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Dariusz Wodziak, Aiwen Dong, Michael F Basin, Anson W Lowe
A recently published study identified Anterior Gradient 2 (AGR2) as a regulator of EGFR signaling by promoting receptor presentation from the endoplasmic reticulum to the cell surface. AGR2 also promotes tissue regeneration in amphibians and fish. Whether AGR2-induced EGFR signaling is essential for tissue regeneration in higher vertebrates was evaluated using a well-characterized murine model for pancreatitis. The impact of AGR2 expression and EGFR signaling on tissue regeneration was evaluated using the caerulein-induced pancreatitis mouse model...
2016: PloS One
Kevin J Sheridan, Beatrix Elisabeth Lechner, Grainne O' Keeffe, Markus A Keller, Ernst R Werner, Herbert Lindner, Gary W Jones, Hubertus Haas, Sean Doyle
Ergothioneine (EGT; 2-mercaptohistidine trimethylbetaine) is a trimethylated and sulphurised histidine derivative which exhibits antioxidant properties. Here we report that deletion of Aspergillus fumigatus egtA (AFUA_2G15650), which encodes a trimodular enzyme, abrogated EGT biosynthesis in this opportunistic pathogen. EGT biosynthetic deficiency in A. fumigatus significantly reduced resistance to elevated H2O2 and menadione, respectively, impaired gliotoxin production and resulted in attenuated conidiation...
October 17, 2016: Scientific Reports
Ramesh Babu Kasetti, Subhash Gaddipati, Shifu Tian, Lei Xue, Winston W-Y Kao, Qingxian Lu, Qiutang Li
Key issues in corneal epithelium biology are the mechanism for corneal epithelium stem cells to maintain the corneal epithelial homeostasis and wound healing responses, and what are the regulatory molecular pathways involved. There are apparent discrepancies about the locations of the progenitor populations responsible for corneal epithelial self-renewal. We have developed a genetic mouse model to trace the corneal epithelial progenitor lineages during adult corneal epithelial homeostasis and wound healing response...
October 13, 2016: Scientific Reports
Hao Zhang, Decheng Geng, Jian Gao, Yanhua Qi, Yi Shi, Yan Wang, Yang Jiang, Yu Zhang, Jiale Fu, Yu Dong, Shangfeng Gao, Rutong Yu, Xiuping Zhou
Dysregulation of Hippo/YAP signaling leads to aberrant cell growth and neoplasia. Although the roles and regulation of Hippo/YAP signaling were extensively studied in cancer biology recently, study systematically checking the expression pattern of core components of this pathway at the tumor tissue level remains lacking. In this study, we thoroughly examined the profile of core components of Hippo/YAP signaling in patient specimens both at the mRNA and at protein levels. We found that the mRNA level of YAP1/TAZ and their target genes, CRY61, CTGF, and BIRC5, was remarkably amplified in glioma tissues...
October 7, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
W Gao, R Su, W Sun, Q Z Wang, X Y Lv, J J Bao, J R Yu, L H Wang, H H Musa, L Chen
The temporal and spatial patterns of Smad and Yes-associated protein 1 (YAP1) expression were investigated in skeletal muscle (gastrocnemius muscle and extensor digitorum longus) at different growth stages (2 days old, 2 and 6 months old) in Hu sheep. Smads were differentially expressed in sheep skeletal muscle, with high expression in the gastrocnemius muscle and lower expression in the extensor digitorum longus. Expression of Smad2, Smad3, and Smad4 at the 2-day-old stage was significantly higher than at other stages (P < 0...
August 26, 2016: Genetics and Molecular Research: GMR
Wiyada Dankai, Monsicha Pongpom, Sirida Youngchim, Chester R Cooper, Nongnuch Vanittanakom
Talaromyces marneffei, formerly Penicillium marneffei, is a thermally dimorphic fungus. It causes a fatal disseminated disease in patients infected with the human immunodeficiency virus (HIV). Studies on the stress defense mechanism of T. marneffei can lead to a better understanding of the pathogenicity and the progression of the disease due to this fungus. The basic leucine-zipper (bZip) transcription factor gene in Saccharomyces cerevisiae, named yap1 (yeast activating protein-1), is known as a crucial central regulator of stress responses including those caused by oxidative agents, cadmium, and drugs...
