Abstract MP239: Hippo Signaling Pathway Maintains Homeostasis Of The Cardiac Conduction System

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Mingjie Zheng ◽  
Jun Wang
Keyword(s):  
Signaling Pathway ◽  
Calcium Homeostasis ◽  
Cardiac Arrhythmias ◽  
Critical Role ◽  
Conduction System ◽  
Conditional Knockout ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway

The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats. The fundamental Hippo signaling pathway plays critical roles in the heart, yet its role in the CCS remains largely unknown. Here, we found that conditional knockout (CKO) of Hippo signaling kinases Lats1 and Lats2 in the CCS using Hcn4 CreERT2 , led to cardiac arrhythmias in adult mice. Compared with controls, Lats1/2 CKO mutant mice had disrupted calcium homeostasis, increased fibrosis and more fibroblast proliferation in the sinoatrial node. Deletion of the Hippo signaling effectors Yap and Taz in the CCS rescued phenotypes caused by Lats1/2 deletion, and these mice had rescued sinus rhythm and reduced fibrosis, which indicated that Lats1/2 function through Yap and Taz in CCS. Our Cleavage Under Targets and Tagmentation (CUT&Tag)-sequencing using Yap antibody followed by RNA-Seq revealed that Yap directly regulates calcium homeostasis genes such as Ryr2 and fibrosis induction genes such as TGF-β family. Further, we discovered that miR-17-92 represses Hippo signaling by directly suppressing Lats2 expression. miR-17-92 CKO in the CCS led to increased Hippo signaling activity and cardiac arrhythmias, indicating that a fine-tuned level of Hippo signaling is critical for CCS homeostasis. Together, our findings reveal the critical role of a miR-Hippo-Yap genetic pathway in maintaining CCS homeostasis.

Abstract 15973: miRNA-Hippo Pathway Plays a Critical Role in the Cardiac Conduction System

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jun Wang ◽  
Sylvia Evans ◽  
James Martin
Keyword(s):  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Critical Role ◽  
Size Control ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Hippo Signaling ◽  
Cardiomyocyte Proliferation ◽  
Critical Function

The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats and the CCS defects can give rise to cardiac arrhythmia, a leading cause for morbidity worldwide. Given the poor self-repair potential in the adult human CCS, it is critical to elucidate the molecular mechanisms limiting the CCS regeneration to facilitate developing efficient cardiovascular therapies. MicroRNAs (miRs) are small non-coding RNAs that repress gene expression post-transcriptionally. The miR-17-92 cluster can induce cardiomyocyte proliferation and regeneration. Hippo signaling, an ancient organ size control pathway, represses cardiomyocyte proliferation and regeneration. Here we found that both miR-17-92 and Hippo signaling were active in the CCS. Specific disruption of either miR-17-92 or Hippo signaling in the CCS gave rise to cardiac arrhythmias in mice. Notably, miR-17-92 regulates Hippo signaling through directly repressing Lats2, a core Hippo pathway component. In miR-17-92 null mutant hearts, up-regulated Lats2 led to increased Hippo pathway activity. Moreover, we performed chromatin immunoprecipitation deep sequencing (ChIP-Seq) using Yap antibody, the Hippo signaling effector, which data suggested that Hippo signaling regulates genes involved in the CCS homeostasis. Together, our data indicate a novel miR-Hippo genetic pathway plays critical function in the CCS.

Abstract 260: A miRNA-Hippo Pathway Promotes Cardiac Conduction System Regeneration

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Jun Wang ◽  
James F Martin
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Size Control ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Hippo Signaling ◽  
Cardiomyocyte Proliferation ◽  
Non Coding Rnas

