scholarly journals TAZ Promotes Cell Proliferation and Epithelial-Mesenchymal Transition and Is Inhibited by the Hippo Pathway

2008 ◽  
Vol 28 (7) ◽  
pp. 2426-2436 ◽  
Author(s):  
Qun-Ying Lei ◽  
Heng Zhang ◽  
Bin Zhao ◽  
Zheng-Yu Zha ◽  
Feng Bai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Epithelial Mesenchymal Transition ◽  
Hippo Pathway ◽  
Ectopic Expression ◽  
Cell Contact ◽  
Mesenchymal Transition ◽  
Multiple Organs ◽  
Mesenchymal Differentiation ◽  
Functional Inactivation ◽  
The Hippo Pathway

ABSTRACT TAZ is a WW domain containing a transcription coactivator that modulates mesenchymal differentiation and development of multiple organs. In this study, we show that TAZ is phosphorylated by the Lats tumor suppressor kinase, a key component of the Hippo pathway, whose alterations result in organ and tissue hypertrophy in Drosophila and contribute to tumorigenesis in humans. Lats phosphorylates TAZ on several serine residues in the conserved HXRXXS motif and creates 14-3-3 binding sites, leading to cytoplasmic retention and functional inactivation of TAZ. Ectopic expression of TAZ stimulates cell proliferation, reduces cell contact inhibition, and promotes epithelial-mesenchymal transition (EMT). Elimination of the Lats phosphorylation sites results in a constitutively active TAZ, enhancing the activity of TAZ in promoting cell proliferation and EMT. Our results elucidate a molecular mechanism for TAZ regulation and indicate a potential function of TAZ as an important target of the Hippo pathway in regulating cell proliferation tumorigenesis.

scholarly journals Hippo signaling promotes JNK-dependent cell migration

2017 ◽  
Vol 114 (8) ◽  
pp. 1934-1939 ◽  
Author(s):  
Xianjue Ma ◽  
Hongxiang Wang ◽  
Jiansong Ji ◽  
Wenyan Xu ◽  
Yihao Sun ◽  
...  
Keyword(s):  
Cell Invasion ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Mesenchymal Transition ◽  
Matrix Metalloproteinase 1 ◽  
Essential Components ◽  
Dependent Cell ◽  
The Hippo Pathway

Overwhelming studies show that dysregulation of the Hippo pathway is positively correlated with cell proliferation, growth, and tumorigenesis. Paradoxically, the detailed molecular roles of the Hippo pathway in cell invasion remain debatable. Using aDrosophilainvasion model in wing epithelium, we show herein that activated Hippo signaling promotes cell invasion and epithelial-mesenchymal transition through JNK, as inhibition of JNK signaling dramatically blocked Hippo pathway activation-induced matrix metalloproteinase 1 expression and cell invasion. Furthermore, we identifybantam-Rox8 modules as essential components downstream of Yorkie in mediating JNK-dependent cell invasion. Finally, we confirm that YAP (Yes-associated protein) expression negatively regulates TIA1 (Rox8 ortholog) expression and cell invasion in human cancer cells. Together, these findings provide molecular insights into Hippo pathway-mediated cell invasion and also raise a noteworthy concern in therapeutic interventions of Hippo-related cancers, as simply inhibiting Yorkie or YAP activity might paradoxically accelerate cell invasion and metastasis.

scholarly journals MiR-1271 Inhibits Cell Proliferation, Invasion and EMT in Gastric Cancer by Targeting FOXQ1

2015 ◽  
Vol 36 (4) ◽  
pp. 1382-1394 ◽  
Author(s):  
Xiao-Jun Xiang ◽  
Jun Deng ◽  
Ya-Wen Liu ◽  
Lu-Ying Wan ◽  
Miao Feng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Tumor Stage ◽  
Luciferase Reporter ◽  
Regulation Mechanism ◽  
Mesenchymal Transition ◽  
Direct Target ◽  
Enhance Tumor Growth

Background/Aims: FOXQ1 overexpression has been reported to enhance tumor growth and invasion. However, the biological function of FOXQ1 and the mechanism underlying its upregulation in gastric cancer (GC) remain unknown. Methods: QPCR was used to detect the expression of miR-1271 and FOXQ1 in specimens from GC patients. FOXQ1-siRNA, and miR-1271 mimics and inhibitor were transfected into human MGC-803 and SGC-7901 cells. The transwell assay was used to examine the cell invasive ability. The regulation mechanism was confirmed by luciferase reporter assay. Markers of epithelial-mesenchymal transition (EMT) were detected by western blot analysis. Results: MiR-1271 was downregulated in both GC tissues and GC cell lines. The expression of miR-1271 was inversely correlated with tumor size (P = 0.017), tumor stage (P = 0.035), lymph node metastasis (P = 0.018), and TNM stage (P = 0.025). Ectopic expression of miR-1271 dramatically suppressed GC cell proliferation, invasion, and EMT. Furthermore, FOXQ1 was identified as a direct target of miR-1271. Knockdown of FOXQ1 inhibited GC cell malignant behavior, whereas FOXQ1 overexpression partially restored the suppression effects of miR-1271. Additionally, miR-1271 expression was negatively correlated with FOXQ1 in GC tissues. Conclusions: MiR-1271 inhibits cell proliferation, invasion, and EMT in GC by directly suppressing FOXQ1 expression.

