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https://www.readbyqxmd.com/read/28720576/deubiquitinating-enzyme-usp9x-suppresses-tumor-growth-via-lats-kinase-and-core-components-of-the-hippo-pathway
#1
Aleksandra Toloczko, Fusheng Guo, Hiu-Fung Yuen, Qing Wen, Stephen Andrew Wood, Yan Shan Ong, Pei Yi Chan, Asfa Alli Shaik, Jayantha Gunaratne, Mark John Dunne, Wanjin Hong, Siew Wee Chan
The core LATS kinases of the Hippo tumor suppressor pathway phosphorylate and inhibit the downstream transcriptional co-activators YAP and TAZ, which are implicated in various cancers. Recent studies have identified various E3 ubiquitin ligases that negatively regulate the Hippo pathway via ubiquitination, yet few deubiquitinating enzymes (DUB) have been implicated. In this study, we report the DUB USP9X is an important regulator of the core kinases of this pathway. USP9X interacted strongly with LATS kinase and to a lesser extent with WW45, KIBRA, and Angiomotin, and LATS co-migrated exclusively with USP9X during gel filtration chromatography analysis...
July 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28713678/drug-development-against-the-hippo-pathway-in-mesothelioma
#2
REVIEW
Gavitt A Woodard, Yi-Lin Yang, Liang You, David M Jablons
Advances in the treatments for malignant pleural mesothelioma (MPM) have been disappointing until recently. Conventional cytotoxic drugs fail in MPM in part because they do not address the cancer stem cell population or stem cell pathways that drive tumor resistance and resurgence following treatment. The Hippo stem cell pathway regulates cell contact inhibition with tumor suppressor genes such as NF2 (Neurofibromatosis 2) upstream controlling YAP (Yes-associated protein 1) oncogenes. NF2 is mutated in 40-50% of all MPM and downstream YAP is constitutively active in greater than 70% of MPM, making the downstream YAP/TEAD (transcriptional enhancer associate domain) complex the ultimate target...
June 2017: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/28700256/hippo-pathway-an-emerging-regulator-of-craniofacial-and-dental-development
#3
J Wang, J F Martin
The evolutionarily conserved Hippo signaling pathway is a vital regulator of organ size that fine-tunes cell proliferation, apoptosis, and differentiation. A number of important studies have revealed critical roles of Hippo signaling and its effectors Yap (Yes-associated protein) and Taz (transcriptional coactivator with PDZ binding motif) in tissue development, homeostasis, and regeneration, as well as in tumorigenesis. In addition, recent studies have shown evidence of crosstalk between the Hippo pathway and other key signaling pathways, such as Wnt signaling, that not only regulates developmental processes but also contributes to disease pathogenesis...
July 1, 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/28698384/palmitic-acid-dysregulates-the-hippo-yap-pathway-and-inhibits-angiogenesis-by-inducing-mitochondrial-damage-and-activating-the-cytosolic-dna-sensor-cgas-sting-irf3-signaling
#4
Liangshuai Yuan, Yun Mao, Wei Luo, Weiwei Wu, Hao Xu, Xing Li Wang, Ying H Shen
Impaired angiogenesis and wound healing carry significant morbidity and mortality in diabetic patients. Metabolic stress from hyperglycemia and elevated free fatty acids have been shown to inhibit endothelial angiogenesis. However, the underlying mechanisms remain poorly understood. In this study, we show that dysregulation of the Hippo-YAP pathway, an important signaling in regulating tissue repair and regeneration, underlies palmitic acid (PA) -induced inhibition of endothelial angiogenesis. PA inhibited endothelial cell proliferation, migration and tube formation, which were associated with increased MST1 expression, YAP phosphorylation/inactivation and nuclear exclusion...
July 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28684311/hippo-effector-yap-directly-regulates-the-expression-of-pd-l1-transcripts-in-egfr-tki-resistant-lung-adenocarcinoma
#5
Byung Soo Lee, Dong Il Park, Da Hye Lee, Jeong Eun Lee, Min-Kyung Yeo, Yeon Hee Park, Dae Sik Lim, Wonyoung Choi, Da Hye Lee, Geon Yoo, Han-Byul Kim, Dahyun Kang, Jae Young Moon, Sung Soo Jung, Ju Ock Kim, Hee Sun Park, Chaeuk Chung
Developments of EGFR-TKI and immunotherapy targeting the PD1/PD-L1 pathway are considered most important medical breakthroughs in lung cancer treatment. Nowadays, 3rd generation EGFR TKI is widely used for T790M positive 1st and 2nd EGFR-TKI resistant lung cancer patients. Immunotherapy is powerful option for lung cancer patients without drug targets and chemotherapy resistant patients. It also has changed the concept of conventional anti-cancer therapy in the point of regulating tumor microenvironment. There are many studies linking these two important pathways...