2016: PloS One
Rafael H Abduch, Ana Carolina Bueno, Leticia F Leal, Marcelo M Cavalcanti, Débora C Gomes, Silvia R Brandalise, Maria J Masterallo, José A Yunes, Carlos E Martinelli, Luiz G Tone, Silvio Tucci, Carlos A F Molina, Fernando S Ramalho, Ayrton C Moreira, Izilda A Cardinalli, Carlos A Scrideli, Leandra N Z Ramalho, Margaret de Castro, Sonir R Antonini
BACKGROUND: Overexpression of the oncogene yes-associated-protein-1 (YAP1) is associated with increased cell proliferation in human cancers. YAP1 is a potential target of the Wnt/beta-catenin pathway, which plays an important role in adrenocortical tumors (ACT). The role of YAP1 in adrenocortical tumorigenesis has not been assessed. AIMS: To evaluate YAP1 expression in normal adrenals and pediatric ACT and its association with disease outcome. To investigate the interaction between YAP1 and the Wnt/beta-catenin pathway in adrenocortical cells...
October 1, 2016: Oncotarget
Jimi Kim, Elizabeth McMillan, Hyun Seok Kim, Niranjan Venkateswaran, Gurbani Makkar, Jaime Rodriguez-Canales, Pamela Villalobos, Jasper Edgar Neggers, Saurabh Mendiratta, Shuguang Wei, Yosef Landesman, William Senapedis, Erkan Baloglu, Chi-Wan B Chow, Robin E Frink, Boning Gao, Michael Roth, John D Minna, Dirk Daelemans, Ignacio I Wistuba, Bruce A Posner, Pier Paolo Scaglioni, Michael A White
The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity. However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal interactions and the swift emergence of unanticipated resistance mechanisms to otherwise effective targeted therapies...
September 28, 2016: Nature
Yeguang Hu, Zhihong Zhang, Mariko Kashiwagi, Toshimi Yoshida, Ila Joshi, Nilamani Jena, Rajesh Somasundaram, Akinola Olumide Emmanuel, Mikael Sigvardsson, Julien Fitamant, Nabeel El-Bardeesy, Fotini Gounari, Richard A Van Etten, Katia Georgopoulos
IKAROS is required for the differentiation of highly proliferative pre-B-cell precursors, and loss of IKAROS function indicates poor prognosis in precursor B-cell acute lymphoblastic leukemia (B-ALL). Here we show that IKAROS regulates this developmental stage by positive and negative regulation of superenhancers with distinct lineage affiliations. IKAROS defines superenhancers at pre-B-cell differentiation genes together with B-cell master regulators such as PAX5, EBF1, and IRF4 but is required for a highly permissive chromatin environment, a function that cannot be compensated for by the other transcription factors...
September 1, 2016: Genes & Development
Dong Keun Rhee, Jung Chae Lim, Steven C Hockman, Faiyaz Ahmad, Dong Ho Woo, Youn Wook Chung, Shiwei Liu, Allison L Hockman, Vincent C Manganiello
Oxidative stress plays a pivotal role in pathogenesis of cardiovascular diseases and diabetes, however, the roles of Protein Kinase A (PKA) and human Phosphodiesterase 3A ( hPDE3A ) remain unknown. Here we show that yeast expressing wild type (WT) hPDE3A or K13R hPDE3A (putative ubiquitinylation site mutant) exhibited resistance or sensitivity to exogenous H2O2, respectively. H2O2-stimulated ROS production was markedly increased in yeast expressing K13R hPDE3A (OxiS1), compared to yeast expressing WT hPDE3A (OxiR1)...
