Skip to main content
SpringerLink
Log in

Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

The tumor suppressor p53 is a major regulator of genes important for cell cycle arrest, senescence, apoptosis, and innate immunity, and has recently been implicated in retinal aging. In this study we sought to identify the genetic networks that regulate p53 function in the retina using quantitative trait locus (QTL) analysis. First we examined age-associated changes in the activation and expression levels of p53; known p53 target proteins and markers of innate immune system activation in primary retinal pigment epithelial (RPE) cells that were harvested from young and aged human donors. We observed increased expression of p53, activated caspase-1, CDKN1A, CDKN2A (p16INK4a), TLR4, and IFNα in aged primary RPE cell lines. We used the Hamilton Eye Institute (HEI) retinal dataset (www.genenetwork.org) to identify genomic loci that modulate expression of genes in the p53 pathway in recombinant inbred BXD mouse strains using a QTL systems biology-based approach. We identified a significant trans-QTL on chromosome 1 (region 172–177 Mb) that regulates the expression of Cdkn1a. Many of the genes in this QTL locus are involved in innate immune responses, including Fc receptors, interferon-inducible family genes, and formin 2. Importantly, we found an age-related increase in FCGR3A and FMN2 and a decrease in IFI16 levels in RPE cultures. There is a complex multigenic innate immunity locus that controls expression of genes in the p53 pathway in the RPE, which may play an important role in modulating age-related changes in the retina.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Allen RD, Dobkins JA, Harper JM, Slayback DL (1999) Genetics of graft-versus-host disease, I. A locus on chromosome 1 influences development of acute graft-versus-host disease in a major histocompatibility complex mismatched murine model. Immunology 96:254–261

    PubMed Central  CAS  PubMed  Google Scholar 

  • Baggetta R, De Andrea M, Gariano GR, Mondini M, Ritta M, Caposio P, Cappello P, Giovarelli M, Gariglio M, Landolfo S (2010) The interferon-inducible gene IFI16 secretome of endothelial cells drives the early steps of the inflammatory response. Eur J Immunol 40:2182–2189

    CAS  PubMed  Google Scholar 

  • Barsotti AM, Beckerman R, Laptenko O, Huppi K, Caplen NJ, Prives C (2012) p53-Dependent induction of PVT1 and miR-1204. J Biol Chem 287:2509–2519

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bhattacharya S, Ray RM, Viar MJ, Johnson LR (2003) Polyamines are required for activation of c-Jun NH2-terminal kinase and apoptosis in response to TNF-alpha in IEC-6 cells. Am J Physiol Gastrointest Liver Physiol 285:G980–991

    CAS  PubMed  Google Scholar 

  • Bhattacharya S, Guo H, Ray RM, Johnson LR (2007) Basic helix-loop-helix protein E47-mediated p21Waf1/Cip1 gene expression regulates apoptosis of intestinal epithelial cells. Biochem J 407:243–254

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bhattacharya S, Ray RM, Johnson LR (2009) Role of polyamines in p53-dependent apoptosis of intestinal epithelial cells. Cell Signal 21:509–522

    CAS  PubMed  Google Scholar 

  • Bhattacharya S, Ray RM, Chaum E, Johnson DA, Johnson LR (2011) Inhibition of Mdm2 sensitizes human retinal pigment epithelial cells to apoptosis. Invest Ophthalmol Vis Sci 52:3368–3380

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bhattacharya S, Chaum E, Johnson DA, Johnson LR (2012) Age-related susceptibility to apoptosis in human retinal pigment epithelial cells is triggered by disruption of p53-Mdm2 association. Invest Ophthalmol Vis Sci 53:8350–8366

    PubMed Central  CAS  PubMed  Google Scholar 

  • Campisi J (2003) Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes. Exp Gerontol 38:5–11

    CAS  PubMed  Google Scholar 

  • Cannons JL, Tangye SG, Schwartzberg PL (2011) SLAM family receptors and SAP adaptors in immunity. Annu Rev Immunol 29:665–705

    CAS  PubMed  Google Scholar 

  • Cao S, Ko A, Partanen M, Pakzad-Vaezi K, Merkur AB, Albiani DA, Kirker AW, Wang A, Cui JZ, Forooghian F, Matsubara JA (2013) Relationship between systemic cytokines and complement factor H Y402H polymorphism in patients with dry age-related macular degeneration. Am J Ophthalmol 156:1176–1183

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chaum E (2001) Comparative analysis of the uptake and expression of plasmid vectors in human ciliary and retinal pigment epithelial cells in vitro. J Cell Biochem 83:671–677

