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Xaralabos Varelas

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https://www.readbyqxmd.com/read/28920925/expression-of-piwi-protein-miwi2-defines-a-distinct-population-of-multiciliated-cells
#1
Gregory A Wasserman, Aleksander D Szymaniak, Anne C Hinds, Kazuko Yamamoto, Hirofumi Kamata, Nicole Ms Smith, Kristie L Hilliard, Claudia Carrieri, Adam T Labadorf, Lee J Quinton, Xingbin Ai, Xaralabos Varelas, Felicia Chen, Joseph P Mizgerd, Alan Fine, Dónal O'Carroll, Matthew R Jones
P-element-induced wimpy testes (Piwi) proteins are known for suppressing retrotransposon activation in the mammalian germline. However, whether Piwi protein or Piwi-dependent functions occur in the mammalian soma is unclear. Contrary to germline-restricted expression, we observed that Piwi-like Miwi2 mRNA is indeed expressed in epithelial cells of the lung in adult mice and that it is induced during pneumonia. Further investigation revealed that MIWI2 protein localized to the cytoplasm of a discrete population of multiciliated airway epithelial cells...
October 2, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28891248/integrin-fak-cdc42-pp1a-signaling-gnaws-at-yap-taz-activity-to-control-incisor-stem-cells
#2
REVIEW
Julia Hicks-Berthet, Xaralabos Varelas
How epithelial tissues are able to self-renew to maintain homeostasis and regenerate in response to injury remains a persistent question. The transcriptional effectors YAP and TAZ are increasingly being recognized as central mediators of epithelial stem cell biology, and a wealth of recent studies have been directed at understanding the control and activity of these factors. Recent work by Hu et al. has added to this knowledge, as they identify an Integrin-FAK-CDC42-PP1A signaling cascade that directs nuclear YAP/TAZ activity in stem cell populations of the mouse incisor, and define convergence on mTORC1 signaling as an important mediator of the proliferation of these cells...
October 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28870693/therapeutic-targeting-of-taz-and-yap-by-dimethyl-fumarate-in-systemic-sclerosis-fibrosis
#3
Tetsuo Toyama, Agnieszka P Looney, Brendon M Baker, Lukasz Stawski, Paul Haines, Robert Simms, Aleksander D Szymaniak, Xaralabos Varelas, Maria Trojanowska
Systemic sclerosis (scleroderma, SSc) is a devastating fibrotic disease with few treatment options. Fumaric acid esters, including dimethyl fumarate (DMF, Tecfidera®) have shown therapeutic effects in several disease models, prompting us to determine whether DMF is effective as a treatment for SSc dermal fibrosis. We found that DMF blocks the pro-fibrotic effects of TGFβ in SSc skin fibroblasts. Mechanistically, we found that DMF treatment reduced nuclear localization of TAZ and YAP proteins via inhibition of PI3-K/Akt1 pathway...
September 1, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28778066/inhibition-of-lsd1-epigenetically-attenuates-oral-cancer-growth-and-metastasis
#4
Saqer F Alsaqer, Mustafa M Tashkandi, Vinay K Kartha, Ya-Ting Yang, Yazeed Alkheriji, Andrew Salama, Xaralabos Varelas, Maria Kukuruzinska, Stefano Monti, Manish V Bais
Lysine-specific demethylase 1 (LSD1) is a nuclear histone demethylase and a member of the amine oxidase (AO) family. LSD1 is a flavin-containing AO that specifically catalyzes the demethylation of mono- and di-methylated histone H3 lysine 4 through an FAD-dependent oxidative reaction. LSD1 is inappropriately upregulated in lung, liver, brain and esophageal cancers, where it promotes cancer initiation, progression, and metastasis. However, unlike other lysine-specific demethylases, the role and specific targets of LSD1 in oral squamous cell carcinoma (OSCC) pathogenesis remain unknown...
