  
Héctor Herranz
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Target Genes ◽  
Hippo Pathway ◽  
Growth Control ◽  
Tissue Growth ◽  
Tumor Formation ◽  
Hippo Signaling ◽  
Cell Cycle Regulators ◽  
The Hippo Pathway

One of the fundamental issues in biology is understanding how organ size is controlled. Tissue growth has to be carefully regulated to generate well-functioning organs, and defects in growth control can result in tumor formation. The Hippo signaling pathway is a universal growth regulator and has been implicated in cancer. In Drosophila, the Hippo pathway acts through the miRNA bantam to regulate cell proliferation and apoptosis. Even though the bantam targets regulating apoptosis have been determined, the target genes controlling proliferation have not been identified thus far. In this study, we identify the gene tribbles as a direct bantam target gene. Tribbles limits cell proliferation by suppressing G2/M transition. We show that tribbles regulation by bantam is central in controlling tissue growth and tumorigenesis. We expand our study to other cell cycle regulators and show that deregulated G2/M transition can collaborate with oncogene activation driving tumor formation.

scholarly journals Distinct transcriptional programs of SOX2 in different types of small cell lung cancers

2019 ◽  
Author(s):  
Yuki Tenjin ◽  
Kumi Matsuura ◽  
Shinji Kudoh ◽  
Shingo Usuki ◽  
Tatsuya Yamada ◽  
...  
Keyword(s):  
Clinical Utility ◽  
Therapeutic Potential ◽  
Hippo Pathway ◽  
Biological Marker ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Different Types ◽  
Signaling Axis ◽  
The Hippo Pathway

AbstractSOX2 is an oncogene in human small cell lung cancer (SCLC), an aggressive neuroendocrine (NE) tumor. However, the roles of SOX2 in SCLC remain unclear, and strategies to selectively target SOX2 in SCLC cells have not yet been established. We herein demonstrated that SOX2 is involved in NE differentiation and tumorigenesis in cooperation with ASCL1, a lineage-specific transcriptional factor, in the classical subtype of SCLC cell lines. ASCL1 recruits SOX2, which promotes INSM1 expression. Precursor SCLC lesions were established in Trp53 (-/-); CCSPrtTA; tetOCre; floxedRb1; floxedHes1 mice, and the NE neoplasms induced were positive for Ascl1, Sox2, and Insm1. In contrast to the ASCL1-SOX2 signaling axis to control the SCLC phenotype in classical subtype SCLC, SOX2 targeted distinct genes, such as those related to the Hippo pathway, in ASCL1-negative, variant subtype SCLC. The present results support the importance of the ASCL1-SOX2 axis as a main subtype of SCLC, and suggest the therapeutic potential of targeting the ASCL1-SOX2 signaling axis and the clinical utility of SOX2 as a biological marker in the classical subtype of SCLC.

scholarly journals XMU-MP-1 induces growth arrest in a model human mini-organ and antagonises cell cycle-dependent paclitaxel cytotoxicity

Cell Division ◽  
2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Ellen Mitchell ◽  
Charlotte E. L. Mellor ◽  
Talveen S. Purba
Keyword(s):  
Cell Cycle ◽  
Hair Follicle ◽  
Cell Cycle Progression ◽  
Hippo Pathway ◽  
Ki 67 ◽  
Hair Matrix ◽  
Novel Strategy ◽  
Target Effect ◽  
Cycle Dependent ◽  
The Hippo Pathway

Abstract Background XMU-MP-1 is an inhibitor of the Hippo pathway kinases MST1/2 and has been shown to promote the downstream activation of the pro-proliferative, pro-regenerative and anti-apoptotic transcriptional regulator YAP1. We tested whether XMU-MP-1 can activate YAP1 in a model human mini-organ, namely the hair follicle, to determine whether it can be pharmacologically exploited to promote regeneration in the hair follicle as a novel strategy to treat pathological hair loss disorders. Results XMU-MP-1 treatment inhibited MOB1 phosphorylation but did not increase active YAP1 in the hair follicle. Rather than promote proliferation, XMU-MP-1 serendipitously decreased the number of Ki-67+, EdU+ and phospho histone H3+ hair matrix keratinocytes and antagonised the cytotoxic effects of paclitaxel. Conclusions XMU-MP-1 perturbs epithelial cell cycle progression in a model human mini-organ. This may arise as an off-target effect, especially when XMU-MP-1 has been described to strongly inhibit 21 additional kinases beyond MST1/2. Therefore, whilst these effects may be dependent on tissue context, researchers should exercise caution when interpreting the effects of XMU-MP-1, especially in tissues with actively proliferating cell populations.

scholarly journals The Hippo Signaling Pathway in Cancer: A Cell Cycle Perspective

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6214
Author(s):  
Yi Xiao ◽  
Jixin Dong
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Functional Conservation ◽  
The Core ◽  
The Hippo Pathway ◽  
Cycle Regulation

Cell cycle progression is an elaborate process that requires stringent control for normal cellular function. Defects in cell cycle control, however, contribute to genomic instability and have become a characteristic phenomenon in cancers. Over the years, advancement in the understanding of disrupted cell cycle regulation in tumors has led to the development of powerful anti-cancer drugs. Therefore, an in-depth exploration of cell cycle dysregulation in cancers could provide therapeutic avenues for cancer treatment. The Hippo pathway is an evolutionarily conserved regulator network that controls organ size, and its dysregulation is implicated in various types of cancers. Although the role of the Hippo pathway in oncogenesis has been widely investigated, its role in cell cycle regulation has not been comprehensively scrutinized. Here, we specifically focus on delineating the involvement of the Hippo pathway in cell cycle regulation. To that end, we first compare the structural as well as functional conservation of the core Hippo pathway in yeasts, flies, and mammals. Then, we detail the multi-faceted aspects in which the core components of the mammalian Hippo pathway and their regulators affect the cell cycle, particularly with regard to the regulation of E2F activity, the G1 tetraploidy checkpoint, DNA synthesis, DNA damage checkpoint, centrosome dynamics, and mitosis. Finally, we briefly discuss how a collective understanding of cell cycle regulation and the Hippo pathway could be weaponized in combating cancer.

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