July 3, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28682834/high-expression-of-yes-activated-protein-1-in-papillary-thyroid-carcinoma-correlates-with-poor-prognosis
#6
Zeming Liu, Wen Zeng, Yusufu Maimaiti, Jie Ming, Yawen Guo, Yan Liu, Chunping Liu, Tao Huang
CONTEXT: The Hippo signal transduction pathway is highly conserved in mammals. It plays a critical role in tissue and organ size by regulating the balance between cell proliferation and apoptosis. However, there have been few reports concerning Yes-activated protein-1 (YAP-1) elevation in papillary thyroid cancer (PTC). OBJECTIVE: The objective of this study was to determine whether YAP-1 expression is a biomarker and high-risk clinicopathologic prognosticator in PTC...
July 4, 2017: Applied Immunohistochemistry & Molecular Morphology: AIMM
https://www.readbyqxmd.com/read/28681838/yap-determines-the-cell-fate-of-injured-mouse-hepatocytes-in-vivo
#7
Norio Miyamura, Shoji Hata, Tohru Itoh, Minoru Tanaka, Miki Nishio, Michiko Itoh, Yoshihiro Ogawa, Shuji Terai, Isao Sakaida, Akira Suzuki, Atsushi Miyajima, Hiroshi Nishina
The presence of senescent, transformed or damaged cells can impair tissue function or lead to tumorigenesis; therefore, organisms have evolved quality control mechanisms to eliminate them. Here, we show that YAP activation induced by inactivation of the Hippo pathway specifically in damaged hepatocytes promotes their selective elimination by using in vivo mosaic analysis in mouse liver. These damaged hepatocytes migrate into the hepatic sinusoids, undergo apoptosis and are engulfed by Kupffer cells. In contrast, YAP activation in undamaged hepatocytes leads to proliferation...
July 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28680534/nsclc-depend-upon-yap-expression-and-nuclear-localization-after-acquiring-resistance-to-egfr-inhibitors
#8
Marc McGowan, Lilach Kleinberg, Ann Rita Halvorsen, Åslaug Helland, Odd Terje Brustugun
Yes-associated protein (YAP) is a downstream target of the Hippo pathway and has been found to be oncogenic driving many cancers into developing metastatic phenotypes leading to poor survival outcomes. This study investigated if YAP expression is associated with drug resistance in two non-small cell lung cancer (NSCLC) lines (HCC827 and H1975) generated to become resistant to the EGFR tyrosine kinase inhibitors (EGFR TKI) erlotinib, gefitinib or the T790M-specific osimertinib. We found that acquired EGFR TKI resistance was associated with YAP over-expression (osimertinib-resistant cells) or YAP amplification (erlotinib- and gefitinib-resistant cells) along with EMT phenotypic changes...
March 2017: Genes & Cancer
https://www.readbyqxmd.com/read/28677804/mapk-and-hippo-signaling-pathways-crosstalk-via-the-raf-1-mst-2-interaction-in-malignant-melanoma
#9
Ruizheng Feng, Junsheng Gong, Lina Wu, Lei Wang, Baolin Zhang, Gang Liang, Huixia Zheng, Hong Xiao
The aim of the present study was to expound on the interactions between the mitogen-activated protein kinase (MAPK) and Hippo pathway members, and to further elucidate the molecular mechanisms of melanoma tumorigenesis. Four melanoma cell lines (C32, HS695T, SK-MEL-28 and A375) were used in the present study. Western blotting was used to assess the expression levels of the MAPK and Hippo pathway effector proteins: rapidly accelerated fibrosarcoma-1 proto-oncogene, serine/threonine kinase (RAF-1); serine/threonine kinase 3 (STK3; also known as MST-2); yes-associated protein (YAP); and tafazzin (TAZ)...