July 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28642262/arterial-stiffness-induces-remodeling-phenotypes-in-pulmonary-artery-smooth-muscle-cells-via-yap-taz-mediated-repression-of-cyclooxygenase-2
#5
Paul B Dieffenbach, Christina Mallarino Haeger, Anna Maria F Coronata, Kyoung Moo Choi, Xaralabos Varelas, Daniel J Tschumperlin, Laura E Fredenburgh
Pulmonary arterial stiffness is an independent risk factor for mortality in pulmonary hypertension (PH) and plays a critical role in PH pathophysiology. Our laboratory has recently demonstrated arterial stiffening early in experimental PH, along with evidence for a mechanobiological feedback loop by which arterial stiffening promotes further cellular remodeling behaviors (Liu F, Haeger CM, Dieffenbach PB, Sicard D, Chrobak I, Coronata AM, Suárez Velandia MM, Vitali S, Colas RA, Norris PC, Marinković A, Liu X, Ma J, Rose CD, Lee SJ, Comhair SA, Erzurum SC, McDonald JD, Serhan CN, Walsh SR, Tschumperlin DJ, Fredenburgh LE...
September 1, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28492365/the-hippo-pathway-effector-yap-is-an-essential-regulator-of-ductal-progenitor-patterning-in-the-mouse-submandibular-gland
#6
Aleksander D Szymaniak, Rongjuan Mi, Shannon E McCarthy, Adam C Gower, Taylor L Reynolds, Michael Mingueneau, Maria Kukuruzinska, Xaralabos Varelas
Salivary glands, such as submandibular glands (SMGs), are composed of branched epithelial ductal networks that terminate in acini that together produce, transport and secrete saliva. Here, we show that the transcriptional regulator Yap, a key effector of the Hippo pathway, is required for the proper patterning and morphogenesis of SMG epithelium. Epithelial deletion of Yap in developing SMGs results in the loss of ductal structures, arising from reduced expression of the EGF family member Epiregulin, which we show is required for the expansion of Krt5/Krt14-positive ductal progenitors...
May 11, 2017: ELife
https://www.readbyqxmd.com/read/28315521/systematic-morphological-profiling-of-human-gene-and-allele-function-via-cell-painting
#7
Mohammad Hossein Rohban, Shantanu Singh, Xiaoyun Wu, Julia B Berthet, Mark-Anthony Bray, Yashaswi Shrestha, Xaralabos Varelas, Jesse S Boehm, Anne E Carpenter
We hypothesized that human genes and disease-associated alleles might be systematically functionally annotated using morphological profiling of cDNA constructs, via a microscopy-based Cell Painting assay. Indeed, 50% of the 220 tested genes yielded detectable morphological profiles, which grouped into biologically meaningful gene clusters consistent with known functional annotation (e.g., the RAS-RAF-MEK-ERK cascade). We used novel subpopulation-based visualization methods to interpret the morphological changes for specific clusters...
March 18, 2017: ELife
https://www.readbyqxmd.com/read/27881410/taz-activation-drives-fibroblast-spheroid-growth-expression-of-profibrotic-paracrine-signals-and-context-dependent-ecm-gene-expression
#8
Amy J Jorgenson, Kyoung Moo Choi, Delphine Sicard, Karry M J Smith, Samantha E Hiemer, Xaralabos Varelas, Daniel J Tschumperlin
Recent studies have implicated the Hippo pathway and its transcriptional effectors YAP and TAZ as necessary for fibroblast activation and tissue fibrosis. To test the specific and sufficient roles for TAZ in driving autonomous fibroblast activation, we cultured NIH3T3 fibroblasts expressing a doxycycline-inducible nuclear-localized mutant of TAZ (TAZ4SA) in scaffold-free 3D hanging drop spheroids, or on matrices of specified mechanical rigidity. Control NIH3T3 fibroblasts formed spheroids in hanging drop culture that remained stable and neither increased nor decreased in size significantly over 15 days...
March 1, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/26980570/altered-rna-editing-in-3-utr-perturbs-microrna-mediated-regulation-of-oncogenes-and-tumor-suppressors
#9
Liye Zhang, Chih-Sheng Yang, Xaralabos Varelas, Stefano Monti
RNA editing is a molecular event that alters specific nucleotides in RNA post-transcriptionally. RNA editing has the potential to impact a variety of cellular processes and is implicated in diseases such as cancer. Yet, the precise mechanisms by which RNA editing controls cellular processes are poorly understood. Here, we characterize sequences altered by RNA editing in patient samples from lymphoma, neuroblastoma and head and neck cancers. We show that A-to-I RNA editing sites are highly conserved across samples of the same tissue type and that most editing sites identified in tumors are also detectable in normal tissues...