miR-27b-3p Inhibits Invasion, Migration and Epithelial-mesenchymal Transition in Gastric Cancer by Targeting RUNX1 and Activation of the Hippo Signaling Pathway

2021 ◽  
Vol 21 ◽  
Author(s):  
Chen-hui Bao ◽  
Lin Guo
Keyword(s):  
Gastric Cancer ◽  
Target Gene ◽  
Epithelial Mesenchymal Transition ◽  
Hippo Pathway ◽  
Mirna Sequence ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Invasion And Migration ◽  
And Migration ◽  
The Hippo Pathway

Background: Gastric cancer (GC) accounts for high mortality, which seriously threatens people’s health. This study set out to probe into the effect and mechanism of miR-27b-3p on invasion and migration of GC. Methods: The miRNA sequence data of GC was acquired from The Cancer Genome Atlas (TCGA) database. The differential expression of miRNAs (DEMis) was acquired through R packages “edgeR” and “limma.” TargetScan, picTar, RNA22, PITA, and miRanda were performed to predict the target gene of miR-27b-3p. Western-blot and RT-PCR were applied to detect the expression level of the selected candidate. Transwell assays evaluated the effect of miR-27b-3p and runt-related transcription factor 1 (RUNX1) on cell migration and invasion. The rescue assay was achieved by co-culture with mimics of miR-27b-3p and vector of RUNX1. The psiCHECK2 vector was used in the luciferase report assay. Results: We found miR-27b-3p was down-regulated in GC and associated with GC patients' poor survival based on the TCGA data and bioinformatics analysis. Furthermore, RUNX1 was the target gene of miR-27b-3p, which was proved by the luciferase report assay. miR-27b-3p and RUNX1 jointly participate in the regulation of the Hippo pathway. The up-regulated miR-27b-3p could inhibit epithelial–mesenchymal transition (EMT) as well as invasion and migration. However, an overexpressed RUNX1 could weaken this phenomenon. Conclusion: miR-27b-3p was down-regulated in GC, and it could regulate the Hippo pathway and affect EMT by inhibiting RUNX1 expression.

Hippo and TGF-β interplay in the lung field

2015 ◽  
Vol 309 (8) ◽  
pp. L756-L767 ◽  
Author(s):  
Akira Saito ◽  
Takahide Nagase
Keyword(s):  
Lung Development ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Current Knowledge ◽  
Hippo Pathway ◽  
Binding Motif ◽  
Lung Field ◽  
Biological Processes ◽  
Mesenchymal Transition ◽  
The Hippo Pathway

The Hippo pathway is comprised of a kinase cascade that involves mammalian Ste20-like serine/threonine kinases (MST1/2) and large tumor suppressor kinases (LATS1/2) and leads to inactivation of transcriptional coactivator with PDZ-binding motif (TAZ) and yes-associated protein (YAP). Protein stability and subcellular localization of TAZ/YAP determine its ability to regulate a diverse array of biological processes, including proliferation, apoptosis, differentiation, stem/progenitor cell properties, organ size control, and tumorigenesis. These actions are enabled by interactions with various transcription factors or through cross talk with other signaling pathways. Interestingly, mechanical stress has been shown to be an upstream regulator of TAZ/YAP activity, and this finding provides a novel clue for understanding how mechanical forces influence a broad spectrum of biological processes, which involve cytoskeletal structure, cell adhesion, and extracellular matrix (ECM) organization. Transforming growth factor-β (TGF-β) pathway is a critical component of lung development and the progression of lung diseases including emphysema, fibrosis, and cancer. In addition, TGF-β is a key regulator of ECM remodeling and cell differentiation processes such as epithelial-mesenchymal transition. In this review, we summarize the current knowledge of the Hippo pathway regarding lung development and diseases, with an emphasis on its interplay with TGF-β signaling.

scholarly journals The Hippo pathway regulates density-dependent proliferation of iPSC-derived cardiac myocytes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Abigail C. Neininger ◽  
Xiaozhaun Dai ◽  
Qi Liu ◽  
Dylan T. Burnette
Keyword(s):  
Cell Proliferation ◽  
Cardiac Myocytes ◽  
Heart Development ◽  
Cardiac Myocyte ◽  
Hippo Pathway ◽  
Cell Contact ◽  
Dependent Manner ◽  
Density Dependent ◽  
Myocyte Proliferation ◽  
The Hippo Pathway

