PVR Expression Research Articles

Pvr expression regulators in equilibrium signal control and maintenance of Drosophila blood progenitors.

Blood progenitors within the lymph gland, a larval organ that supports hematopoiesis in Drosophila melanogaster, are maintained by integrating signals emanating from niche-like cells and those from differentiating blood cells. We term the signal from differentiating cells the 'equilibrium signal' in order to distinguish it from the 'niche signal'. Earlier we showed that equilibrium signaling utilizes Pvr (the Drosophila PDGF/VEGF receptor), STAT92E, and adenosine deaminase-related growth factor A (ADGF-A) (Mondal et al., 2011). Little is known about how this signal initiates during hematopoietic development. To identify new genes involved in lymph gland blood progenitor maintenance, particularly those involved in equilibrium signaling, we performed a genetic screen that identified bip1 (bric à brac interacting protein 1) and Nucleoporin 98 (Nup98) as additional regulators of the equilibrium signal. We show that the products of these genes along with the Bip1-interacting protein RpS8 (Ribosomal protein S8) are required for the proper expression of Pvr.

Regulation of NKG2D and DNAM-1 ligand expression in HCMV infected fibroblasts: role of the DNA damage response pathway and of viral replication.

Event Abstract Back to Event Regulation of NKG2D and DNAM-1 ligand expression in HCMV infected fibroblasts: role of the DNA damage response pathway and of viral replication. Benedetta Pignoloni1*, Valentina Dell'Oste2, Giorgio Gribaudo3, Marco Cippitelli1, Cinzia Fionda1, Giulia Malgarini1, Alessandra Zingoni1, Santo Landolfo2, Angela Santoni1 and Cristina Cerboni1* 1 Sapienza, University of Rome, Department of Molecular Medicine, Italy 2 University of Turin, Department of Public Health and Microbiology, Italy 3 University of Turin, Department of Life Sciences and Systems Biology, Italy Human cytomegalovirus (HCMV) evolved several strategies to evade NK and cytotoxic T cells, including the specific down-modulation of ligands of the activating receptors NKG2D and DNAM-1. Despite this, we believe that there is a window of opportunity to develop an adequate immune response, during which activating molecules can be expressed as a consequence of viral-induced stress response, and before immune-evasion events occurs. To this purpose we focused on MICA, ULBP3 (NKG2DL) and PVR (DNAM-1L) expression, and investigated the role of the DNA damage response (DDR) and its central mediator ATM, that is crucial in the regulation of NKG2DL and DNAM-1L expression. Human primary fibroblasts (HFF) infected with the AD169 strain significantly increased MICA, ULBP3 and PVR expression. However, if infected cells were treated with caffeine, an inhibitor of ATM/ATR kinases, ligand up-regulation was prevented, demonstrating that the DDR pathway was crucial in regulating these activating molecules also in the context of HCMV infection. Notably, DDR was necessary for HCMV productive replication as well, since little or no infectious virus was recovered from caffeine-treated cells. Ligand up-regulation was however observed to be HCMV replication-independent, as demonstrated by using Foscarnet, an inhibitor of viral DNA elongation, and related to HCMV-mediated exit from G0/G1 phases of the cell cycle. We are currently addressing the involvement of early viral proteins in ligand up-regulation capable of modulating early events responsible for an effective immune response. Keywords: NK cells, Human Cytomegalovirus, NKG2D, DNAM-1, DDR Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Innate immunity Citation: Pignoloni B, Dell'Oste V, Gribaudo G, Cippitelli M, Fionda C, Malgarini G, Zingoni A, Landolfo S, Santoni A and Cerboni C (2013). Regulation of NKG2D and DNAM-1 ligand expression in HCMV infected fibroblasts: role of the DNA damage response pathway and of viral replication.. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00253 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 13 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Benedetta Pignoloni, Sapienza, University of Rome, Department of Molecular Medicine, Rome, 00161, Italy, benedetta.pignoloni@uniroma1.it Prof. Cristina Cerboni, Sapienza, University of Rome, Department of Molecular Medicine, Rome, 00161, Italy, cristina.cerboni@uniroma1.it Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Benedetta Pignoloni Valentina Dell'Oste Giorgio Gribaudo Marco Cippitelli Cinzia Fionda Giulia Malgarini Alessandra Zingoni Santo Landolfo Angela Santoni Cristina Cerboni Google Benedetta Pignoloni Valentina Dell'Oste Giorgio Gribaudo Marco Cippitelli Cinzia Fionda Giulia Malgarini Alessandra Zingoni Santo Landolfo Angela Santoni Cristina Cerboni Google Scholar Benedetta Pignoloni Valentina Dell'Oste Giorgio Gribaudo Marco Cippitelli Cinzia Fionda Giulia Malgarini Alessandra Zingoni Santo Landolfo Angela Santoni Cristina Cerboni PubMed Benedetta Pignoloni Valentina Dell'Oste Giorgio Gribaudo Marco Cippitelli Cinzia Fionda Giulia Malgarini Alessandra Zingoni Santo Landolfo Angela Santoni Cristina Cerboni Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

