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Apoorva Verma, Fu Lin, Tan Ying Chong, Muhammad Nur Hidayat, Chacko Jobichen, Hao Fan, J Sivaraman
The Hippo tumor suppressor pathway is an important regulator of cell proliferation and apoptosis, and signal transduction occurs through phosphorylation of the effector protein TAZ by the serine/threonine kinase LATS1/2. Here, we report the biophysical and computational studies to characterize the interaction between TAZ and LATS1/2 through WW domain-PPxY motif binding. We show that the TAZ WW domain exhibits a binding preference for the second of the two PPxY motifs of LATS1 in vitro. We modelled the structure of the domain in complex with LATS1 PPxY2 peptide and, through molecular dynamics simulations, show that WW domain-PPxY2 complex is stable with some flexibility in the peptide region...
May 19, 2018: Biochemical and Biophysical Research Communications
Tito Panciera, Luca Azzolin, Daniele Di Biagio, Antonio Totaro, Michelangelo Cordenonsi, Stefano Piccolo
Here we present protocols to isolate primary differentiated cells and turn them into stem/progenitor cells (SCs) of the same lineage by transient expression of the transcription factor YAP. With this method, luminal differentiated (LD) cells of the mouse mammary gland are converted into cells that exhibit molecular and functional properties of mammary SCs. YAP also turns fully differentiated pancreatic exocrine cells into pancreatic duct-like progenitors. Similarly, to endogenous, natural SCs, YAP-induced stem-like cells ("ySCs") can be eventually expanded as organoid cultures long term in vitro, without further need of ectopic YAP/TAZ, as ySCs are endowed with a heritable self-renewing SC-like state...
May 7, 2018: Journal of Visualized Experiments: JoVE
Jinglai Zhang, Huijuan Yuan, Songyan Feng, Keke Wen, Xugeng Guo
A series of thermally activated delayed fluorescence (TADF) emitters using asymmetric-triazine-cored triad as the electron-accepting unit have been investigated theoretically. Based on two experimentally reported TADF molecules (TPXZ-as-TAZ and oDPXZ-as-TAZ), two new molecules (mDPXZ-as-TAZ and pDPXZ-as-TAZ) have been designed to explore the isomeric effect on their TADF properties. The present results reveal that the absorption and emission spectra calculated by the time-dependent density functional theory (TD-DFT) method at the M06-2X level are match well the available experimental findings, and mDPXZ-as-TAZ and pDPXZ-as-TAZ are found to exhibit the same yellow emission as their analogue oDPXZ-as-TAZ...
May 17, 2018: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
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No abstract text is available yet for this article.
May 15, 2018: Cancer Research
Klara Kukowski, Joshua Hatton, Evguenii I Kozliak, Alena Kubátová
Exposure to water and high air humidity may affect the preservation of wood products as many preservatives are water-soluble and thus likely to leach. In this study, depletion of a common fungicide, tebuconazole (TAZ), from treated wood was investigated using a 14 C-labeled tracer. The wood species and treatment technique were chosen to be representative of products such as windows and doors; specifically, ponderosa pine was dip treated with a solvent-based, metal-free formulation. The impact of different aqueous settings including high air humidity, and either simulated continuous or intermittent rain was evaluated over a period of two months...
August 15, 2018: Science of the Total Environment
Samuel A Manning, Lucas G Dent, Shu Kondo, Ziqing W Zhao, Nicolas Plachta, Kieran F Harvey
The Hippo pathway is an evolutionarily conserved signaling network that integrates diverse cues to control organ size and cell fate. The central downstream pathway protein in Drosophila is the transcriptional co-activator Yorkie (YAP and TAZ in humans), which regulates gene expression with the Scalloped/TEA domain family member (TEAD) transcription factors [1-8]. A central regulatory step in the Hippo pathway is phosphorylation of Yorkie by the NDR family kinase Warts, which promotes Yorkie cytoplasmic localization by stimulating association with 14-3-3 proteins [9-12]...
April 24, 2018: Current Biology: CB
Huirong Liu, Suya Du, Tiantian Lei, Hailian Wang, Xia He, Rongsheng Tong, Yi Wang
The Hippo pathway, initially identified through screenings for mutant tumor suppressors in Drosophila, is an evolutionarily conserved signaling pathway that controls organ size by regulating cell proliferation and apoptosis. Abnormal regulation of the Hippo pathway may lead to cancer in mammals. As the major downstream effectors of the Hippo pathway, unphosphorylated Yes-associated protein (YAP) and its homolog transcriptional co-activator TAZ (also called WWTR1) (hereafter called YAP/TAZ) are translocated into the nucleus...
