Effects Of Yes-associated Protein 1 Research Articles

YAP1 promotes high glucose-induced inflammation and extracellular matrix deposition in glomerular mesangial cells by modulating NF-κB/JMJD3 pathway.

Diabetic nephropathy (DN) is one of the most serious microvascular complications of late-stage diabetes. Glomerular mesangial cell (GMC) proliferation and excessive extracellular matrix (ECM) deposition are the main pathological characteristics associated with the occurrence and development of DN. Yes-associated protein 1 (YAP1) can bind to several transcription factors and is associated with the development of various diseases. However, the effects of YAP1 on DN remain unclear. The aim of the present study was to explore the regulatory effect and potential mechanism of YAP1 in glucose-induced inflammation and ECM deposition in high-glucose-treated GMCs. In the present study, HBZY-1 cell models treated with high glucose were constructed, and the effects of YAP1 on the proliferation, inflammation, ECM deposition and fibrosis of HBZY-1 cells were detected. The results showed that YAP1 was highly expressed in HBZY-1 cells treated with high glucose and that YAP1 silencing decreased cell viability, the levels of inflammatory cytokines, ECM deposition and the degree of fibrosis in cells. Further experiments revealed that NF-κB/Jumonji domain-containing protein D3 (JMJD3) signaling pathway inhibitors alleviated the promoting effect of YAP1 overexpression on inflammatory response and ECM deposition in HBZY-1 cells treated with high glucose. In conclusion, it was demonstrated that YAP1 can promote high glucose-induced inflammation and ECM deposition by activating the NF-κB/JMJD3 signaling pathway in GMCs.

Estradiol-17β regulates proliferation and apoptosis of sheep endometrial epithelial cells by regulating the relative abundance of YAP1

Yes-associated protein 1 (YAP1) transcription regulator of the Hippo protein kinase pathway, serves as a key regulator of tissue growth and organ size by regulating cell proliferation and apoptosis. Effects of YAP1 on proliferation and apoptosis of sheep endometrial epithelial cells (EEC) as a result of estradiol-17β (E2) treatment, however, remain unclear. In the present study, the abundance of YAP1 protein in the uterine horn was greater than that in the uterine body or cervix. The YAP1 protein was primarily localized in the endometrial luminal and glandular epithelial cells of the uterine horn of ewes on day 2 of the estrous cycle. Compared with control samples, there was a lesser abundance of YAP1 mRNA transcript that was associated with a lesser proliferation and greater apoptosis of EEC. There were also lesser concentrations of epidermal growth factor and insulin-like growth factor 1 in the spent culture medium when there was a lesser abundance of YAP1 mRNA in EEC compared with those in the control group. When there was a greater abundance of YAP1 mRNA transcript, there were greater concentrations of epidermal growth factor and insulin-like growth factor 1 in the spent media. Furthermore, with estradiol-17β treatment the abundance of YAP1 mRNA transcript was similar to that of the control samples. Taken together, estradiol-17β may function as an essential regulator of EEC proliferation and apoptosis by modulation of concentrations of YAP1 protein in the sheep uterus. These results indicate there are molecular mechanisms of estradiol-17β and YAP1 in EEC proliferation and apoptosis of ewes.

Mechanism of YAP1-JUN promoting proliferation and EMT transformation of human laryngeal squamous cell carcinoma cells

Objective To investigate the role of Yes-associated protein 1 (YAP1)-JUN in promoting the proliferation and epithelial mesenchymal transitions (EMT) transformation of laryngeal squamous cell carcinoma. Methods The expression and subcellular localization of YAP1 were detected by tissue immunofluorescence assay. The effects of YAP1 on the proliferation of laryngeal squamous cell were examined by cell clone formation experiment. Western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were used to detect the effect of YAP1 on the expression and transcriptional level of EMT-related molecular markers. The interaction between YAP1 and JUN was detected by immunocoprecipitation (CoIP) and Western blot assay, which regulated the expression of downstream genes to control the EMT process. Results The expression of YAP1 in laryngeal squamous cell carcinoma tissue increased and transferred from cytoplasm to nucleus. The number of clones increased significantly after YAP1 up regulation (P<0.01). The expression level of key gene E-cadherin in epithelial cells was significantly inhibited after YAP1 up (P<0.01), while the expression level of the key genes of interstitial cells, β-catenin, vimentin and N-cadherin was significantly up (P<0.01). YAP1 was interacted with nuclear transcription factor JUN, and the proliferation ability of YAP1 decreased significantly (P<0.01) after the inhibition of JUN expression (P<0.01), and the expression of EMT related molecular markers decreased significantly (P<0.01). Conclusions YAP1 combined with JUN gene promotes the proliferation and EMT transformation of human laryngeal squamous cell carcinoma cells. Key words: Laryngeal neoplasms; Carcinoma, squamous cell; Yes-associated protein 1; Cell proliferation; Epithelial-mesenchymal transition

Helicobacter pylori-induced YAP1 nuclear translocation promotes gastric carcinogenesis by enhancing IL-1β expression.

