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Nazem El Husseini, Barbara F Hales
Members of the P53 transcription factor family, P53, P63, and P73, play important roles in normal development and in regulating the expression of genes that control apoptosis and cell cycle progression in response to genotoxic stress. P53 is involved in the DNA damage response pathway that is activated by hydroxyurea in organogenesis-stage murine embryos. The extent to which P63 and P73 contribute to this stress response is not known. To address this question, we examined the roles of P53, P63, and P73 in mediating the response of Trp53-positive and Trp53-deficient murine embryos to a single dose of hydroxyurea (400 mg/kg) on gestational day 9...
April 1, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
Alice Nemajerova, Ivano Amelio, Jakob Gebel, Volker Dötsch, Gerry Melino, Ute M Moll
The p53 family of transcription factors (p53, p63 and p73) covers a wide range of functions critical for development, homeostasis and health of mammals across their lifespan. Beside the well-established tumor suppressor role, recent evidence has highlighted novel non-oncogenic functions exerted by p73. In particular, p73 is required for multiciliated cell (MCC) differentiation; MCCs have critical roles in brain and airways to move fluids across epithelial surfaces and to transport germ cells in the reproductive tract...
October 27, 2017: Cell Death and Differentiation
Marta Martin-Lopez, Laura Maeso-Alonso, Sandra Fuertes-Alvarez, Diego Balboa, Virginia Rodríguez-Cortez, Jere Weltner, Inmaculada Diez-Prieto, Andrew Davis, Yaning Wu, Timo Otonkoski, Elsa R Flores, Pablo Menéndez, Margarita M Marques, Maria C Marin
The generation of induced pluripotent stem cells (iPSCs) by somatic cell reprogramming holds great potential for modeling human diseases. However, the reprogramming process remains very inefficient and a better understanding of its basic biology is required. The mesenchymal-to-epithelial transition (MET) has been recognized as a crucial step for the successful reprogramming of fibroblasts into iPSCs. It has been reported that the p53 tumor suppressor gene acts as a barrier of this process, while its homolog p63 acts as an enabling factor...
September 7, 2017: Cell Death & Disease
Milya Davlieva, Angel Tovar-Yanez, Kimberly DeBruler, Paul G Leonard, Michael R Zianni, Cesar A Arias, Yousif Shamoo
The cyclic antimicrobial lipopeptide daptomycin (DAP) triggers the LiaFSR membrane stress response pathway in enterococci and many other Gram-positive organisms. LiaR is the response regulator that, upon phosphorylation, binds in a sequence-specific manner to DNA to regulate transcription in response to membrane stress. In clinical settings, non-susceptibility to DAP by Enterococcus faecium is correlated frequently with a mutation in LiaR of Trp73 to Cys (LiaRW73C ). We have determined the structure of the activated E...
November 6, 2016: Journal of Molecular Biology
Rong Wang, Andrew Freywald, Yue Chen, Jianqing Xu, Xin Tan, Jim Xiang
Human immunodeficiency virus type-1 (HIV-1)-specific dendritic cell (DC) vaccines have been used in clinical trials. However, they have been found to only induce some degree of immune responses in these studies. We previously demonstrated that the HIV-1 Gag-specific Gag-Texo vaccine stimulated Gag-specific effector CD8(+) cytotoxic T lymphocyte (CTL) responses, leading to completely protective, but very limited, therapeutic immunity. In this study, we constructed a recombinant adenoviral vector, adenovirus (AdV)4-1BBL, which expressed mouse 4-1BB ligand (4-1BBL), and generated transgenic 4-1BBL-engineered OVA-Texo/4-1BBL and Gag-Texo/4-1BBL vaccines by transfecting ovalbumin (OVA)-Texo and Gag-Texo cells with AdV4-1BBL, respectively...