May 8, 2018: Oncology Reports
Amin Ardestani, Blaz Lupse, Kathrin Maedler
The evolutionarily conserved Hippo pathway is a key regulator of organ size and tissue homeostasis. Its dysregulation is linked to multiple pathological disorders. In addition to regulating development and growth, recent studies show that Hippo pathway components such as MST1/2 and LATS1/2 kinases, as well as YAP/TAZ transcriptional coactivators, are regulated by metabolic pathways and that the Hippo pathway controls metabolic processes at the cellular and organismal levels in physiological and metabolic disease states such as obesity, type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD), cardiovascular disorders, and cancer...
May 5, 2018: Trends in Endocrinology and Metabolism: TEM
Federica Lo Sardo, Sabrina Strano, Giovanni Blandino
Lung cancer is the leading cause of cancer death in the world and there is no current treatment able to efficiently treat the disease as the tumor is often diagnosed at an advanced stage. Moreover, cancer cells are often resistant or acquire resistance to the treatment. Further knowledge of the mechanisms driving lung tumorigenesis, aggressiveness, metastasization, and resistance to treatments could provide new tools for detecting the disease at an earlier stage and for a better response to therapy. In this scenario, Yes Associated Protein (YAP) and Trascriptional Coactivator with PDZ-binding motif (TAZ), the final effectors of the Hippo signaling transduction pathway, are emerging as promising therapeutic targets...
May 6, 2018: Cancers
Yusuke Takehara, Toshiko Yamochi, Tasuku Nagumo, Tomonari Cho, Fumihiko Urushibara, Kohei Ono, Tomonori Fujii, Naoko Okamoto, Yosuke Sasaki, Sakiko Tazawa, Mayumi Honma, Tomoko Norose, Eisuke Shiozawa, Genshu Tate, Masafumi Takimoto
Gene mutations are involved in the development of malignant mesothelioma. Important mutations have been identified in the genes for cyclin-dependent kinase inhibitor 2A (p16) alternative reading frame, breast cancer-associated protein 1 ( BAP1 ) and neurofibromatosis type 2 ( NF2 ). Previously, the utility of detecting the loss of BAP1 by immunohistochemistry (IHC) and p16-deletion by fluorescence in situ hybridization has been identified in several studies. However, NF2 -associated examinations have not been performed...
May 2018: Oncology Letters
Chloé Philippe, Benoît Pinson, Jim Dompierre, Véronique Pantesco, Benoît Viollet, Bertrand Daignan-Fornier, Michel Moenner
AICAR (Acadesine) is a pharmacological precursor of purine nucleotide biosynthesis with anti-tumoral properties. Although recognized as an AMP mimetic activator of the protein kinase AMPK, the AICAR monophosphate derivative ZMP was also shown to mediate AMPK-independent effects. In order to unveil these AMPK-independent functions, we performed a transcriptomic analysis in AMPKα1/α2 double knockout murine embryonic cells. Kinetic analysis of the cellular response to AICAR revealed the up-regulation of the large tumor suppressor kinases (Lats) 1 and 2 transcripts, followed by the repression of numerous genes downstream of the transcriptional regulators Yap1 and Taz...
May 3, 2018: Neoplasia: An International Journal for Oncology Research
Ying Shen, Xiao Gao, Wanyan Tan, Teng Xu
Several of the thousands of human long noncoding RNAs (lncRNAs) have been functionally characterized, yet their potential involvement in colorectal carcinoma (CRC) remains poorly understood. In present study, we aim to investigate the role of lncRNA LINC00174 in CRC carcinogenesis. We observed that increased expression of LINC00174 in CRC tissues and cells in comparison to their corresponding controls. Moreover, the aberrant overexpression of LINC00174 indicated the poor prognosis of CRC patients. Silence of LINC00174 was able to repress CRC cell growth in vitro and in vivo...
May 2, 2018: Gene
Stanley Artap, Lauren J Manderfield, Cheryl L Smith, Andrey Poleshko, Haig Aghajanian, Kelvin See, Li Li, Rajan Jain, Jonathan A Epstein
The Hippo signaling pathway has been implicated in control of cell and organ size, proliferation, and endothelial-mesenchymal transformation. This pathway impacts upon two partially redundant transcription cofactors, Yap and Taz, that interact with other factors, including members of the Tead family, to affect expression of downstream genes. Yap and Taz have been shown to regulate, in a cell-autonomous manner, myocardial proliferation, myocardial hypertrophy, regenerative potential, and overall size of the heart...
May 1, 2018: Developmental Biology
Jianxiong Ji, Ran Xu, Xin Zhang, Mingzhi Han, Yangyang Xu, Yuzhen Wei, Kaikai Ding, Shuai Wang, Bin Huang, Anjing Chen, Di Zhang, Zheng Jiang, Shuo Xu, Qing Zhang, Wenjie Li, Shilei Ni, Jian Wang, Xingang Li
Increased Actin-like 6A (ACTL6A) expression has been implicated in the development of diverse cancers and recently associated with the Hippo signaling pathway, which is known to regulate biological properties, including proliferation, tissue regeneration, stem cell biology, as well as tumorigenesis. Here we first show that ACTL6A is upregulated in human gliomas and its expression is associated with glioma patient survival. ACTL6A promotes malignant behaviors of glioma cells in vitro and in orthotopic xenograft model...
