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Yap hippo

Xuhao Ni, Jinhui Tao, Joseph Barbi, Qian Chen, Benjamin V Park, Zhiguang Li, Nailing Zhang, Andriana Lebid, Anjali Ramaswamy, Ping Wei, Ying Zheng, Xuehong Zhang, Xingmei Wu, Paolo D A Vignali, Cuiping Yang, Huabin Li, Drew Pardoll, Ling Lu, Duojia Pan, Fan Pan
Regulatory T cells (Tregs) are critical for maintaining self-tolerance and immune homeostasis, but their suppressive function can impede effective anti-tumor immune responses. Foxp3 is a transcription factor expressed in Tregs that is required for their function. However, the pathways and microenvironmental cues governing Foxp3 expression and Treg function are not completely understood. Herein, we report that Yes-associated protein (YAP), a co-activator of the Hippo pathway, is highly expressed in Tregs and bolsters Foxp3 expression and Treg function in vitro and in vivo...
June 15, 2018: Cancer Discovery
Mei Yi, Junjun Li, Shengnan Chen, Jing Cai, Yuanyuan Ban, Qian Peng, Ying Zhou, Zhaoyang Zeng, Shuping Peng, Xiaoling Li, Wei Xiong, Guiyuan Li, Bo Xiang
BACKGROUND: Cancer stem cells (CSCs) or tumor-initiating cells (TICs) represent a small population of cancer cells with self-renewal and tumor-initiating properties. Unlike the bulk of tumor cells, CSCs or TICs are refractory to traditional therapy and are responsible for relapse or disease recurrence in cancer patients. Stem cells have distinct metabolic properties compared to differentiated cells, and metabolic rewiring contributes to self-renewal and stemness maintenance in CSCs. MAIN BODY: Recent advances in metabolomic detection, particularly in hyperspectral-stimulated raman scattering microscopy, have expanded our knowledge of the contribution of lipid metabolism to the generation and maintenance of CSCs...
June 15, 2018: Journal of Experimental & Clinical Cancer Research: CR
Jung-Chien Cheng, Evan Y Wang, Yuyin Yi, Avinash Thakur, Shu-Huei Tsai, Pamela A Hoodless
Dysregulation of the Hippo pathway in the liver results in overgrowth and eventually tumorigenesis. To date, several upstream mechanisms have been identified that affect the Hippo pathway; that ultimately regulate YAP, the major downstream effector of the pathway. However, upstream regulators of the Hippo pathway in the liver remain poorly defined. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that has been shown to stimulate hepatocellular carcinoma (HCC) cell proliferation, but whether the Hippo pathway is involved in S1P-stimulated HCC cell proliferation remains to be determined...
June 14, 2018: Molecular Cancer Research: MCR
Takaaki Sugihara, Nathan W Werneburg, Matthew C Hernandez, Lin Yang, Ayano Kabashima, Petra Hirsova, Lavanya Yohanathan, Carlos Sosa, Mark Joseph Truty, George Vasmatzis, Gregory J Gores, Rory L Smoot
The hippo pathway effector, Yes-associated protein (YAP) is a transcriptional co-activator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2 - LATS1/2) culminating in phosphorylation of YAP at Serine 127 (S127) and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models...
June 14, 2018: Molecular Cancer Research: MCR
Fu Zhao, Zhijun Yang, Yang Chen, Qiangyi Zhou, Jing Zhang, Jiang Liu, Bo Wang, Qiyang He, Li Zhang, Yanbin Yu, Pinan Liu
OBJECTIVE: Vestibular schwannomas (VSs) can cause serious neurological defects including hearing loss and facial paralysis. The aim of this study is to identify whether Hippo signaling could be potential targetable pathway for clinical treatment in VSs. METHODS: Gene expression profiling was performed in ten sporadic VSs and four normal nerves to identify aberrant genes expression of the Hippo pathway. Western blotting and immunohistochemical staining were both used to examine the expression of Hippo core components in twenty VS samples...