AbstractInducing cardiac myocytes to proliferate is considered a potential therapy to target heart disease, however, modulating cardiac myocyte proliferation has proven to be a technical challenge. The Hippo pathway is a kinase signaling cascade that regulates cell proliferation during the growth of the heart. Inhibition of the Hippo pathway increases the activation of the transcription factors YAP/TAZ, which translocate to the nucleus and upregulate transcription of pro-proliferative genes. The Hippo pathway regulates the proliferation of cancer cells, pluripotent stem cells, and epithelial cells through a cell–cell contact-dependent manner, however, it is unclear if cell density-dependent cell proliferation is a consistent feature in cardiac myocytes. Here, we used cultured human iPSC-derived cardiac myocytes (hiCMs) as a model system to investigate this concept. hiCMs have a comparable transcriptome to the immature cardiac myocytes that proliferate during heart development in vivo. Our data indicate that a dense syncytium of hiCMs can regain cell cycle activity and YAP expression and activity when plated sparsely or when density is reduced through wounding. We found that combining two small molecules, XMU-MP-1 and S1P, increased YAP activity and further enhanced proliferation of low-density hiCMs. Importantly, these compounds had no effect on hiCMs within a dense syncytium. These data add to a growing body of literature that link Hippo pathway regulation with cardiac myocyte proliferation and demonstrate that regulation is restricted to cells with reduced contact inhibition.

scholarly journals Inactivation of 3-hydroxybutyrate dehydrogenase type 2 promotes proliferation and metastasis of nasopharyngeal carcinoma by iron retention

2019 ◽  
Vol 122 (1) ◽  
pp. 102-110 ◽  
Author(s):  
Bo Li ◽  
Zhipeng Liao ◽  
Yingxi Mo ◽  
Weilin Zhao ◽  
Xiaohui Zhou ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Nasopharyngeal Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Colorimetric Assay ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
Iron Level ◽  
Intracellular Iron ◽  
Mesenchymal Transition

Abstract Background 3-Hydroxybutyrate dehydrogenase type 2 (BDH2) is known to catalyse a rate-limiting step in the biogenesis of the mammalian siderophore and regulate intracellular iron metabolism. Here we aim to explore the expression and possible function of BDH2 in nasopharyngeal carcinoma (NPC). Methods The transcription and protein expression of BDH2 in NPC were determined by both real-time RT-PCR and immunohistochemistry staining assays. Cell proliferation, migration and invasion were evaluated by MTT assay, wound-healing assay and Transwell assay, respectively. The profile of genes regulated by restoring BDH2 expression in NPC cells was analysed by cDNA microarray. The level of iron in NPC cells was detected by iron colorimetric assay. Results The expression of BDH2 was significantly downregulated in NPC. Ectopic expression of BDH2 inhibited NPC cell proliferation and colony formation. Meanwhile, BDH2 suppressed the migration and invasion of NPC cells by reversing the epithelial–mesenchymal transition (EMT). In addition, a higher level of BDH2 decreased the growth and metastasis of NPC cells via reducing intracellular iron level. Conclusions Our findings suggest that BDH2 may be a candidate tumour-suppressor gene in NPC. Decreasing intracellular iron could be an effective therapeutic approach for NPC.

scholarly journals The Hippo pathway regulates density-dependent proliferation of iPSC-derived cardiac myocytes

2021 ◽  
Author(s):  
Abigail C. Neininger ◽  
Xiaozhaun Dai ◽  
Qi Liu ◽  
Dylan T. Burnette
Keyword(s):  
Cell Proliferation ◽  
Cardiac Myocytes ◽  
Heart Development ◽  
Cardiac Myocyte ◽  
Hippo Pathway ◽  
Cell Contact ◽  
Dependent Manner ◽  
Density Dependent ◽  
Myocyte Proliferation ◽  
The Hippo Pathway

ABSTRACTInducing cardiac myocytes to proliferate is considered a potential therapy to target heart disease, however, modulating cardiac myocyte proliferation has proven to be a technical challenge. The Hippo pathway is a kinase signaling cascade that regulates cell proliferation during the growth of the heart. Inhibition of the Hippo pathway increases the activation of the transcription factors YAP/TAZ, which translocate to the nucleus and upregulate transcription of pro-proliferative genes. The Hippo pathway regulates the proliferation of cancer cells, pluripotent stem cells, and epithelial cells through a cell-cell contact-dependent manner, however it is unclear if cell density-dependent cell proliferation is a consistent feature in cardiac myocytes. Here, we used cultured human iPSC-derived cardiac myocytes (hiCMs) as a model system to investigate this concept. hiCMs have a comparable transcriptome to the immature cardiac myocytes that proliferate during heart development in vivo. Our data indicate that a dense syncytium of hiCMs can regain cell cycle activity and YAP expression and activity when plated sparsely or when density is reduced through wounding. We found that combining two small molecules, XMU-MP-1 and S1P, increased YAP activity and further enhanced proliferation of low-density hiCMs. Importantly, these compounds had no effect on hiCMs within a dense syncytium. These data add to a growing body of literature that link the Hippo pathway regulation with cardiac myocyte proliferation and demonstrate that regulation is restricted to cells with reduced contact inhibition.

Sign in / Sign up

Export Citation Format

Share Document