June 30, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28673931/mechanical-cue-induced-yap-instructs-skp2-dependent-cell-cycle-exit-and-oncogenic-signaling
#10
Wonyul Jang, Tackhoon Kim, Ja Seung Koo, Sang-Kyum Kim, Dae-Sik Lim
Mechanical tensions are usually generated during development at spatially defined regions within tissues. Such physical cues dictate the cellular decisions of proliferation or cell cycle arrest. Yet, the mechanisms by which mechanical stress controls the cell cycle are not yet fully understood. Here, we report that mechanical cues function upstream of Skp2 transcription in human breast cancer cells. We found that YAP, the mechano-responsive oncogenic Hippo signaling effector, directly promotes Skp2 transcription...
July 3, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28672915/induction-of-reprogramming-of-human-amniotic-epithelial-cells-into-ips-cells-by-overexpression-of-yap-oct4-and-sox2-through-the-activation-of-the-hippo-yap-pathway
#11
Yanhui Zhao, Xinfeng Fei, Jianming Guo, Gang Zou, Weidong Pan, Jingju Zhang, Yongyi Huang, Te Liu, Weiwei Cheng
The present study has reported a novel method for producing induced pluripotent stem (iPS) cells. Primary human amniotic epithelial cells (HuAECs) were isolated from the amniotic membranes of pregnant women who received Cesarean sections. These cells were infected with retroviruses carrying octamer-binding transcription factor 4 (Oct4), (sex determining region Y)-box 2 (Sox2) and Yes-associated protein (Yap) (OSY). Following in vitro culture for ~14 days, epithelial-like HuAECs exhibited several iPS clone-like cell colonies (OSY-iPS)...
July 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28661054/platelet-derived-growth-factor-regulates-yap-transcriptional-activity-via-src-family-kinase-dependent-tyrosine-phosphorylation
#12
Rory L Smoot, Nathan W Werneburg, Takaaki Sugihara, Matthew C Hernandez, Lin Yang, Christine Mehner, Rondell P Graham, Steven F Bronk, Mark J Truty, Gregory J Gores
The Hippo pathway effector YAP is implicated in the pathogenesis of cholangiocarcinoma (CCA). The Hippo pathway relies on signaling cross talk for its regulation. Given the importance of platelet derived growth factor receptor (PDGFR) signaling in CCA biology, our aim was to examine potential YAP regulation by PDGFR. We employed human and mouse CCA specimens and cell lines for these studies. Initially, we confirmed upregulation of PDGFRβ and PDGFR ligands in human and mouse CCA specimens and cell lines. YAP, a transcriptional co-activator, was localized to the nucleus in human CCA specimens and a cell line, as well as patient derived xenografts (PDX)...
June 29, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28652775/wwc3-downregulation-correlates-with-poor-prognosis-and-inhibition-of-hippo-signaling-in-human-gastric-cancer
#13
Jiabin Hou, Jin Zhou
The aim of this study was to investigate the clinicopathological significance and biological roles of WWC3 in human gastric cancer (GC). Clinical significance of WWC3 in human GCs was examined by using immunohistochemistry (IHC). WWC3 was downregulated in 48 of 111 human GCs, and its downregulation was associated with advanced stage, positive nodal status, and higher relapse rate. Importantly, WWC3 downregulation correlated with poor survival. It was also found that WWC3 protein expression was downregulated in GC cell lines compared with normal cell line GES-1...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28644436/the-lats1-and-lats2-tumor-suppressors-beyond-the-hippo-pathway
#14
REVIEW
Noa Furth, Yael Aylon
Proper cellular functionality and homeostasis are maintained by the convergent integration of various signaling cascades, which enable cells to respond to internal and external changes. The Dbf2-related kinases LATS1 and LATS2 (LATS) have emerged as central regulators of cell fate, by modulating the functions of numerous oncogenic or tumor suppressive effectors, including the canonical Hippo effectors YAP/TAZ, the Aurora mitotic kinase family, estrogen signaling and the tumor suppressive transcription factor p53...
June 23, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28637242/yap-and-wwtr1-regulate-the-expression-of-sex-determining-genes-in-sertoli-cells-but-their-inactivation-does-not-cause-sex-reversal
#15
Adrien Levasseur, Marilène Paquet, Derek Boerboom, Alexandre Boyer
Yes-associated protein (YAP) and WW containing transcription regulator 1 (WWTR1) are two functionally redundant transcriptional regulators that are downstream effectors of the Hippo signaling pathway, and that act as major regulators of cell growth and differentiation. To elucidate their role in Sertoli cells, primary Sertoli cell culture from Yapflox/flox; Wwtr1flox/flox animals were infected with a Cre recombinase-expressing adenovirus. Concomitant inactivation of Yap and Wwtr1 resulted in a decrease in the mRNA levels of the male sex differentiation genes Dhh, Dmrt1, Sox9 and Wt1, whereas those of genes involved in female differentiation (Wnt4, Rspo1 and Foxl2) were induced...