June 11, 2018: World Neurosurgery
Chengyong Lei, Shidong Lv, Hongyi Wang, Chuan Liu, Qiliang Zhai, Shanci Wang, Guixing Cai, Dingheng Lu, Zhen Sun, Qiang Wei
The role of leukemia inhibitory factor receptor (LIFR), which is important in the signal transduction of the interleukin-6 cytokine family, is still undefined in clear cell renal cell carcinoma (ccRCC). Thus, we examined the function and mechanism of LIFR in ccRCC. Low LIFR expression correlated with a poor prognosis and an aggressive tumor phenotype. Moreover, integrated LIFR DNA and mRNA analysis revealed that promoter methylation and copy number variation contributed to the reduced LIFR expression. LIFR knockdown increased 786-O and Caki-2 cell invasion and migration...
June 14, 2018: DNA and Cell Biology
Qingping Guo, Jiale Wang, Zeyu Cao, Yongchang Tang, Chao Feng, Feizhou Huang
Despite advances in surgery and chemotherapy, the prognosis of patients with hepatocellular carcinoma (HCC) remains poor. In the present study, the role of S100A1 in the progression of HCC was investigated. Immunohistochemical staining was used to measure the expression of S100A1 in HCC tissues. S100A1 was knocked down by siRNA. A battery of experiments was used to evaluate the biology functions of S100A1. It was found that S100A1 was upregulated in HCC tissues, and its upregulation was associated with a large tumor size, low differentiation and shorter survival time...
June 5, 2018: International Journal of Oncology
Wenying Angela Liu, She Chen, Zhizhong Li, Choong Heon Lee, Ghayda Mirzaa, William B Dobyns, M Elizabeth Ross, Jiangyang Zhang, Song-Hai Shi
Proper organization and orderly mitosis of radial glial progenitors (RGPs) drive the formation of a laminated mammalian cortex in the correct size. However, the molecular underpinnings of the intricate process remain largely unclear. Here we show that RGP behavior and cortical development are controlled by temporally distinct actions of partitioning-defective 3 (PARD3) in concert with dynamic HIPPO signaling. RGPs lacking PARD3 exhibit developmental stage-dependent abnormal switches in division mode, resulting in an initial overproduction of RGPs located largely outside the ventricular zone at the expense of deep-layer neurons...
June 13, 2018: Genes & Development
Shiyuan Huang, Xiaona Wang, Xinmei Wu, Jiale Yu, JinJing Li, Xiaoyuan Huang, Chunfang Zhu, Hongshan Ge
Yes-associated protein (Yap) was the core transcriptional co-activator in the downstream Hippo pathway that regulated cell proliferation and tissue growth. However, its role in the regulation of myoblast differentiation remains unclear. Regulation of mitochondrial networks by dynamin-related protein 1 (Drp1) and mitofusion 2 (Mfn2) is crucial for the activation of myoblast differentiation. In the present study, we investigated the interplay between the Hippo-Yap pathway and protein contents of Mfn2 and Drp1 during myoblast differentiation...
June 13, 2018: American Journal of Physiology. Cell Physiology
Yoonmi Lee, Nam Hee Kim, Eunae Sandra Cho, Ji Hye Yang, Yong Hoon Cha, Hee Eun Kang, Jun Seop Yun, Sue Bean Cho, Seon-Hyeong Lee, Petra Paclikova, Tomasz W Radaszkiewicz, Vitezslav Bryja, Chi Gu Kang, Young Soo Yuk, So Young Cha, Soo-Youl Kim, Hyun Sil Kim, Jong In Yook
Phosphorylation-dependent YAP translocation is a well-known intracellular mechanism of the Hippo pathway; however, the molecular effectors governing YAP cytoplasmic translocation remains undefined. Recent findings indicate that oncogenic YAP paradoxically suppresses Wnt activity. Here, we show that Wnt scaffolding protein Dishevelled (DVL) is responsible for cytosolic translocation of phosphorylated YAP. Mutational inactivation of the nuclear export signal embedded in DVL leads to nuclear YAP retention, with an increase in TEAD transcriptional activity...
