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https://www.readbyqxmd.com/read/28334506/molecular-features-of-the-yap-inhibitor-verteporfin-synthesis-of-hexasubstituted-dipyrrins-as-potential-inhibitors-of-yap-taz-the-downstream-effectors-of-the-hippo-pathway
#1
Floriane Gibault, Fabrice Bailly, Matthieu Corvaisier, Mathilde Coevoet, Guillemette Huet, Patricia Melnyk, Philippe Cotelle
Porphyrin derivatives, and in particular Verteporfin (VP), a photosensitizer initially designed for cancer therapy, have been identified as inhibitors of YAP-TEAD interaction and transcriptional activity. We herein report the efficient convergent synthesis of the dipyrrin western half-part of protoporphyrin IX dimethyl ester (PPIX-DME) where the sensitive vinyl group was created at the final stage by a dehydroiodation reaction. Two other dipyrrin derivatives were synthesized including dipyrrin 19 containing two vinyl groups...
March 23, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28332498/a-genome-wide-screen-identifies-yap-wbp2-interplay-conferring-growth-advantage-on-human-epidermal-stem-cells
#2
Gernot Walko, Samuel Woodhouse, Angela Oliveira Pisco, Emanuel Rognoni, Kifayathullah Liakath-Ali, Beate M Lichtenberger, Ajay Mishra, Stephanie B Telerman, Priyalakshmi Viswanathan, Meike Logtenberg, Lisa M Renz, Giacomo Donati, Sven R Quist, Fiona M Watt
Individual human epidermal cells differ in their self-renewal ability. To uncover the molecular basis for this heterogeneity, we performed genome-wide pooled RNA interference screens and identified genes conferring a clonal growth advantage on normal and neoplastic (cutaneous squamous cell carcinoma, cSCC) human epidermal cells. The Hippo effector YAP was amongst the top positive growth regulators in both screens. By integrating the Hippo network interactome with our data sets, we identify WW-binding protein 2 (WBP2) as an important co-factor of YAP that enhances YAP/TEAD-mediated gene transcription...
March 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/28323616/yap-is-essential-for-mechanical-force-production-and-epithelial-cell-proliferation-during-lung-branching-morphogenesis
#3
Chuwen Lin, Erica Yao, Kuan Zhang, Xuan Jiang, Stacey Croll, Katherine Thompson-Peer, Pao-Tien Chuang
Branching morphogenesis is a fundamental program for tissue patterning. We show that active YAP, a key mediator of Hippo signaling, is distributed throughout the murine lung epithelium and loss of epithelial YAP severely disrupts branching. Failure to branch is restricted to regions where YAP activity is removed. This suggests that YAP controls local epithelial cell properties. In support of this model, mechanical force production is compromised and cell proliferation is reduced in Yap mutant lungs. We propose that defective force generation and insufficient epithelial cell number underlie the branching defects...
March 21, 2017: ELife
https://www.readbyqxmd.com/read/28299672/roles-of-runx-in-hippo-pathway-signaling
#4
Antonino Passaniti, Jessica L Brusgard, Yiting Qiao, Marius Sudol, Megan Finch-Edmondson
The Runt-domain (RD) transcription factors (RUNX genes) are an important family of transcriptional mediators that interact with a variety of proteins including the Hippo pathway effector proteins, YAP and TAZ. In this chapter we focus on two examples of RUNX-TAZ/YAP interactions that have particular significance in human cancer. Specifically, recent evidence has found that RUNX2 cooperates with TAZ to promote epithelial to mesenchymal transition mediated by the soluble N-terminal ectodomain of E-Cadherin, sE-Cad...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28289060/the-crumbs3-polarity-protein
#5
Ben Margolis
The Crumbs proteins are evolutionarily conserved apical transmembrane proteins. Drosophila Crumbs was discovered via its crucial role in epithelial polarity during fly embryogenesis. Crumbs proteins have variable extracellular domains but a highly conserved intracellular domain that can bind FERM and PDZ domain proteins. Mammals have three Crumbs genes and this review focuses on Crumbs3, the major Crumbs isoform expressed in mammalian epithelial cells. Although initial work has highlighted the role of Crumbs3 in polarity, more recent studies have found it has an important role in tissue morphogenesis functioning as a linker between the apical membrane and the actin cytoskeleton...