May 3, 2018: Cell Death & Disease
Ameer L Elaimy, Santosh Guru, Cheng Chang, Jianhong Ou, John J Amante, Lihua Julie Zhu, Hira Lal Goel, Arthur M Mercurio
The role of vascular endothelial growth factor (VEGF) signaling in cancer is not only well known in the context of angiogenesis but also important in the functional regulation of tumor cells. Autocrine VEGF signaling mediated by its co-receptors called neuropilins (NRPs) appears to be essential for sustaining the proliferation and survival of cancer stem cells (CSCs), which are implicated in mediating tumor growth, progression, and drug resistance. Therefore, understanding the mechanisms involved in VEGF-mediated support of CSCs is critical to successfully treating cancer patients...
May 1, 2018: Science Signaling
Aiqing Zhao, Shu Yang, Bini Wang, Xiaohong Tian, Youlin Zhang
Human Zn deficiency is prevalent in developing countries, and staple grains are commonly bio-fortified to increase their Zn contents. We measured Zn content, distribution, and bioavailability in calcareous soil and in wheat plants (Triticum aestivum L.) in Shaanxi Province, China, when either an organic Zn-ethylenediaminetetraacetate (Zn-EDTA) or an inorganic zinc sulfate heptahydrate (ZnSO4 ·7H2 O) Zn source was banded below the seedbed or broadcasted into soil. Compared with ZnSO4 ·7H2 O, Zn-EDTA fertilization produced higher Zn concentration and uptake in wheat plants...
April 21, 2018: Chemosphere
Huozhen Pan, Ming Liao, Pengshu Song
Hepatic fibrosis is a repair response to liver injury, and hepatic stellate cell activation is the center of hepatic fibrosis, which involves Hippo, Notch, Wnt/β-catenin, and TGF-β/Smad signaling pathways. YAP/TAZ is an important nucleus factor for Hippo tumor suppressor pathway and its activity is the key to the growth of whole organs, cell proliferation, and specific amplification of progenitor cells in the process of tissue renewal and regeneration. As the hub of signaling pathways, such as Hippo, Notch, Wnt/β-catenin, TGF-β/Smad signaling, YAP/TAZ regulates the genesis and development of liver fibrosis...
March 28, 2018: Zhong Nan da Xue Xue Bao. Yi Xue Ban, Journal of Central South University. Medical Sciences
Sun-Hye Jeong, Dae-Sik Lim
NAFLD induces the development of advanced liver diseases such as NASH and liver cancer. Therefore, understanding the mechanism of NAFLD development is critical for its prevention and treatment. Ablation of PTEN or Hippo pathway components induces liver cancer in a murine model by hyperactive AKT or YAP/TAZ, respectively. Although the regulation of these two pathways occurs in the same hepatocyte, the details of crosstalk between Hippo-YAP/TAZ and PTEN-AKT pathways in liver homeostasis and tumorigenesis still remain unclear...
April 27, 2018: BMB Reports
Zhaoping Qin, Wei Xia, Gary J Fisher, John J Voorhees, Taihao Quan
BACKGROUND: Transcription factors YAP and TAZ function as the primary mediators of the Hippo pathway. Yet, crosstalk of YAP and TAZ with other signaling pathways remains relatively unexplored. We have explored the impact of YAP and TAZ levels on the TGF-β/Smad signaling pathway in human skin dermal fibroblasts. METHODS: YAP and TAZ levels in dermal fibroblasts were reduced in dermal fibroblasts by siRNA-mediated knockdown. The effects of YAP and TAZ reduction on TGF-β/Smad signaling were examined by quantitative real-time PCR, Western analysis, and immunostaining...
April 25, 2018: Cell Communication and Signaling: CCS
Wenjia Lou, Christian A Reynolds, Yiran Li, Jenney Liu, Maik Hüttemann, Michael Schlame, David Stevenson, Douglas Strathdee, Miriam L Greenberg
Barth syndrome (BTHS) is an X-linked genetic disorder resulting from mutations in the tafazzin gene (TAZ), which encodes the transacylase that remodels the mitochondrial phospholipid cardiolipin (CL). While most BTHS patients exhibit pronounced skeletal myopathy, the mechanisms linking defective CL remodeling and skeletal myopathy have not been determined. In this study, we constructed a CRISPR-generated stable tafazzin knockout (TAZ-KO) C2C12 myoblast cell line. TAZ-KO cells exhibit mitochondrial deficits consistent with other models of BTHS, including accumulation of monolyso-CL (MLCL), decreased mitochondrial respiratory, and increased mitochondrial ROS production...
April 22, 2018: Biochimica et Biophysica Acta
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