June 12, 2018: Nature Communications
Mateus Mota, William P Jackson, Sarah K Bailey, Praveen Vayalil, Aimee Landar, Jack W Rostas, Madhuri S Mulekar, Rajeev S Samant, Lalita A Shevde
The NF2 gene encodes the tumor and metastasis suppressor protein Merlin. Merlin exerts its tumor suppressive role by inhibiting proliferation and inducing contact-growth inhibition and apoptosis. In the current investigation, we determined that loss of Merlin in breast cancer tissues is concordant with the loss of the inhibitory SMAD, SMAD7, of the TGF-β pathway. This was reflected as dysregulated activation of TGF-β signaling that co-operatively engaged with effectors of the Hippo pathway (YAP/TAZ/TEAD)...
June 9, 2018: Carcinogenesis
Fan Yao, Zhicheng Zhou, Jongchan Kim, Qinglei Hang, Zhenna Xiao, Baochau N Ton, Liang Chang, Na Liu, Liyong Zeng, Wenqi Wang, Yumeng Wang, Peijing Zhang, Xiaoyu Hu, Xiaohua Su, Han Liang, Yutong Sun, Li Ma
Dysregulation of YAP localization and activity is associated with pathological conditions such as cancer. Although activation of the Hippo phosphorylation cascade is known to cause cytoplasmic retention and inactivation of YAP, emerging evidence suggests that YAP can be regulated in a Hippo-independent manner. Here, we report that YAP is subject to non-proteolytic, K63-linked polyubiquitination by the SCFSKP2 E3 ligase complex (SKP2), which is reversed by the deubiquitinase OTUD1. The non-proteolytic ubiquitination of YAP enhances its interaction with its nuclear binding partner TEAD, thereby inducing YAP's nuclear localization, transcriptional activity, and growth-promoting function...
June 11, 2018: Nature Communications
Jing Cai, Xuewen Song, Wei Wang, Terry Watnick, York Pei, Feng Qian, Duojia Pan
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder caused by mutations in PKD1 or PKD2 and affects one in 500-1000 humans. Limited treatment is currently available for ADPKD. Here we identify the Hippo signaling effector YAP and its transcriptional target, c-Myc, as promoters of cystic kidney pathogenesis. While transgenic overexpression of YAP promotes proliferation and tubule dilation in mouse kidneys, loss of YAP/TAZ or c-Myc suppresses cystogenesis in a mouse ADPKD model resulting from Pkd1 deficiency...
June 11, 2018: Genes & Development
Sergio Rivas, Inés M Antón, Francisco Wandosell
Wild-type p53 (wtp53) is described as a tumour suppressor gene, and mutations in p53 occur in many human cancers. Indeed, in high-grade malignant glioma, numerous molecular genetics studies have established central roles of RTK-PI3K-PTEN and ARF-MDM2-p53 INK4a-RB pathways in promoting oncogenic capacity. Deregulation of these signalling pathways, among others, drives changes in the glial/stem cell state and environment that permit autonomous growth. The initially transformed cell may undergo subsequent modifications, acquiring a more complete tumour-initiating phenotype responsible for disease advancement to stages that are more aggressive...
June 9, 2018: Cancers
Maud Debaugnies, Adriana Sánchez-Danés, Sandrine Rorive, Maylis Raphaël, Mélanie Liagre, Marie-Astrid Parent, Audrey Brisebarre, Isabelle Salmon, Cédric Blanpain
YAP and TAZ are key downstream regulators of the Hippo pathway, regulating cell proliferation and differentiation. YAP and TAZ activation has been reported in different cancer types. However, it remains unclear whether they are required for the initiation of major skin malignancies like basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Here, we analyze the expression of YAP and TAZ in these skin cancers and evaluate cancer initiation in knockout mouse models. We show that YAP and TAZ are nuclear and highly expressed in different BCC types in both human and mice...
