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.

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 Cell contact and Nf2/Merlin-dependent regulation of TEAD palmitoylation and activity

2019 ◽  
Vol 116 (20) ◽  
pp. 9877-9882 ◽  
Author(s):  
Nam-Gyun Kim ◽  
Barry M. Gumbiner
Keyword(s):  
Cell Density ◽  
Ubiquitin Ligase ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Hippo Pathway ◽  
E3 Ubiquitin Ligase ◽  
Cell Contact ◽  
Dependent Manner ◽  
Inhibition Of Proliferation ◽  
The Hippo Pathway

The Hippo pathway is involved in regulating contact inhibition of proliferation and organ size control and responds to various physical and biochemical stimuli. It is a kinase cascade that negatively regulates the activity of cotranscription factors YAP and TAZ, which interact with DNA binding transcription factors including TEAD and activate the expression of target genes. In this study, we show that the palmitoylation of TEAD, which controls the activity and stability of TEAD proteins, is actively regulated by cell density independent of Lats, the key kinase of the Hippo pathway. The expression of fatty acid synthase and acetyl-CoA carboxylase involved in de novo biosynthesis of palmitate is reduced by cell density in an Nf2/Merlin-dependent manner. Depalmitoylation of TEAD is mediated by depalmitoylases including APT2 and ABHD17A. Palmitoylation-deficient TEAD4 mutant is unstable and degraded by proteasome through the activity of the E3 ubiquitin ligase CHIP. These findings show that TEAD activity is tightly controlled through the regulation of palmitoylation and stability via the orchestration of FASN, depalmitoylases, and E3 ubiquitin ligase in response to cell contact.

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 Targeting the Hippo Pathway in Prostate Cancer: What’s New?

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 611
Author(s):  
Kelly Coffey
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Hippo Pathway ◽  
Effector Proteins ◽  
Migration And Invasion ◽  
Cell Contact ◽  
Cellular Localisation ◽  
Kinase Cascade ◽  
The Hippo Pathway ◽  
Emergence Of Resistance

Identifying novel therapeutic targets for the treatment of prostate cancer (PC) remains a key area of research. With the emergence of resistance to androgen receptor (AR)-targeting therapies, other signalling pathways which crosstalk with AR signalling are important. Over recent years, evidence has accumulated for targeting the Hippo signalling pathway. Discovered in Drosophila melanogasta, the Hippo pathway plays a role in the regulation of organ size, proliferation, migration and invasion. In response to a variety of stimuli, including cell–cell contact, nutrients and stress, a kinase cascade is activated, which includes STK4/3 and LATS1/2 to inhibit the effector proteins YAP and its paralogue TAZ. Transcription by their partner transcription factors is inhibited by modulation of YAP/TAZ cellular localisation and protein turnover. Trnascriptional enhanced associate domain (TEAD) transcription factors are their classical transcriptional partner but other transcription factors, including the AR, have been shown to be modulated by YAP/TAZ. In PC, this pathway can be dysregulated by a number of mechanisms, making it attractive for therapeutic intervention. This review looks at each component of the pathway with a focus on findings from the last year and discusses what knowledge can be applied to the field of PC.

scholarly journals NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway

2011 ◽  
Vol 193 (4) ◽  
pp. 633-642 ◽  
Author(s):  
Sandra Habbig ◽  
Malte P. Bartram ◽  
Roman U. Müller ◽  
Ricarda Schwarz ◽  
Nikolaos Andriopoulos ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Negative Regulator ◽  
Hippo Signaling ◽  
Transcriptional Coactivator ◽  
Hippo Signaling Pathway ◽  
The Hippo Pathway ◽  
Potent Negative Regulator

The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.

Abstract 172: Thrombopoietin Receptor Agonists Protect Human Cardiac Myocytes from Injury by Activation of Cell Survival Pathways

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
John E Baker ◽  
Jidong Su ◽  
Stacy Koprowski ◽  
Anuradha Dhanasekaran ◽  
Tom P Aufderheide ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Survival Pathways ◽  
Thrombopoietin Receptor ◽  
Reoxygenation Injury ◽  
Hypoxia Reoxygenation