March 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/26235047/crumbs3-mediated-polarity-directs-airway-epithelial-cell-fate-through-the-hippo-pathway-effector-yap
#10
Aleksander D Szymaniak, John E Mahoney, Wellington V Cardoso, Xaralabos Varelas
Epithelial cells undergo dynamic polarity changes as organs pattern, but the relationship between epithelial polarity and cell fate is poorly understood. Using the developing lung as a model, we found that distinct alterations in apical-basal polarity dictate airway epithelial differentiation. We demonstrate that Crb3, a Crumbs isoform that determines epithelial apical domain identity, is required for airway differentiation by controlling the localization of the transcriptional regulator Yap. We show that Crb3 promotes the interaction between Yap and the Hippo pathway kinases Lats1/2 at apical cell junctions to induce Yap phosphorylation and cytoplasmic retention, which drive cell differentiation...
August 10, 2015: Developmental Cell
https://www.readbyqxmd.com/read/25794680/a-yap-taz-regulated-molecular-signature-is-associated-with-oral-squamous-cell-carcinoma
#11
Samantha E Hiemer, Liye Zhang, Vinay K Kartha, Trevor S Packer, Munirah Almershed, Vikki Noonan, Maria Kukuruzinska, Manish V Bais, Stefano Monti, Xaralabos Varelas
UNLABELLED: Oral squamous cell carcinoma (OSCC) is a prevalent form of cancer that develops from the epithelium of the oral cavity. OSCC is on the rise worldwide, and death rates associated with the disease are particularly high. Despite progress in understanding the mutational and expression landscape associated with OSCC, advances in deciphering these alterations for the development of therapeutic strategies have been limited. Further insight into the molecular cues that contribute to OSCC is therefore required...
June 2015: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/25758863/distinct-polarity-cues-direct-taz-yap-and-tgf%C3%AE-receptor-localization-to-differentially-control-tgf%C3%AE-induced-smad-signaling
#12
Masahiro Narimatsu, Payman Samavarchi-Tehrani, Xaralabos Varelas, Jeffrey L Wrana
We and others have shown that the Hippo pathway effectors TAZ and YAP direct Smad activity to regulate TGFβ family-induced cellular responses in stem cell and cancer biology. In polarized epithelial cells we showed that the Crumbs complex promotes Hippo-dependent cytoplasmic TAZ/YAP localization that restricts TGFβ-induced Smad nuclear accumulation and activity. In this Developmental Cell issue, basal-lateral restriction of TGFβ receptors is proposed as the sole mechanism suppressing Smad signaling in epithelial cells...
March 9, 2015: Developmental Cell
https://www.readbyqxmd.com/read/25564622/notch3-jagged-signaling-controls-the-pool-of-undifferentiated-airway-progenitors
#13
Munemasa Mori, John E Mahoney, Maria R Stupnikov, Jesus R Paez-Cortez, Aleksander D Szymaniak, Xaralabos Varelas, Dan B Herrick, James Schwob, Hong Zhang, Wellington V Cardoso
Basal cells are multipotent airway progenitors that generate distinct epithelial cell phenotypes crucial for homeostasis and repair of the conducting airways. Little is known about how these progenitor cells expand and transition to differentiation to form the pseudostratified airway epithelium in the developing and adult lung. Here, we show by genetic and pharmacological approaches that endogenous activation of Notch3 signaling selectively controls the pool of undifferentiated progenitors of upper airways available for differentiation...
January 15, 2015: Development
https://www.readbyqxmd.com/read/25532687/head-and-neck-cancer-from-research-to-therapy-and-cure
#14
Xaralabos Varelas, Maria A Kukuruzinska
Cumulative findings from many research groups have identified new signaling mechanisms associated with head and neck cancers. We summarize these findings, including discussion of aberrant NOTCH, PI3K, STAT3, immune recognition, oxidative pathway, and regulation of cell cycle and cell death. The genomic landscape of head and neck cancers has been shown to differ depending on human papillomavirus (HPV) status. We discuss studies examining the integration of HPV into genomic regions, as well as the epigenetic alterations that occur in response to HPV infection, and how these may help reveal new biomarker and treatment predictors...