June 6, 2018: EMBO Reports
Jin-Xiu Pan, Lei Xiong, Kai Zhao, Peng Zeng, Bo Wang, Fu-Lei Tang, Dong Sun, Hao-Han Guo, Xiao Yang, Shun Cui, Wen-Fang Xia, Lin Mei, Wen-Cheng Xiong
YAP (yes-associated protein) is a transcriptional factor that is negatively regulated by Hippo pathway, a conserved pathway for the development and size control of multiple organs. The exact function of YAP in bone homeostasis remains controversial. Here we provide evidence for YAP's function in promoting osteogenesis, suppressing adipogenesis, and thus maintaining bone homeostasis. YAP is selectively expressed in osteoblast (OB)-lineage cells. Conditionally knocking out Yap in the OB lineage in mice reduces cell proliferation and OB differentiation and increases adipocyte formation, resulting in a trabecular bone loss...
2018: Bone Research
Yang Liu, Faji Yang, Jun Li, Jinglin Wang, Xun Wang, Yuheng Zhang, Xianwen Yuan, Wei Zhu, Xiaolei Shi
The liver has the potential to regenerate after injury. It is a challenge to improve liver regeneration (LR) after liver resection in clinical practice. Bone morrow-derived mesenchymal stem cells (MSCs) have shown to have a role in various liver diseases. To explore the effects of MSCs on LR, we established a model of 70% partial hepatectomy (PHx). Results revealed that infusion of MSCs could improve LR through enhancing cell proliferation and cell growth during the first 2 days after PHx, and MSCs could also restore liver synthesis function...
2018: Stem Cells International
Xiaogui Yi, Jia Yu, Chao Ma, Li Li, Lingfei Luo, Hongtao Li, Hua Ruan, Honghui Huang
Hippo pathway regulates cell proliferation and differentiation. Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) are effectors of Hippo pathway. The function of Yap/Taz in embryonic liver development has yet to be reported. Here yap1 and taz were found expressed in liver and other digestive organs in zebrafish embryos, and knockout of yap1 or taz did not lead to visible defects during embryogenesis. Interestingly, Taz was significantly increased in yap1 mutants, which may account for their normal development, albeit losing Yap1...
May 30, 2018: Biochemical and Biophysical Research Communications
Xingrong Du, Jing Wen, Yanyan Wang, Peer W F Karmaus, Alireza Khatamian, Haiyan Tan, Yuxin Li, Cliff Guy, Thanh-Long M Nguyen, Yogesh Dhungana, Geoffrey Neale, Junmin Peng, Jiyang Yu, Hongbo Chi
Dendritic cells orchestrate the crosstalk between innate and adaptive immunity. CD8α+ dendritic cells present antigens to CD8+ T cells and elicit cytotoxic T cell responses to viruses, bacteria and tumours 1 . Although lineage-specific transcriptional regulators of CD8α+ dendritic cell development have been identified 2 , the molecular pathways that selectively orchestrate CD8α+ dendritic cell function remain elusive. Moreover, metabolic reprogramming is important for dendritic cell development and activation3,4 , but metabolic dependence and regulation of dendritic cell subsets are largely uncharacterized...
May 30, 2018: Nature
Sumie Kato, María Francisca Liberona, Javier Cerda-Infante, Marianela Sanchez, Jenny F Henriquez, Carolina Bizama, Maria Loreto Bravo, Pamela Gonzalez, Roger Gejman, Jorge Branes, Karen García, Carolina Ibañez, Gareth Ivor Owen, Juan Carlos Roa, Viviana Montecinos, Mauricio Arturo Cuello
Cell plasticity of 'stem-like' cancer-initiating cells (CICs) is a hallmark of cancer, allowing metastasis and cancer progression. Here, we studied whether simvastatin, a lipophilic statin, could impair the metastatic potential of CICs in high-grade serous ovarian cancer (HGS-ovC), the most lethal among the gynecologic malignancies. qPCR, immunoblotting, and immunohistochemistry were used to assess simvastatin effects on proteins involved in stemness and epithelial-mesenchymal cell plasticity (EMT). Its effects on tumor growth and metastasis were evaluated using different models (e...
May 30, 2018: Endocrine-related Cancer
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