March 13, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28279717/yap-and-wwtr1-new-targets-for-skin-cancer-treatment
#6
Thomas Andl, Linli Zhou, Kun Yang, Ana Luisa Kadekaro, Yuhang Zhang
The core components of the Hippo signaling pathway are a cascade of kinases that govern the phosphorylation of downstream transcriptional co-activators, namely, YES-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1, also known as TAZ). The Hippo signaling pathway is considered an important tumor-suppressor pathway, and its dysregulation has been noted in a variety of human cancers, in which YAP/WWTR1 enable cancerous cells to overcome contact inhibition, and to grow and spread uncontrollably...
March 6, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28274274/a-novel-form-of-necrosis-triad-occurs-in-human-huntington-s-disease
#7
Emiko Yamanishi, Kazuko Hasegawa, Kyota Fujita, Shizuko Ichinose, Saburo Yagishita, Miho Murata, Kazuhiko Tagawa, Takumi Akashi, Yoshinobu Eishi, Hitoshi Okazawa
We previously reported transcriptional repression-induced atypical cell death of neuron (TRIAD), a new type of necrosis that is mainly regulated by Hippo pathway signaling and distinct from necroptosis regulated by RIP1/3 pathway. Here, we examined the ultrastructural and biochemical features of neuronal cell death in the brains of human HD patients in parallel with the similar analyses using mutant Htt-knock-in (Htt-KI) mice. LATS1 kinase, the critical regulator and marker of TRIAD, is actually activated in cortical neurons of postmortem human HD and of Htt-KI mouse brains, while apoptosis promoter kinase Plk1 was inactivated in human HD brains...
March 8, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28273460/agrin-as-a-mechanotransduction-signal-regulating-yap-through-the-hippo-pathway
#8
Sayan Chakraborty, Kizito Njah, Ajaybabu V Pobbati, Ying Bena Lim, Anandhkumar Raju, Manikandan Lakshmanan, Vinay Tergaonkar, Chwee Teck Lim, Wanjin Hong
The Hippo pathway effectors YAP and TAZ act as nuclear sensors of mechanical signals in response to extracellular matrix (ECM) cues. However, the identity and nature of regulators in the ECM and the precise pathways relaying mechanoresponsive signals into intracellular sensors remain unclear. Here, we uncover a functional link between the ECM proteoglycan Agrin and the transcriptional co-activator YAP. Importantly, Agrin transduces matrix and cellular rigidity signals that enhance stability and mechanoactivity of YAP through the integrin-focal adhesion- and Lrp4/MuSK receptor-mediated signaling pathways...
March 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/28259973/furin-promotes-epithelial-mesenchymal-transition-in-pancreatic-cancer-cells-via-hippo-yap-pathway
#9
Youli Zhang, Meng Zhou, Hong Wei, Hailang Zhou, Junbo He, Ying Lu, Dawei Wang, Baoding Chen, Jian Zeng, Wanxin Peng, Fengyi Du, Aihua Gong, Min Xu
Furin, a well-characterized proprotein convertase, plays an important role in many diseases and links to tumor metastasis. However, the role of furin in pancreatic cancer progression remains to be elucidated. In the present study, we found that furin promotes the growth and the epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. First, we found that furin knockdown significantly inhibited proliferation, invasion and migration in BxPC3 and SW1990 cells, while furin overexpression promoted the above behavior in PANC1 and PaTu8988 cells...
March 2, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28257933/genetic-ablation-of-the-mammalian-sterile-20-like-kinase-1-mst1-improves-cell-reprogramming-efficiency-and-increases-induced-pluripotent-stem-cell-proliferation-and-survival
#10
Abigail Robertson, Tamer M A Mohamed, Zeinab El Maadawi, Nicholas Stafford, Thuy Bui, Dae-Sik Lim, Elizabeth J Cartwright, Delvac Oceandy
Adult fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSC) for use in various applications. However, there are challenges in iPSC generation including low reprogramming efficiency, yield, cell survival and viability. Since the Hippo signalling pathway is a key pathway involved in regulating cell proliferation and survival, we here test whether modification of the Hippo pathway will enhance the efficiency of iPSC generation and improve their survival. The Hippo pathway was modified by genetic ablation of the mammalian sterile-20 like kinase 1 (Mst1), a major component of the pathway...
February 27, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28250241/stimulation-of-ovarian-follicle-growth-following-ampk-inhibition
#11
Xiaowei Lu, Song Guo, Yuan Cheng, Jae-Hong Kim, Yi Feng, Yun Feng
Previous studies showed that the protein kinase B (Akt)-mammalian target of rapamycin (mTOR) and Hippo signaling-Yes associated protein (YAP) pathways play important roles in promoting follicle growth. Additionally, other studies demonstrated that 5' adenosine monophosphate-activated protein kinase (AMPK) is an upstream regulatory element of mTOR and YAP. Here, we used AMPK inhibitor (Compound C) to in vitro culture ovaries from 10-day-old mice followed by in vivo grafting into adult hosts, or to in situ treat ovaries of 3-week-old mice by intrabursal injection followed by gonadotropin stimulation...