The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats and CCS defects can give rise to cardiac arrhythmia, a leading cause for morbidity worldwide. Given the poor self-repair potential in the adult human CCS, it is critical to elucidate the molecular mechanisms limiting CCS regeneration to facilitate developing efficient cardiovascular therapies. microRNAs (miRs) are small non-coding RNAs that repress gene expression post-transcriptionally. The miR-17-92 cluster can induce cardiomyocyte proliferation and regeneration. Hippo signaling, an ancient organ size control pathway, represses cardiomyocyte proliferation and regeneration. Here we found that both miR-17-92 and Hippo signaling were active in CCS. Disruption of either miR-17-92 or Hippo signaling in heart gave rise to cardiac arrhythmias in mice. Notably, miR-17-92 regulates Hippo signaling through repressing Lats2, a core Hippo pathway component. In miR-17-92 null mutant hearts, up-regulated Lats2 led to increased Hippo pathway activity. Moreover, we performed chromatin immunoprecipitation deep sequencing (ChIP-Seq) using YAP, the Hippo signaling effector, which suggested that Hippo signaling regulates genes involved in CCS homeostasis. Together, we propose a novel miR-Hippo genetic pathway that promotes CCS regeneration.

scholarly journals Hippo Signaling Pathway Has a Critical Role in Zika Virus Replication and in the Pathogenesis of Neuroinflammation

2020 ◽  
Vol 190 (4) ◽  
pp. 844-861 ◽  
Author(s):  
Gustavo Garcia ◽  
Sayan Paul ◽  
Sara Beshara ◽  
V. Krishnan Ramanujan ◽  
Arunachalam Ramaiah ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Virus Replication ◽  
Zika Virus ◽  
Critical Role ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway

scholarly journals Yes-associated protein 1 is required for proliferation and function of bovine granulosa cells in vitro†

2019 ◽  
Vol 101 (5) ◽  
pp. 1001-1017 ◽  
Author(s):  
Michele R Plewes ◽  
Xiaoying Hou ◽  
Pan Zhang ◽  
Aixin Liang ◽  
Guohua Hua ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Nuclear Localization ◽  
Granulosa Cells ◽  
Hippo Pathway ◽  
Critical Role ◽  
Small Cells ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
The Hippo Pathway

Abstract Yes-associated protein 1 (YAP1) is a major component of the Hippo signaling pathway. Although the exact extracellular signals that control the Hippo pathway are currently unknown, increasing evidence supports a critical role for the Hippo pathway in embryonic development, regulation of organ size, and carcinogenesis. Granulosa cells (GCs) within the ovarian follicle proliferate and produce steroids and growth factors, which facilitate the growth of follicle and maturation of the oocyte. We hypothesize that YAP1 plays a role in proliferation and estrogen secretion of GCs. In the current study, we examined the expression of the Hippo signaling pathway in bovine ovaries and determined whether it was important for GC proliferation and estrogen production. Mammalian STE20-like protein kinase 1 (MST1) and large tumor suppressor kinase 2 (LATS2) were identified as prominent upstream components of the Hippo pathway expressed in granulosa and theca cells of the follicle and large and small cells of the corpus luteum. Immunohistochemistry revealed that YAP1 was localized to the nucleus of growing follicles. In vitro, nuclear localization of the downstream Hippo signaling effector proteins YAP1 and transcriptional co-activator with PDZ-binding motif (TAZ) was inversely correlated with GC density, with greater nuclear localization under conditions of low cell density. Treatment with verteporfin and siRNA targeting YAP1 or TAZ revealed a critical role for these transcriptional co-activators in GC proliferation. Furthermore, knockdown of YAP1 in GCs inhibited follicle-stimulating hormone (FSH)-induced estradiol biosynthesis. The data indicate that Hippo pathway transcription co-activators YAP1/TAZ play an important role in GC proliferation and estradiol synthesis, two processes necessary for maintaining normal follicle development.

scholarly journals Overexpressed WDR3 Induces the Activation of Hippo Pathway by Interacting with GATA4 in Pancreatic Cancer

2020 ◽  
Author(s):  
Wenjie Su ◽  
Shikai Zhu ◽  
Kai Chen ◽  
Hongji Yang ◽  
Mingwu Tian ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Human Cancer ◽  
Critical Role ◽  
Biological Role ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Pancreatic Cancer Cells ◽  
Independent Functions