July 2015: Cellular & Molecular Immunology
Lorena Diaz, Truc T Tran, Jose M Munita, William R Miller, Sandra Rincon, Lina P Carvajal, Aye Wollam, Jinnethe Reyes, Diana Panesso, Natalia L Rojas, Yousif Shamoo, Barbara E Murray, George M Weinstock, Cesar A Arias
Daptomycin (DAP) is a lipopeptide antibiotic frequently used as a "last-resort" antibiotic against vancomycin-resistant Enterococcus faecium (VRE). However, an important limitation for DAP therapy against VRE is the emergence of resistance during therapy. Mutations in regulatory systems involved in cell envelope homeostasis are postulated to be important mediators of DAP resistance in E. faecium. Thus, in order to gain insights into the genetic bases of DAP resistance in E. faecium, we investigated the presence of changes in 43 predicted proteins previously associated with DAP resistance in enterococci and staphylococci using the genomes of 19 E...
August 2014: Antimicrobial Agents and Chemotherapy
Carolina Medina-Bolívar, Emilio González-Arnay, Flaminia Talos, Miriam González-Gómez, Ute M Moll, Gundela Meyer
Trp73, a member of the p53 gene family, plays a crucial role in neural development. We describe two main phenotypic variants of p73 deficiency in the brain, a severe one characterized by massive apoptosis in the cortex leading to early postnatal death and a milder, non-/low-apoptosis one in which 50% of pups may reach adulthood using an intensive-care breeding protocol. Both variants display the core triad of p73 deficiency: cortical hypoplasia, hippocampal malformations, and ventriculomegaly. We studied the development of the neocortex in p73 KO mice from early embryonic life into advanced age (25 months)...
August 1, 2014: Journal of Comparative Neurology
Rajiv Dixit, Grey Wilkinson, Gonzalo I Cancino, Tarek Shaker, Lata Adnani, Saiqun Li, Daniel Dennis, Deborah Kurrasch, Jennifer A Chan, Eric C Olson, David R Kaplan, Céline Zimmer, Carol Schuurmans
The three-layered piriform cortex, an integral part of the olfactory system, processes odor information relayed by olfactory bulb mitral cells. Specifically, mitral cell axons form the lateral olfactory tract (LOT) by targeting lateral olfactory tract (lot) guidepost cells in the piriform cortex. While lot cells and other piriform cortical neurons share a pallial origin, the factors that specify their precise phenotypes are poorly understood. Here we show that in mouse, the proneural genes Neurog1 and Neurog2 are coexpressed in the ventral pallium, a progenitor pool that first gives rise to Cajal-Retzius (CR) cells, which populate layer I of all cortical domains, and later to layer II/III neurons of the piriform cortex...
January 8, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Daniela Kenzelmann Broz, Laura D Attardi
The mechanisms by which the TP53/TRP53 transcription factor acts as a tumor suppressor remain incompletely understood. To gain new insights into TP53/TRP53 biology, we used ChIP-seq and RNA-seq technologies to define global TRP53 transcriptional networks in primary cells subjected to DNA damage. Intriguingly, we identified a TRP53-regulated autophagy program, which can be coordinately regulated by the TRP53 family members TRP63 and TRP73 in certain settings. While autophagy is not involved in TRP53-dependent cell cycle arrest, it contributes to both TRP53-driven apoptosis in response to DNA damage and TRP53-mediated transformation suppression...
September 2013: Autophagy
Badri Vardarajan, David Vergote, Fadel Tissir, Mark Logue, Jing Yang, Nathalie Daude, Kunie Ando, Ekaterina Rogaeva, Joseph Lee, Rong Cheng, Jean-Pierre Brion, Mahdi Ghani, Beipei Shi, Clinton T Baldwin, Satyabrata Kar, Richard Mayeux, Paul Fraser, André M Goffinet, Peter St George-Hyslop, Lindsay A Farrer, David Westaway
BACKGROUND: P73 belongs to the p53 family of cell survival regulators with the corresponding locus Trp73 producing the N-terminally distinct isoforms, TAp73 and DeltaNp73. Recently, two studies have implicated the murine Trp73 in the modulation in phospho-tau accumulation in aged wild type mice and in young mice modeling Alzheimer's disease (AD) suggesting that Trp73, particularly the DeltaNp73 isoform, links the accumulation of amyloid peptides to the creation of neurofibrillary tangles (NFTs)...