March 1, 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/28249901/endothelin-promotes-colorectal-tumorigenesis-by-activating-yap-taz
#12
Zhen Wang, Peng Liu, Xin Zhou, Tianxiang Wang, Xu Feng, Yi-Ping Sun, Yue Xiong, Hai-Xin Yuan, Kun-Liang Guan
Endothelin receptor A (ETAR) promotes tumorigenesis by stimulating cell proliferation, migration and survival. However, the mechanism of ETAR in promoting tumor growth is largely unknown. In this study, we demonstrate that ETAR stimulates colon cell proliferation, migration, and tumorigenesis through the activation of YAP/TAZ, two transcription co-activators of the Hippo tumor suppressor pathway. Endothelin-1 (ET-1) treatment induced YAP/TAZ dephosphorylation, nuclear accumulation, and transcriptional activation in multiple colon cancer cells...
March 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28249813/induction-of-chromosome-instability-by-activation-of-yes-associated-protein-and-forkhead-box-m1-in-liver-cancer
#13
Sofia M E Weiler, Federico Pinna, Thomas Wolf, Teresa Lutz, Aman Geldiyev, Carsten Sticht, Maria Knaub, Stefan Thomann, Michaela Bissinger, Shan Wan, Stephanie Rössler, Diana Becker, Norbert Gretz, Hauke Lang, Frank Bergmann, Vladimir Ustiyan, Tatiana V Kalin, Stephan Singer, Ju-Seog Lee, Jens U Marquardt, Peter Schirmacher, Vladimir V Kalinichenko, Kai Breuhahn
BACKGROUND & AIMS: Many different types of cancer cells have chromosome instability. The hippo pathway leads to phosphorylation of the transcriptional activator yes associated protein 1 (YAP1, YAP), which regulates proliferation and has been associated with development of liver cancer. We investigated the effects of hippo signaling via YAP on chromosome stability and hepatocarcinogenesis in humans and mice. METHODS: We analyzed transcriptome data from 242 patients with hepatocellular carcinoma (HCC) to search for gene signatures associated with chromosomal instability; we investigated associations with overall survival time and cancer recurrence using Kaplan-Meier curves...
February 26, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28244491/new-evidence-for-non-canonical-hippo-signaling-in-cancer
#14
Jonathan Cooper, Filippo G Giancotti
The molecular mechanisms governing self-renewal and differentiation of the mammary epithelium are incompletely defined; a better understanding of the events implicated in the specification and expansion of luminal progenitors is of particular importance as many breast cancers originate from their transformation. Britschgi et al. found that, in addition to phosphorylating and inactivating YAP, LATS functions as a scaffold to facilitate estrogen receptor-α ubiquitylation by the E3 ligase CRL4 and consequently suppresses luminal progenitor specification and expansion...
February 28, 2017: Cell Research
https://www.readbyqxmd.com/read/28229253/the-biology-of-uveal-melanoma
#15
Adriana Amaro, Rosaria Gangemi, Francesca Piaggio, Giovanna Angelini, Gaia Barisione, Silvano Ferrini, Ulrich Pfeffer
Uveal melanoma (UM), a rare cancer of the eye, is distinct from cutaneous melanoma by its etiology, the mutation frequency and profile, and its clinical behavior including resistance to targeted therapy and immune checkpoint blockers. Primary disease is efficiently controlled by surgery or radiation therapy, but about half of UMs develop distant metastasis mostly to the liver. Survival of patients with metastasis is below 1 year and has not improved in decades. Recent years have brought a deep understanding of UM biology characterized by initiating mutations in the G proteins GNAQ and GNA11...
February 22, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28223311/single-tumor-initiating-cells-evade-immune-clearance-by-recruiting-type-ii-macrophages
#16
Xiaocan Guo, Yang Zhao, Huan Yan, Yingcheng Yang, Shuying Shen, Xiaoming Dai, Xinyan Ji, Fubo Ji, Xing-Guo Gong, Li Li, Xueli Bai, Xin-Hua Feng, Tingbo Liang, Junfang Ji, Lei Chen, Hongyang Wang, Bin Zhao
Tumor infiltrated type II (M2) macrophages promote tumorigenesis by suppressing immune clearance, promoting proliferation, and stimulating angiogenesis. Interestingly, macrophages were also found to enrich in small foci of altered hepatocytes containing liver tumor-initiating cells (TICs). However, whether and how TICs specifically recruit macrophages and the function of these macrophages in tumor initiation remain unknown due to technical difficulties. In this study, by generating genetically defined liver TICs, we demonstrate that TICs actively recruit M2 macrophages from as early as the single-cell stage...