Abstract Background: WD repeat domain 3 (WDR3) is involved in a variety of cellular processes including gene regulation, cell cycle progression, signal transduction and apoptosis. However, the biological role of WDR3 in pancreatic cancer and the associated mechanism remains unclear. We seek to explore the immune-independent functions and relevant mechanism for WDR3 in pancreatic cancer.Methods: The GEPIA web tool was searched, and IHC assays were conducted to determine the mRNA and protein expression levels of WDR3 in pancreatic cancer patients. MTS, colony formation, and transwell assays were conducted to determine the biological role of WDR3 in human cancer. Western blot analysis, RT-qPCR, and immunohistochemistry were used to detect the expression of specific genes. An immunoprecipitation assay was used to explore protein-protein interactions.Results: Our study proved that overexpressed WDR3 was correlated with poor survival in pancreatic cancer and that WDR3 silencing significantly inhibited the proliferation, invasion and tumor growth of pancreatic cancer. Furthermore, WDR3 activated the Hippo signaling pathway by inducing yes association protein 1 (YAP1) expression, and the combination of WDR3 silencing and administration of the YAP1 inhibitor TED-347 had a synergistic inhibitory effect on the progression of pancreatic cancer. Finally, the upregulation of YAP1 expression induced by WDR3 was dependent on an interaction with GATA binding protein 4 (GATA4), the transcription factor of YAP1, in pancreatic cancer cells.Conclusions: We identified a novel mechanism by which WDR3 plays a critical role in promoting pancreatic cancer progression by activating the Hippo signaling pathway through an interaction with GATA4. Therefore, WDR3 is potentially a therapeutic target for pancreatic cancer treatment.

Cfi-400945 Induces Cytokinesis Failure By Activating Hippo Signaling Pathway in Diffuse Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Yi Zhao ◽  
Juan Yang ◽  
Jiarui Liu ◽  
Shuai Ren ◽  
Yiqing Cai ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
B Cell ◽  
Signaling Pathway ◽  
Cell Lymphoma ◽  
Critical Role ◽  
B Cell Lymphoma ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Targeting mitosis has been found to be a therapeutic strategy for cancer since microtubule poisons have proved efficacy in a broad range of malignancies. Cytokinesis failure can increase chromosomal instability beyond a critical threshold that triggers tumor suppression. Thus, agents developed to block cytokinesis can stop proliferation of cancer cells. We previously demonstrated that the polo-like kinase 4 (PLK4) inhibitor, CFI-400945, triggers growth inhibition and apoptotic death in diffuse large B-cell lymphoma (DLBCL). Since PLK4 is involved in centrosome duplication for cell division, we aimed to explore the effects of CFI-400945 on cytokinesis in DLBCL cells. Here, we demonstrated that CFI-400945 induces cytokinesis failure in DLBCL. CFI-400945-treated cells led to binucleated/multinucleated cells (Fig. 1a). Previous study showed that the Hippo signaling pathway played a critical role in cytokinesis. Consistent with this finding, we found that CFI-400945 led to phosphorylation of LATS1 and YAP (Fig. 1b). Confocal microscopy confirmed the reduced nuclear YAP upon treatment of CFI-400945 (Fig. 1c). These results show that reduced nuclear YAP levels and activities contribute to growth inhibition by CFI-400945 in DLBCL cells. In addition, we further explored the synergy of CFI-400945 and doxorubicin (DOX) both in vitro and in vivo. A combined treatment of CFI-400945 and DOX significantly inhibited DLBCL cell survival and induced more apoptosis compared with CFI-400945 or DOX alone (Fig. 1d, Fig. 1e).In the mice xenograft model, the combination of CFI-400945 and DOX significantly delayed tumor progression compared to those treated with vehicle or DOX alone (Fig. 1f). Tumors from combination-treated mice displayed an increase in γ-H2AX staining and a reduction in Ki67 staining (Fig. 1g). Strikingly, tumor cells were generally larger, heterogeneous in size and frequently binucleated (Fig. 1h). Combined, our results indicate for the first time that CFI-400945 treatment induces cytokinesis failure and activation of Hippo signaling pathway, leading to vulnerability to mitotic catastrophe. Moreover, this study proves an attractive combination treatment that simultaneous targeting PLK4 with CFI-400945 could exacerbate mitotic defects to improve response of anthracycline-based chemotherapy in DLBCL. Figure 1 Disclosures No relevant conflicts of interest to declare.