February 15, 2013: Molecular Neurodegeneration
Katrin-Janine Heiliger, Julia Hess, Donata Vitagliano, Paolo Salerno, Herbert Braselmann, Giuliana Salvatore, Clara Ugolini, Isolde Summerer, Tatjana Bogdanova, Kristian Unger, Gerry Thomas, Massimo Santoro, Horst Zitzelsberger
For an identification of novel candidate genes in thyroid tumourigenesis, we have investigated gene copy number changes in a Trk-T1 transgenic mouse model of thyroid neoplasia. For this aim, 30 thyroid tumours from Trk-T1 transgenics were investigated by comparative genomic hybridisation. Recurrent gene copy number alterations were identified and genes located in the altered chromosomal regions were analysed by Gene Ontology term enrichment analysis in order to reveal gene functions potentially associated with thyroid tumourigenesis...
June 2012: Endocrine-related Cancer
Ai Fukuyo, Yasuko In, Toshimasa Ishida, Koji Tomoo
To clarify the higher eukaryotic initiation factor 4E (eIF4E) binding selectivity of 4E-binding protein 2 (4E-BP2) than of 4E-BP1, as determined by Trp fluorescence analysis, the crystal structure of the eIF4E binding region of 4E-BP2 in complex with m(7) GTP-bound human eIF4E has been determined by X-ray diffraction analysis and compared with that of 4E-BP1. The crystal structure revealed that the Pro47-Ser65 moiety of 4E-BP2 adopts a L-shaped conformation involving extended and α-helical structures and extends over the N-terminal loop and two different helix regions of eIF4E through hydrogen bonds, and electrostatic and hydrophobic interactions; these features were similarly observed for 4E-BP1...
September 2011: Journal of Peptide Science: An Official Publication of the European Peptide Society
Myoungkun Jeoung, Phillip J Bridges
The oviduct is a dynamic structure whose function relies upon cyclic changes in the morphology of both ciliated and secretory luminal epithelial cells. Unfortunately, infection of these epithelial cells by sexually transmitted pathogens can lead to pelvic inflammatory disease, ectopic pregnancies and infertility. The disruption of normal, cyclic apoptosis in the oviducal epithelium appears to be a causal factor of oviducal pathology and therefore, these pathways represent a potential target for diagnosis and therapeutic intervention...
2011: Reproduction, Fertility, and Development
Rajiv Dixit, Céline Zimmer, Ronald R Waclaw, Pierre Mattar, Tarek Shaker, Christopher Kovach, Cairine Logan, Kenneth Campbell, François Guillemot, Carol Schuurmans
Cajal-Retzius cells are essential pioneer neurons that guide neuronal migration in the developing neocortex. During development, Cajal-Retzius cells arise from distinct progenitor domains that line the margins of the dorsal telencephalon, or pallium. Here, we show that the proneural gene Ascl1 is expressed in Cajal-Retzius cell progenitors in the pallial septum, ventral pallium, and cortical hem. Using a short-term lineage trace, we demonstrate that it is primarily the Ascl1-expressing progenitors in the pallial septum and ventral pallium that differentiate into Cajal-Retzius cells...
November 2011: Cerebral Cortex
L Gonzalez-Cano, M Herreros-Villanueva, R Fernandez-Alonso, A Ayuso-Sacido, G Meyer, J M Garcia-Verdugo, A Silva, M M Marques, M C Marin
The question of how neural progenitor cells maintain its self-renewal throughout life is a fundamental problem in cell biology with implications in cancer, aging and neurodegenerative diseases. In this work, we have analyzed the p73 function in embryonic neural progenitor cell biology using the neurosphere (NS)-assay and showed that p73-loss has a significant role in the maintenance of neurosphere-forming cells in the embryonic brain. A comparative study of NS from Trp73-/-, p53KO, p53KO;Trp73-/- and their wild-type counterparts demonstrated that p73 deficiency results in two independent, but related, phenotypes: a smaller NS size (related to the proliferation and survival of the neural-progenitors) and a decreased capacity to form NS (self-renewal)...