Gastric cancer (GC) is one of the most common and malignant pathologies, and a significant portion of GC incidences develops from Helicobacter pylori (Hp)‐induced chronic gastritis. Although the exact mechanisms of GC are complex and poorly understood, gastric carcinogenesis is a good model to investigate how inflammation and infection collaboratively promote tumorigenesis. Yes‐associated protein 1 (YAP1) is the key effector of the Hippo pathway, which is silenced in most human cancers. Herein, we verified the tumor‐promoting effect of YAP1 in vitro, in vivo, and in human specimens. We revealed that YAP1 displays nuclear translocation and works with TEAD to activate transcription of the crucial inflammatory cytokine IL‐1β in gastric cells infected with Hp. As IL‐1ß accounts for inflammation‐associated tumorigenesis, this process can lead to gastric carcinogenesis. Thus, in addition to activating proliferation genes, YAP1 also plays a major role in inflammation amplification by activating inflammatory cytokine genes. Excitingly, our research demonstrates that transfection of mutant plasmid YAP‐5SA/S94A or addition of the drug verteporfin, both of which are thought to disrupt the YAP1‐TEAD interaction, can arrest the carcinogenesis process. These findings can provide new approaches to GC treatment.

Effect of YAP1 on pancreatic stellate cell activation and tumor microenvironment.

e16199Background: Activated pancreatic stellate cells (PSCs) secrete excessive molecules to support tumor microenvironment. Yes-associated protein 1(YAP1) can regulates cellular mechanics, which is...

Yes-associated protein 1 promotes the differentiation and mineralization of cementoblast.

Yes-associated protein 1 (YAP1) transcriptional coactivator is a mediator of mechanosensitive signaling. Cementum, which covers the tooth root surface, continuously senses external mechanical stimulation. Cementoblasts are responsible for the mineralization and maturation of the cementum. However, the effect of YAP1 on cementoblast differentiation remains largely unknown. In this study, we initially demonstrated that YAP1 overexpression enhanced the mineralization ability of cementoblasts. YAP1 upregulated the mRNA and protein expression of several cementogenesis markers, such as alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and dentin matrix acidic phosphoprotein 1 (DMP1). The YAP1 overexpression group showed higher intensities of ALP and Alizarin red stain than the YAP1-knockdown group. Unexpectedly, a sharp increase in the expression of dentin sialophosphoprotein (DSPP) was induced by the overexpression of YAP1. Knockdown of YAP1 suppressed DSPP transcriptional activity. YAP1 overexpression activated Smad-dependent BMP signaling and slightly inhibited Erk1/2 signaling pathway activity. Treatment with specific BMP antagonist (LDN193189) prevented the upregulation of the mRNA levels of ALP, RUNX2, and OCN, as well as intensity of ALP-stained and mineralized nodules in cementoblasts. The Erk1/2 signaling pathway inhibitor (PD 98,059) upregulated these cementogenesis markers. Thus, our study suggested that YAP1 enhanced cementoblast mineralization in vitro. YAP1 exerted its effect on the cementoblast partly by regulating the Smad-dependent BMP and Erk1/2 signaling pathways.

YAP1 Regulates OCT4 Activity and SOX2 Expression to Facilitate Self-Renewal and Vascular Mimicry of Stem-Like Cells.

Non-small cell lung cancer (NSCLC) is highly correlated with smoking and has very low survival rates. Multiple studies have shown that stem-like cells contribute to the genesis and progression of NSCLC. Our results show that the transcriptional coactivator yes-associated protein 1 (YAP1), which is the oncogenic component of the Hippo signaling pathway, is elevated in the stem-like cells from NSCLC and contributes to their self-renewal and ability to form angiogenic tubules. Inhibition of YAP1 by a small molecule or depletion of YAP1 by siRNAs suppressed self-renewal and vascular mimicry of stem-like cells. These effects of YAP1 were mediated through the embryonic stem cell transcription factor, Sox2. YAP1 could transcriptionally induce Sox2 through a physical interaction with Oct4; Sox2 induction occurred independent of TEAD2 transcription factor, which is the predominant mediator of YAP1 functions. The binding of Oct4 to YAP1 could be detected in cell lines as well as tumor tissues; the interaction was elevated in NSCLC samples compared to normal tissue as seen by proximity ligation assays. YAP1 bound to Oct4 through the WW domain, and a peptide corresponding to this region could disrupt the interaction. Delivery of the WW domain peptide to stem-like cells disrupted the interaction and abrogated Sox2 expression, self-renewal, and vascular mimicry. Depleting YAP1 reduced the expression of multiple epithelial-mesenchymal transition genes and prevented the growth and metastasis of tumor xenografts in mice; overexpression of Sox2 in YAP1 null cells rescued these functions. These results demonstrate a novel regulation of stem-like functions by YAP1, through the modulation of Sox2 expression.