DNAM-1 ligand expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK–T cell interaction

AbstractAn important role for natural killer (NK) cells in the regulation of T-cell responses is emerging, although the receptor pairs regulating the NK–T-cell interaction have still not been identified. We found that superantigen-stimulated T cells express Nectin-2 (CD112) and poliovirus receptor (PVR; CD155), the ligands of the activating NK receptor DNAX accessory molecule-1 (DNAM-1; CD226). Interestingly, only PVR was present at the T cell surface, particularly on cells in the S and G2/M phases of the cell cycle. The up-regulation of PVR expression involves DNA-damage response (DDR)–dependent pathways, because we found that pharmacologic inhibition of ATM and ATR kinases reduced PVR expression and that PVR was almost exclusively induced on cells expressing the DDR marker γH2AX. Oxidative stress contributed to DDR activation, and our results showed impaired PVR levels in the presence of the reactive oxygen species (ROS) scavenger N-acetyl-cysteine (NAC), being monocytes the main ROS source needed for optimal PVR expression on activated T cells. Interestingly, in accordance with ligand expression, NK cells lysed allogeneic proliferating more efficiently than nonproliferating T lymphocytes, with a mechanism requiring the cooperation between DNAM-1 and NKG2D. These results could contribute to unraveling the role of NK cells in the down-regulation of T-cell responses in physiologic and pathologic processes such as autoimmunity or GVHD.

Elimination of Oncogenic Neighbors by JNK-Mediated Engulfment in Drosophila

A newly emerged oncogenic cell in the epithelial population has to confront antitumor selective pressures in the host tissue. However, the mechanisms by which surrounding normal tissue exerts antitumor effects against oncogenically transformed cells are poorly understood. In Drosophila imaginal epithelia, clones of cells mutant for evolutionarily conserved tumor suppressor genes such as scrib or dlg lose their epithelial integrity and are eliminated from epithelia when surrounded by wild-type tissue. Here, we show that surrounding normal cells activate nonapoptotic JNK signaling in response to the emergence of oncogenic mutant cells. This JNK activation leads to upregulation of PVR, the Drosophila PDGF/VEGF receptor. Genetic and time-lapse imaging analyses reveal that PVR expression in surrounding cells activates the ELMO/Mbc-mediated phagocytic pathway, thereby eliminating oncogenic neighbors by engulfment. Our data indicate that JNK-mediated cell engulfment could be an evolutionarily conserved intrinsic tumor-suppression mechanism that eliminates premalignant cells from epithelia.

Characterization of mouse lines transgenic with the human poliovirus receptor gene

Two mouse lines transgenic with the human poliovirus receptor gene (PVR), TGM-PRG-1 and TGM-PRG-3, were characterized to determine whether transgene copy number and PVR expression levels influence susceptibility to poliovirus. The mouse lines have been bred for more than 10 generations and the transgene was stably transmitted to progeny as determined by Southern blot hybridization and restriction fragment length polymorphism. The transgene copy number is 10 in the TGM-PRG-3 mouse line and one in the TGM-PRG-1 mouse line. Abundance of PVR RNA is on average three-fold higher in TGM-PRG-3 relative to TGM-PRG-1 tissues, and the abundance of the receptor molecule is three-fold higher in TGM-PRG-3 central nervous system tissues compared to TGM-PRG-1 tissues as determined by Western blot analysis. When TGM-PRG-1 and TGM-PRG-3 mice were inoculated intracranially with a neurovirulent type III poliovirus strain, they developed clinical symptoms and CNS lesions characteristic of human poliomyelitis. These results indicate that the PVR gene is expressed as a functional receptor in the CNS of both mouse lines rendering the mice susceptible to poliovirus infection. Even though the two mouse lines have different copy numbers of the transgene and different levels of PVR RNA and protein, they are similar in their susceptibility to poliovirus.