    CAS  PubMed  Google Scholar 

  • Chen B, He L, Savell VH, Jenkins JJ, Parham DM (2000) Inhibition of the interferon-gamma/signal transducers and activators of transcription (STAT) pathway by hypermethylation at a STAT-binding site in the p21WAF1 promoter region. Cancer Res 60:3290–3298

    CAS  PubMed  Google Scholar 

  • Chen H, Liu B, Lukas TJ, Neufeld AH (2008) The aged retinal pigment epithelium/choroid: a potential substratum for the pathogenesis of age-related macular degeneration. PLoS One 3:e2339

    PubMed Central  PubMed  Google Scholar 

  • Chen M, Muckersie E, Forrester JV, Xu H (2010) Immune activation in retinal aging: a gene expression study. Invest Ophthalmol Vis Sci 51:5888–5896

    PubMed  Google Scholar 

  • Choubey D (2012) DNA-responsive inflammasomes and their regulators in autoimmunity. Clin Immunol 142:223–231

    PubMed Central  CAS  PubMed  Google Scholar 

  • Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:2853–2868

    CAS  PubMed  Google Scholar 

  • Costa S, Borgogna C, Mondini M, De Andrea M, Meroni PL, Berti E, Gariglio M, Landolfo S (2011) Redistribution of the nuclear protein IFI16 into the cytoplasm of ultraviolet B-exposed keratinocytes as a mechanism of autoantigen processing. Br J Dermatol 164:282–290

    CAS  PubMed  Google Scholar 

  • Datta B, Li B, Choubey D, Nallur G, Lengyel P (1996) p202, an interferon-inducible modulator of transcription, inhibits transcriptional activation by the p53 tumor suppressor protein, and a segment from the p53-binding protein 1 that binds to p202 overcomes this inhibition. J Biol Chem 271:27544–27555

    CAS  PubMed  Google Scholar 

  • Duan X, Ponomareva L, Veeranki S, Panchanathan R, Dickerson E, Choubey D (2011) Differential roles for the interferon-inducible IFI16 and AIM2 innate immune sensors for cytosolic DNA in cellular senescence of human fibroblasts. Mol Cancer Res 9:589–602

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dunaief JL, Dentchev T, Ying GS, Milam AH (2002) The role of apoptosis in age-related macular degeneration. Arch Ophthalmol 120:1435–1442

    PubMed  Google Scholar 

  • Faix J, Grosse R (2006) Staying in shape with formins. Dev Cell 10:693–706

    CAS  PubMed  Google Scholar 

  • Freeman NE, Templeton JP, Orr WE, Lu L, Williams RW, Geisert EE (2011) Genetic networks in the mouse retina: growth associated protein 43 and phosphatase tensin homolog network. Mol Vis 17:1355–1372

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fujiuchi N, Aglipay JA, Ohtsuka T, Maehara N, Sahin F, Su GH, Lee SW, Ouchi T (2004) Requirement of IFI16 for the maximal activation of p53 induced by ionizing radiation. J Biol Chem 279:20339–20344

    CAS  PubMed  Google Scholar 

  • Garfinkel S, Brown S, Wessendorf JH, Maciag T (1994) Post-transcriptional regulation of interleukin 1 alpha in various strains of young and senescent human umbilical vein endothelial cells. Proc Natl Acad Sci USA 91:1559–1563

    PubMed Central  CAS  PubMed  Google Scholar 

  • Geisert EE, Lu L, Freeman-Anderson NE, Templeton JP, Nassr M, Wang X, Gu W, Jiao Y, Williams RW (2009) Gene expression in the mouse eye: an online resource for genetics using 103 strains of mice. Mol Vis 15:1730–1763

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gessner JE, Heiken H, Tamm A, Schmidt RE (1998) The IgG Fc receptor family. Ann Hematol 76:231–248

    CAS  PubMed  Google Scholar 

  • Gugliesi F, Mondini M, Ravera R, Robotti A, de Andrea M, Gribaudo G, Gariglio M, Landolfo S (2005) Up-regulation of the interferon-inducible IFI16 gene by oxidative stress triggers p53 transcriptional activity in endothelial cells. J Leukoc Biol 77:820–829

    CAS  PubMed  Google Scholar 

  • Gupta S, Radha V, Furukawa Y, Swarup G (2001) Direct transcriptional activation of human caspase-1 by tumor suppressor p53. J Biol Chem 276:10585–10588

    CAS  PubMed  Google Scholar 

  • Hasty P, Christy BA (2013) p53 as an intervention target for cancer and aging. Pathobiol Aging Age Relat Dis 3:22702

    Google Scholar 

  • Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A (2001) The innate immune response to bacterial flagellin is mediated by toll-like receptor 5. Nature 410:1099–1103