September 19, 2016: Biochemical Journal
Tsung-Jen Liao, Chung-Jung Tsai, Hyunbum Jang, David Fushman, Ruth Nussinov
Is RASSF5 a tumor suppressor or activator? RASSF5 links K-Ras and the Hippo pathway. Hippo's signaling promotes YAP1 phosphorylation and degradation. YAP1 overexpression promotes cancer. Most reports point to RASSF5 suppressing cancer; however, some point to its promoting cancer. Our mechanistic view explains how RASSF5 can activate MST1/2 and suppress cancer in vivo; but inhibits MST1/2 in vitro. We propose that both activation and inhibition of MST1/2 can take place via SARAH heterodimerization. Our thesis in vivo, membrane-anchored Ras dimers (or nanoclusters) can promote SARAH domain heterodimerization, Raf-like MST1/2 kinase domain homodimerization and trans-autophosphorylation...
September 16, 2016: Current Opinion in Structural Biology
Jacob A Galan, Joseph Avruch
The MST1 and MST2 protein kinases comprise the GCK-II subfamily of protein kinases. In addition to their amino-terminal kinase catalytic domain, related to that of the Saccharomyces cerevisiae protein kinase Ste20, their most characteristic feature is the presence near the carboxy terminus of a unique helical structure called a SARAH domain; this segment allows MST1/MST2 to homodimerize and to heterodimerize with the other polypeptides that contain SARAH domains, the noncatalytic polypeptides RASSF1-6 and Sav1/WW45...
October 4, 2016: Biochemistry
Kevin M Elias, Megan M Emori, Thomas Westerling, Henry Long, Anna Budina-Kolomets, Fugen Li, Emily MacDuffie, Michelle R Davis, Alexander Holman, Brian Lawney, Matthew L Freedman, John Quackenbush, Myles Brown, Ronny Drapkin
Regulation of lineage-restricted transcription factors has been shown to influence malignant transformation in several types of cancer. Whether similar mechanisms are involved in ovarian cancer pathogenesis is unknown. PAX8 is a nuclear transcription factor that controls the embryologic development of the Müllerian system, including the fallopian tubes. Recent studies have shown that fallopian tube secretory epithelial cells (FTSECs) give rise to the most common form of ovarian cancer, high-grade serous ovarian carcinomas (HGSOCs)...
August 18, 2016: JCI Insight
Zhi Chen, HuaiPing Shi, Shuang Sun, HuiFen Xu, DuoYao Cao, Jun Luo
Milk fat metabolism is a complex procedure controlled by several factors. MiRNAs (microRNAs) regulate expression of genes and influence a series of biological procedures, such as fatty acid metabolism. Here we screened expression of goat mammary gland's miRNA during peak-lactation and late-lactation, and found that miR-181b expresses remarkably. Moreover, we illustrated that the over-expression of miR-181b impaired fat metabolism while the knockdown of miR-181b promoted fat metabolism in GMEC. These findings extend the discovery of miR-181b functioning in mediating adipocyte differentiation, by suggesting its role in impairing fat metabolism, which develops our cognition on the importance of miRNAs in milk fat metabolism and synthesis...
October 15, 2016: Experimental Cell Research
Rohit Mehra, Pankaj Vats, Marcin Cieslik, Xuhong Cao, Fengyun Su, Sudhanshu Shukla, Aaron M Udager, Rui Wang, Jincheng Pan, Katayoon Kasaian, Robert Lonigro, Javed Siddiqui, Kumpati Premkumar, Ganesh Palapattu, Alon Weizer, Khaled S Hafez, J Stuart Wolf, Ankur Sangoi, Kiril Trpkov, Adeboye O Osunkoya, Ming Zhou, Giovanna A Giannico, Jesse K McKenney, Saravana M Dhanasekaran, Arul M Chinnaiyan
Mucinous tubular and spindle cell carcinoma (MTSCC) is a relatively rare subtype of renal cell carcinoma with distinctive morphologic and cytogenetic features. Here we carry out whole exome and transcriptome sequencing of a multi-institutional cohort of MTSCC (n=22). We demonstrate the presence of either biallelic loss of Hippo pathway tumor suppressor genes (TSGs) and/or evidence of alteration of Hippo pathway genes in 85% of samples. PTPN14 (31%) and NF2 (22%) were the most commonly implicated Hippo pathway genes while other genes such as SAV1 and HIPK2 were also involved in a mutually exclusive fashion...