Thrombopoietin confers immediate protection against injury caused by ischemia/reperfusion in the rat heart at a dose that does not increase platelet levels. Eltrombopag is a small molecule agonist of the thrombopoietin receptor; the physiological target of thrombopoietin. Administration of thrombopoietin and eltrombopag result in a dose- and time-dependent increase in platelet counts in patients with thrombocytopenia. However, the ability of eltrombopag and thrombopoietin to immediately protect human cardiac myocytes against injury and the mechanisms underlying myocyte protection are not known. Human cardiac myocytes (7500 cells, n=10/group) were treated with eltrombopag (0.1- 30.0 μM) or thrombopoietin ( 0.1 - 30.0 ng/ml) and then subjected to 5 hours of hypoxia (95% N 2 /5%CO 2 ) and 16 hours of reoxygenation to determine their ability to confer resistance to necrotic and apoptotic myocardial injury . The thrombopoietin receptor (c-Mpl) was detected in unstimulated human cardiac myocytes by western blotting. Eltrombopag and thrombopoietin confer immediate protection to human cardiac myocytes against injury from hypoxia/reoxygenation by decreasing necrotic and apoptotic cell death in a concentration-dependent manner with an optimal concentration of 3 μM for eltrombopag and 1.0 ng/ml for thrombopoietin. The extent of protection conferred to cardiac myocytes with eltrombopag is equivalent to that of thrombopoietin. Eltrombopag and thrombopoietin activate multiple pro-survival pathways; inhibition of JAK-2 (AG-490, 10 μM), p38 MAPK (SB203580, 10 μM), p44/42 MAPK (PD98059, 10 μM), Akt/PI 3 kinase (Wortmannin, 100 nM), and src kinase (PP1, 20 μM) prior to and during hypoxia abolished cardiac myocyte protection by eltrombopag and thrombopoietin. These inhibitors had no effect on hypoxia/reoxygenation injury in myocytes when used alone. Eltrombopag and thrombopoietin may represent important and potent agents for immediately and substantially increasing protection of human cardiac myocytes, and may offer long-lasting benefit through activation of pro-survival pathways during ischemia.

scholarly journals Transcriptional Coactivator TAZ Negatively Regulates Tumor Suppressor p53 Activity and Cellular Senescence

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 171
Author(s):  
Chiharu Miyajima ◽  
Yuki Kawarada ◽  
Yasumichi Inoue ◽  
Chiaki Suzuki ◽  
Kana Mitamura ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Cellular Senescence ◽  
Hippo Pathway ◽  
Physiological Role ◽  
Underlying Mechanism ◽  
Binding Motif ◽  
Dependent Manner ◽  
Transcriptional Coactivator ◽  
Tumor Suppressor P53

Transcriptional coactivator with a PDZ-binding motif (TAZ) is one of the mammalian orthologs of Drosophila Yorkie, a transcriptional coactivator of the Hippo pathway. TAZ has been suggested to function as a regulator that modulates the expression of cell proliferation and anti-apoptotic genes in order to stimulate cell proliferation. TAZ has also been associated with a poor prognosis in several cancers, including breast cancer. However, the physiological role of TAZ in tumorigenesis remains unclear. We herein demonstrated that TAZ negatively regulated the activity of the tumor suppressor p53. The overexpression of TAZ down-regulated p53 transcriptional activity and its downstream gene expression. In contrast, TAZ knockdown up-regulated p21 expression induced by p53 activation. Regarding the underlying mechanism, TAZ inhibited the interaction between p53 and p300 and suppressed the p300-mediated acetylation of p53. Furthermore, TAZ knockdown induced cellular senescence in a p53-dependent manner. These results suggest that TAZ negatively regulates the tumor suppressor functions of p53 and attenuates p53-mediated cellular senescence.

scholarly journals Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer

2019 ◽  
Vol 20 (19) ◽  
pp. 4709 ◽  
Author(s):  
Seong-Hun Kim ◽  
Hua Jin ◽  
Ruo Yu Meng ◽  
Da-Yeah Kim ◽  
Yu Chuan Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Cancer Cells ◽  
Ursolic Acid ◽  
Hippo Pathway ◽  
Dependent Manner ◽  
Gastric Cancer Cells ◽  
Protein Levels ◽  
Tumor Tissues ◽  
The Hippo Pathway

The Hippo pathway is often dysregulated in many carcinomas, which results in various stages of tumor progression. Ursolic acid (UA), a natural compound that exists in many herbal plants, is known to obstruct cancer progression and exerts anti-carcinogenic effect on a number of human cancers. In this study, we aimed to examine the biological mechanisms of action of UA through the Hippo pathway in gastric cancer cells. MTT assay showed a decreased viability of gastric cancer cells after treatment with UA. Following treatment with UA, colony numbers and the sizes of gastric cancer cells were significantly diminished and apoptosis was observed in SNU484 and SNU638 cells. The invasion and migration rates of gastric cancer cells were suppressed by UA in a dose-dependent manner. To further determine the gene expression patterns that are related to the effects of UA, a microarray analysis was performed. Gene ontology analysis revealed that several genes, such as the Hippo pathway upstream target gene, ras association domain family (RASSF1), and its downstream target genes (MST1, MST2, and LATS1) were significantly upregulated by UA, while the expression of YAP1 gene, together with oncogenes (FOXM1, KRAS, and BATF), were significantly decreased. Similar to the gene expression profiling results, the protein levels of RASSF1, MST1, MST2, LATS1, and p-YAP were increased, whereas those of CTGF were decreased by UA in gastric cancer cells. The p-YAP expression induced in gastric cancer cells by UA was reversed with RASSF1 silencing. In addition, the protein levels in the Hippo pathway were increased in the UA-treated xenograft tumor tissues as compared with that in the control tumor tissues; thus, UA significantly inhibited the tumorigenesis of gastric cancer in vivo in xenograft animals. Collectively, UA diminishes the proliferation and metastasis of gastric cancer via the regulation of Hippo pathway through Rassf1, which suggests that UA can be used as a potential chemopreventive and therapeutic agent for gastric cancer.

Sign in / Sign up

Export Citation Format

Share Document