December 2014: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/25502501/mechanosignaling-through-yap-and-taz-drives-fibroblast-activation-and-fibrosis
#15
Fei Liu, David Lagares, Kyoung Moo Choi, Lauren Stopfer, Aleksandar Marinković, Vladimir Vrbanac, Clemens K Probst, Samantha E Hiemer, Thomas H Sisson, Jeffrey C Horowitz, Ivan O Rosas, Laura E Fredenburgh, Carol Feghali-Bostwick, Xaralabos Varelas, Andrew M Tager, Daniel J Tschumperlin
Pathological fibrosis is driven by a feedback loop in which the fibrotic extracellular matrix is both a cause and consequence of fibroblast activation. However, the molecular mechanisms underlying this process remain poorly understood. Here we identify yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis...
February 15, 2015: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/25043473/the-hippo-pathway-effector-yap-controls-patterning-and-differentiation-of-airway-epithelial-progenitors
#16
John E Mahoney, Munemasa Mori, Aleksander D Szymaniak, Xaralabos Varelas, Wellington V Cardoso
How epithelial progenitor cells integrate local signals to balance expansion with differentiation during organogenesis is still little understood. Here, we provide evidence that the Hippo pathway effector Yap is a key regulator of this process in the developing lung. We show that when epithelial tubules are forming and branching, a nucleocytoplasmic shift in Yap localization marks the boundary between the airway and the distal lung compartments. At this transition zone, Yap specifies a transcriptional program that controls Sox2 expression and ultimately generates the airway epithelium...
July 28, 2014: Developmental Cell
https://www.readbyqxmd.com/read/24742667/protein-n-glycosylation-in-oral-cancer-dysregulated-cellular-networks-among-dpagt1-e-cadherin-adhesion-and-canonical-wnt-signaling
#17
REVIEW
Xaralabos Varelas, Meghan P Bouchie, Maria A Kukuruzinska
N-Linked glycosylation (N-glycosylation) of proteins has long been associated with oncogenesis, but not until recently have the molecular mechanisms underlying this relationship begun to be unraveled. Here, we review studies describing how dysregulation of the N-glycosylation-regulating gene, DPAGT1, drives oral cancer. DPAGT1 encodes the first and rate-limiting enzyme in the assembly of the lipid-linked oligosaccharide precursor in the endoplasmic reticulum and thus mediates N-glycosylation of many cancer-related proteins...
July 2014: Glycobiology
https://www.readbyqxmd.com/read/24715453/the-hippo-pathway-effectors-taz-and-yap-in-development-homeostasis-and-disease
#18
REVIEW
Xaralabos Varelas
Studies over the past 20 years have defined the Hippo signaling pathway as a major regulator of tissue growth and organ size. Diverse roles for the Hippo pathway have emerged, the majority of which in vertebrates are determined by the transcriptional regulators TAZ and YAP (TAZ/YAP). Key processes regulated by TAZ/YAP include the control of cell proliferation, apoptosis, movement and fate. Accurate control of the levels and localization of these factors is thus essential for early developmental events, as well as for tissue homeostasis, repair and regeneration...
April 2014: Development
https://www.readbyqxmd.com/read/24648515/the-transcriptional-regulators-taz-and-yap-direct-transforming-growth-factor-%C3%AE-induced-tumorigenic-phenotypes-in-breast-cancer-cells
#19
Samantha E Hiemer, Aleksander D Szymaniak, Xaralabos Varelas
Uncontrolled transforming growth factor-β (TGFβ) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFβ-mediated cues are directed to induce tumorigenic events is poorly understood, particularly given that TGFβ has clear tumor suppressing activity in other contexts. Here, we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFβ-induced tumorigenic phenotypes in breast cancer cells...
May 9, 2014: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/24332857/switch-enhancers-interpret-tgf-%C3%AE-and-hippo-signaling-to-control-cell-fate-in-human-embryonic-stem-cells
#20
Tobias A Beyer, Alexander Weiss, Yuliya Khomchuk, Kui Huang, Abiodun A Ogunjimi, Xaralabos Varelas, Jeffrey L Wrana
A small toolkit of morphogens is used repeatedly to direct development, raising the question of how context dictates interpretation of the same cue. One example is the transforming growth factor β (TGF-β) pathway that in human embryonic stem cells fulfills two opposite functions: pluripotency maintenance and mesendoderm (ME) specification. Using proteomics coupled to analysis of genome occupancy, we uncover a regulatory complex composed of transcriptional effectors of the Hippo pathway (TAZ/YAP/TEAD), the TGF-β pathway (SMAD2/3), and the pluripotency regulator OCT4 (TSO)...
December 26, 2013: Cell Reports
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