Hippo Signaling Pathway has a critical role in Zika Virus Replication and in the Pathogenesis of Neuroinflammation

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Gustavo Garcia ◽  
Sayan Paul ◽  
Sara Beshara ◽  
Krishnan Ramanujan V ◽  
Arunachalam Ramaiah ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Virus Replication ◽  
Zika Virus ◽  
Critical Role ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway

scholarly journals Overexpressed WDR3 induces the activation of Hippo pathway by interacting with GATA4 in pancreatic cancer

2021 ◽  
Author(s):  
Wenjie Su ◽  
Shikai Zhu ◽  
Kai Chen ◽  
Hongji Yang ◽  
Mingwu Tian ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Biological Role ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Pancreatic Cancer Cells ◽  
Independent Functions

Abstract Background: WD repeat domain 3 (WDR3) is involved in a variety of cellular processes including gene regulation, cell cycle progression, signal transduction and apoptosis. However, the biological role of WDR3 in pancreatic cancer and the associated mechanism remains unclear. We seek to explore the immune-independent functions and relevant mechanism for WDR3 in pancreatic cancer.Methods: The GEPIA web tool was searched, and IHC assays were conducted to determine the mRNA and protein expression levels of WDR3 in pancreatic cancer patients. MTS, colony formation, and transwell assays were conducted to determine the biological role of WDR3 in human cancer. Western blot analysis, RT-qPCR, and immunohistochemistry were used to detect the expression of specific genes. An immunoprecipitation assay was used to explore protein-protein interactions.Results: Our study proved that overexpressed WDR3 was correlated with poor survival in pancreatic cancer and that WDR3 silencing significantly inhibited the proliferation, invasion, and tumor growth of pancreatic cancer. Furthermore, WDR3 activated the Hippo signaling pathway by inducing yes association protein 1 (YAP1) expression, and the combination of WDR3 silencing and administration of the YAP1 inhibitor TED-347 had a synergistic inhibitory effect on the progression of pancreatic cancer. Finally, the upregulation of YAP1 expression induced by WDR3 was dependent on an interaction with GATA binding protein 4 (GATA4), the transcription factor of YAP1, which interaction induced the nuclear translocation of GATA4 in pancreatic cancer cells.Conclusions: We identified a novel mechanism by which WDR3 plays a critical role in promoting pancreatic cancer progression by activating the Hippo signaling pathway through the interaction with GATA4. Therefore, WDR3 is potentially a therapeutic target for pancreatic cancer treatment.

scholarly journals PRC1 Stabilizes Cardiac Contraction by Regulating Cardiac Sarcomere Assembly and Cardiac Conduction System Construction

2021 ◽  
Vol 22 (21) ◽  
pp. 11368
Author(s):  
Xixia Peng ◽  
Gang Feng ◽  
Yanyong Zhang ◽  
Yuhua Sun
Keyword(s):  
Cardiac Development ◽  
Critical Role ◽  
Conduction System ◽  
Cardiac Contraction ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Loss Of Function ◽  
Atrioventricular Canal ◽  
Cardiac Sarcomere

Cardiac development is a complex process that is strictly controlled by various factors, including PcG protein complexes. Several studies have reported the critical role of PRC2 in cardiogenesis. However, little is known about the regulation mechanism of PRC1 in embryonic heart development. To gain more insight into the mechanistic role of PRC1 in cardiogenesis, we generated a PRC1 loss-of-function zebrafish line by using the CRISPR/Cas9 system targeting rnf2, a gene encoding the core subunit shared by all PRC1 subfamilies. Our results revealed that Rnf2 is not involved in cardiomyocyte differentiation and heart tube formation, but that it is crucial to maintaining regular cardiac contraction. Further analysis suggested that Rnf2 loss-of-function disrupted cardiac sarcomere assembly through the ectopic activation of non-cardiac sarcomere genes in the developing heart. Meanwhile, Rnf2 deficiency disrupts the construction of the atrioventricular canal and the sinoatrial node by modulating the expression of bmp4 and other atrioventricular canal marker genes, leading to an impaired cardiac conduction system. The disorganized cardiac sarcomere and defective cardiac conduction system together contribute to defective cardiac contraction. Our results emphasize the critical role of PRC1 in the cardiac development.

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