June 16, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28634071/the-novel-yap-target-gene-sgk1-upregulates-taz-activity-by-blocking-gsk3%C3%AE-mediated-taz-destabilization
#16
Geon Yoo, Tackhoon Kim, Chaeuk Chung, Deog-Su Hwang, Dae-Sik Lim
YAP (Yes-associated protein) and TAZ (transcription activator with PDZ binding motif) are important in tissue regeneration and cancer development, highlighting the importance of discovering partners that regulate their oncogenicity. SGK1 (serum/glucocorticoid regulated kinase 1), initially identified as a homolog of Akt in phosphoinositide 3-kinase signaling, acts as a serine/threonine protein kinase in multiple oncogenic pathways. However, possible links between SGK1 and Hippo-YAP/TAZ signaling remain unexplored...
June 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28616573/yap-and-the-hippo-pathway-in-pediatric-cancer
#17
REVIEW
Atif A Ahmed, Abdalla D Mohamed, Melissa Gener, Weijie Li, Eugenio Taboada
The Hippo pathway is an important signaling pathway that controls cell proliferation and apoptosis. It is evolutionarily conserved in mammals and is stimulated by cell-cell contact, inhibiting cell proliferation in response to increased cell density. During early embryonic development, the Hippo signaling pathway regulates organ development and size, and its functions result in the coordinated balance between proliferation, apoptosis, and differentiation. Its principal effectors, YAP and TAZ, regulate signaling by the embryonic stem cells and determine cell fate and histogenesis...
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28611154/cytoresistance-after-acute-kidney-injury-is-limited-to-the-recovery-period-of-proximal-tubule-integrity-and-possibly-involves-hippo-yap-signaling
#18
Takamasa Iwakura, Yoshihide Fujigaki, Tomoyuki Fujikura, Takayuki Tsuji, Naro Ohashi, Akihiko Kato, Hideo Yasuda
Rat proximal tubule (PT) cells that have recovered from severe acute kidney injury induced by uranyl acetate (UA) develop cytoresistance to subsequent UA treatments. We reported that enhanced G1 arrest might contribute to cytoresistance. Herein, we examined these mechanisms by investigating Yes-associated protein (YAP), a regulator of cell number, and survivin, a downstream mediator of YAP that inhibits apoptosis. Rats pretreated with saline (vehicle group) or UA (AKI group) were injected with UA 2 weeks, 2 months, or 6 months after treatment...
June 2017: Physiological Reports
https://www.readbyqxmd.com/read/28602051/yes-associated-protein-expression-is-correlated-to-the-differentiation-of-prostate-adenocarcinoma
#19
Myung-Giun Noh, Sung Sun Kim, Eu Chang Hwang, Dong Deuk Kwon, Chan Choi
Background: Yes-associated protein (YAP) in the Hippo signaling pathway is a growth control pathway that regulates cell proliferation and stem cell functions. Abnormal regulation of YAP was reported in human cancers including liver, lung, breast, skin, colon, and ovarian cancer. However, the function of YAP is not known in prostate adenocarcinoma. The purpose of this study was to investigate the role of YAP in tumorigenesis, differentiation of the carcinoma, and prognosis of prostate adenocarcinoma...
June 9, 2017: Journal of Pathology and Translational Medicine
https://www.readbyqxmd.com/read/28593479/rna-binding-protein-dnd1-inhibits-epithelial-mesenchymal-transition-and-cancer-stem-cell-related-traits-on-hepatocellular-carcinoma-cells
#20
Weiling Xu, Fangchao Gong, Ting Zhang, Baorong Chi, Jingyu Wang
OBJECTIVES: To investigate the roles of Dead end 1 (Dnd1) in modulating cancer stem cell-related traits of hepatocellular carcinoma (HCC). RESULTS: Dead end (Dnd1) inhibited spheroid formation, suppressed the expression of stemness-related genes, and increased sensitivity to sorafenib in HCC cells. Mechanistically, Dnd1 could bind to 3'-UTR of LATS2, the key kinase of Hippo pathway, thus elevating LATS2 mRNA stability and its expression, subsequently leading to phosphorylation of YAP and its cytoplasmic retention...
June 7, 2017: Biotechnology Letters
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