September 7, 2016: Cancer Discovery
Guangyuan Chen, Jiabin Xie, Ping Huang, Zhihong Yang
The Hippo pathway is dysregulated in multiple types of human cancer, including ovarian cancer. Nuclear expression of yes-associated protein 1 (YAP1), a downstream transcription coactivator of the Hippo pathway, has been demonstrated to promote tumorigenesis in ovarian cancer and may serve as a poor prognostic indicator. However, transcriptional coactivator with PDZ binding motif (TAZ), a downstream target of the Hippo pathway and paralog of YAP in mammalian cells, has not been fully investigated in ovarian cancer...
September 2016: Oncology Letters
Kavneet Kaur, Aanchal Kakkar, Anupam Kumar, Suvendu Purkait, Supriya Mallick, Vaishali Suri, Mehar C Sharma, Pramod K Julka, Deepak Gupta, Ashish Suri, Chitra Sarkar
Medulloblastoma (MB) is a childhood tumor comprising four molecular subgroups: WNT, SHH, group 3 and group 4, with diagnostic and prognostic connotations. Very few studies are available on molecular subgrouping of adult MBs due to their rarity. Recently, loss of chromosome14q has been reported in SHH MBs, with downregulation of miR-379/miR-656 cluster (C14MC) in pediatric SHH MBs. Hence, the present study on adult MBs was undertaken to enumerate clinicopathological characteristics and molecular subgroups, and to analyze expression of C14MC and its transcriptional regulators, MEF2, JUN and ESRRG...
August 30, 2016: Journal of Neuro-oncology
Robert A Jones, Tyler J Robinson, Jeff C Liu, Mariusz Shrestha, Veronique Voisin, YoungJun Ju, Philip E D Chung, Giovanna Pellecchia, Victoria L Fell, SooIn Bae, Lakshmi Muthuswamy, Alessandro Datti, Sean E Egan, Zhe Jiang, Gustavo Leone, Gary D Bader, Aaron Schimmer, Eldad Zacksenhaus
Triple-negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which no specific treatment is currently available. Although the retinoblastoma tumor-suppressor gene (RB1) is frequently lost together with TP53 in TNBC, it is not directly targetable. There is thus great interest in identifying vulnerabilities downstream of RB1 that can be therapeutically exploited. Here, we determined that combined inactivation of murine Rb and p53 in diverse mammary epithelial cells induced claudin-low-like TNBC with Met, Birc2/3-Mmp13-Yap1, and Pvt1-Myc amplifications...
October 3, 2016: Journal of Clinical Investigation
Jandee Lee, Woo Kyung Lee, Mi-Youn Seol, Seul Gi Lee, Daham Kim, Hyunji Kim, Jongsun Park, Sang Geun Jung, Woong Youn Chung, Eun Jig Lee, Young Suk Jo
Persistent cellular proliferation and metabolic reprogramming are essential processes in carcinogenesis. Here, we performed Gene Set Enrichment Analysis (GSEA) and found that that LETM1, a mitochondrial calcium transporter, is associated with cellular growth signals such as platelet-derived growth factor (PDGF) receptor signaling and insulin signaling pathways. These results were then verified by qRT-PCR and immnunoblotting. Mechanistically, up-regulation of LETM1 induced YAP1 nuclear accumulation, increasing the expression of PDGFB, PDGFRB and THBS4...
August 20, 2016: Oncotarget
Koki Itooka, Kazuo Takahashi, Shingo Izawa
Cold atmospheric pressure plasma (CAP) has potential to be utilized as an alternative method for sterilization in food industries without thermal damage or toxic residues. In contrast to the bactericidal effects of CAP, information regarding the efficacy of CAP against eukaryotic microorganisms is very limited. Therefore, herein we investigated the effects of CAP on the budding yeast Saccharomyces cerevisiae, with a focus on the cellular response to CAP. The CAP treatment caused oxidative stress responses including the nuclear accumulation of the oxidative stress responsive transcription factor Yap1, mitochondrial fragmentation, and enhanced intracellular oxidation...
November 2016: Applied Microbiology and Biotechnology
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