December 16, 2010: Cell Death & Disease
David P Kateete, Moses Okee, Fred A Katabazi, Alfred Okeng, Jeniffer Asiimwe, Henry W Boom, Kathleen D Eisenach, Moses L Joloba
BACKGROUND: Rhomboids are ubiquitous proteins with diverse functions in all life kingdoms, and are emerging as important factors in the biology of some pathogenic apicomplexa and Providencia stuartii. Although prokaryotic genomes contain one rhomboid, actinobacteria can have two or more copies whose sequences have not been analyzed for the presence putative rhomboid catalytic signatures. We report detailed phylogenetic and genomic analyses devoted to prokaryotic rhomboids of an important genus, Mycobacterium...
October 29, 2010: BMC Microbiology
Xiao W Mao, Lora M Green, Tsehay Mekonnen, Nathan Lindsey, Daila S Gridley
UNLABELLED: The aim of this study was to examine the induction of oxidative stress and apoptosis-associated gene expression profiles in retina after proton irradiation exposure at 0.5 to 4 Gy. MATERIALS AND METHODS: One eye of each Sprague-Dawley rat (6 per group) was irradiated with a conformal proton beam to total doses of 0, 0.5, 1 and 4 Gy. Retinal tissues were isolated for characterization of gene expression profiles 6 hours after proton radiation. RESULTS: For oxidative stress, many genes responsible for regulating the production of reactive oxygen species (ROS) were significantly up-regulated (Fmo2, Gpx2, Noxa1 and Sod3) compared to controls...
July 2010: In Vivo
André Schuster, Tobias Schilling, Vincenzo De Laurenzi, Andreas F Koch, Sarah Seitz, Frank Staib, Andreas Teufel, Snorri S Thorgeirsson, Peter Galle, Gerry Melino, Wolfgang Stremmel, Peter H Krammer, Martina Müller
BACKGROUND & AIMS: p73 belongs to the p53 family of transcription factors known to regulate cell cycle and apoptosis. The Trp73 gene has two promoters that drive the expression of two major p73 isoform subfamilies: TA and ΔN. In general, TAp73 isoforms show proapoptotic activities, whereas members of the N-terminally truncated (ΔN) p73 subfamily that lack the transactivation domain show antiapoptotic functions. We found that upregulation of ΔNp73 in hepatocellular carcinoma (HCC) correlated with reduced survival...
July 1, 2010: Cell Cycle
Richard Tomasini, Katsuya Tsuchihara, Margareta Wilhelm, Masashi Fujitani, Alessandro Rufini, Carol C Cheung, Fatima Khan, Annick Itie-Youten, Andrew Wakeham, Ming-Sound Tsao, Juan L Iovanna, Jeremy Squire, Igor Jurisica, David Kaplan, Gerry Melino, Andrea Jurisicova, Tak W Mak
The Trp53 gene family member Trp73 encodes two major groups of protein isoforms, TAp73 and DeltaNp73, with opposing pro- and anti-apoptotic functions; consequently, their relative ratio regulates cell fate. However, the precise roles of p73 isoforms in cellular events such as tumor initiation, embryonic development, and cell death remain unclear. To determine which aspects of p73 function are attributable to the TAp73 isoforms, we generated and characterized mice in which exons encoding the TAp73 isoforms were specifically deleted to create a TAp73-deficient (TAp73(-/-)) mouse...
October 1, 2008: Genes & Development
Veronika Obsilova, Eliska Nedbalkova, Jan Silhan, Evzen Boura, Petr Herman, Jaroslav Vecer, Miroslav Sulc, Jan Teisinger, Fred Dyda, Tomas Obsil
Tyrosine hydroxylase (TH) catalyzes the first step in the biosynthesis of catecholamines. Regulation of TH enzyme activity is controlled through the posttranslational modification of its regulatory domain. The regulatory domain of TH can be phosphorylated at four serines (8, 19, 31, and 40) by a variety of protein kinases. Phosphorylation of Ser19 does not by itself increase TH activity but induces its binding to the 14-3-3 protein. That leads to the enhancement of TH activity with a still not fully understood mechanism...
February 12, 2008: Biochemistry
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