February 21, 2017: Genes & Development
https://www.readbyqxmd.com/read/28222762/the-hippo-component-yap-localizes-in-the-nucleus-of-human-papilloma-virus-positive-oropharyngeal-squamous-cell-carcinoma
#17
Faisal Alzahrani, Leanne Clattenburg, Shanmugam Muruganandan, Martin Bullock, Kaitlyn MacIsaac, Michael Wigerius, Blair A Williams, M Elise R Graham, Matthew H Rigby, Jonathan R B Trites, S Mark Taylor, Christopher J Sinal, James P Fawcett, Robert D Hart
BACKGROUND: HPV infection causes cervical cancer, mediated in part by the degradation of Scribble via the HPV E6 oncoprotein. Recently, Scribble has been shown to be an important regulator of the Hippo signaling cascade. Deregulation of the Hippo pathway induces an abnormal cellular transformation, epithelial to mesenchymal transition, which promotes oncogenic progression. Given the recent rise in oropharyngeal HPV squamous cell carcinoma we sought to determine if Hippo signaling components are implicated in oropharyngeal squamous cell carcinoma...
February 22, 2017: Journal of Otolaryngology—Head & Neck Surgery
https://www.readbyqxmd.com/read/28213440/muscle-yap-is-a-regulator-of-neuromuscular-junction-formation-and-regeneration
#18
Kai Zhao, Chengyong Shen, Yisheng Lu, Zhihui Huang, Lei Li, Christopher D Rand, Jinxiu Pan, Xiang-Dong Sun, Zhibing Tan, Hongsheng Wang, Guanglin Xing, Yu Cao, Guoqing Hu, Jiliang Zhou, Wen-Cheng Xiong, Lin Mei
Yes-associated protein (Yap) is a major effector of the Hippo pathway that regulates cell proliferation and differentiation during development and restricts tissue growth in adult animals. However, its role in synapse formation remains poorly understood. In this study, we characterized Yap's role in the formation of neuromuscular junction (NMJ). In HSA-Yap(-/-) mice where Yap was mutated specifically in muscle cells, AChR clusters were smaller and were distributed in a broader region in the middle of muscle fibers, suggesting that muscle Yap is necessary for the size and location of AChR clusters...
February 17, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28202507/yap-taz-mediated-upregulation-of-gab2-leads-to-increased-sensitivity-to-growth-factor-induced-activation-of-the-pi3k-pathway
#19
Chao Wang, Chao Gu, Kang Jin Jeong, Dong Zhang, Wei Guo, Yiling Lu, Zhenlin Ju, Nattapon Panupinthu, Ji Yeon Yang, Mihai Mike Gagea, Patrick Kwok Shing Ng, Fan Zhang, Gordon B Mills
The transcription regulators YAP and TAZ function as effectors of the HIPPO signaling cascade, critical for organismal development, cell growth, and cellular reprogramming, and YAP/TAZ is commonly misregulated in human cancers. The precise mechanism by which aberrant YAP/TAZ promotes tumor growth remains unclear. The HIPPO tumor suppressor pathway phosphorylates YAP and TAZ, resulting in cytosolic sequestration with subsequent degradation. Here, we report that the PI3K/AKT pathway, which is critically involved in the pathophysiology of endometrial cancer, interacts with the HIPPO pathway at multiple levels...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28183853/mark4-inhibits-hippo-signaling-to-promote-proliferation-and-migration-of-breast-cancer-cells
#20
Emad Heidary Arash, Ahmed Shiban, Siyuan Song, Liliana Attisano
The Hippo pathway is a critical regulator of tissue size, and aberrations in pathway regulation lead to cancer. MST1/2 and LATS1/2 kinases comprise the core of the pathway that, in association with adaptor proteins SAV and MOB, functions in a sequential manner to phosphorylate and inhibit the transcription factors YAP and TAZ. Here we identify mammalian MARK family members as activators of YAP/TAZ. We show that depletion of MARK4 in MDA-MB-231 breast cancer cells results in the loss of nuclear YAP/TAZ and decreases the expression of YAP/TAZ targets...
March 2017: EMBO Reports
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