    CAS  PubMed  Google Scholar 

  • Haywood ME, Hogarth MB, Slingsby JH, Rose SJ, Allen PJ, Thompson EM, Maibaum MA, Chandler P, Davies KA, Simpson E, Walport MJ, Morley BJ (2000) Identification of intervals on chromosomes 1, 3, and 13 linked to the development of lupus in BXSB mice. Arthritis Rheum 43:349–355

    CAS  PubMed  Google Scholar 

  • Hertel P, Daniel J, Stegehake D, Vaupel H, Kailayangiri S, Gruel C, Woltersdorf C, Liebau E (2013) The ubiquitin-fold modifier 1 (Ufm1) cascade of Caenorhabditis elegans. J Biol Chem 288:10661–10671

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hobeika AC, Etienne W, Torres BA, Johnson HM, Subramaniam PS (1999) IFN-gamma induction of p21(WAF1) is required for cell cycle inhibition and suppression of apoptosis. J Interferon Cytokine Res 19:1351–1361

    CAS  PubMed  Google Scholar 

  • Hogarth MB, Slingsby JH, Allen PJ, Thompson EM, Chandler P, Davies KA, Simpson E, Morley BJ, Walport MJ (1998) Multiple lupus susceptibility loci map to chromosome 1 in BXSB mice. J Immunol 161:2753–2761

    CAS  PubMed  Google Scholar 

  • Jablonski MM, Freeman NE, Orr WE, Templeton JP, Lu L, Williams RW, Geisert EE (2011) Genetic pathways regulating glutamate levels in retinal Muller cells. Neurochem Res 36:594–603

    PubMed Central  CAS  PubMed  Google Scholar 

  • Johnstone RW, Kerry JA, Trapani JA (1998) The human interferon-inducible protein, IFI 16, is a repressor of transcription. J Biol Chem 273:17172–17177

    CAS  PubMed  Google Scholar 

  • Karsten CM, Kohl J (2012) The immunoglobulin, IgG Fc receptor and complement triangle in autoimmune diseases. Immunobiology 217:1067–1079

    CAS  PubMed  Google Scholar 

  • Kikuchi S, Fossati-Jimack L, Moll T, Amano H, Amano E, Ida A, Ibnou-Zekri N, Laporte C, Santiago-Raber ML, Rozzo SJ, Kotzin BL, Izui S (2005) Differential role of three major New Zealand Black-derived loci linked with Yaa-induced murine lupus nephritis. J Immunol 174:1111–1117

    CAS  PubMed  Google Scholar 

  • Kitagawa M, Kitagawa K, Kotake Y, Niida H, Ohhata T (2013) Cell cycle regulation by long non-coding RNAs. Cell Mol Life Sci 70:4785–4794

    PubMed Central  CAS  PubMed  Google Scholar 

  • Klettner A (2012) Oxidative stress induced cellular signaling in RPE cells. Front Biosci (Schol Ed) 4:392–411

    Google Scholar 

  • Komatsu M, Chiba T, Tatsumi K, Iemura S, Tanida I, Okazaki N, Ueno T, Kominami E, Natsume T, Tanaka K (2004) A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier. EMBO J 23:1977–1986

    PubMed Central  CAS  PubMed  Google Scholar 

  • Krtolica A, Campisi J (2002) Cancer and aging: a model for the cancer promoting effects of the aging stroma. Int J Biochem Cell Biol 34:1401–1414

    CAS  PubMed  Google Scholar 

  • Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133:1019–1031

    CAS  PubMed  Google Scholar 

  • Kumar V, Ali SR, Konrad S, Zwirner J, Verbeek JS, Schmidt RE, Gessner JE (2006) Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice. J Clin Invest 116:512–520

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kwak JC, Ongusaha PP, Ouchi T, Lee SW (2003) IFI16 as a negative regulator in the regulation of p53 and p21(Waf1). J Biol Chem 278:40899–40904

    CAS  PubMed  Google Scholar 

  • Lin H, Yan J, Wang Z, Hua F, Yu J, Sun W, Li K, Liu H, Yang H, Lv Q, Xue J, Hu ZW (2013) Loss of immunity-supported senescence enhances susceptibility to hepatocellular carcinogenesis and progression in toll-like receptor 2-deficient mice. Hepatology 57:171–182

    CAS  PubMed  Google Scholar 

  • Ma CS, Deenick EK (2011) The role of SAP and SLAM family molecules in the humoral immune response. Ann N Y Acad Sci 1217:32–44

    CAS  PubMed  Google Scholar 

  • Means TK, Hayashi F, Smith KD, Aderem A, Luster AD (2003) The toll-like receptor 5 stimulus bacterial flagellin induces maturation and chemokine production in human dendritic cells. J Immunol 170:5165–5175

    CAS  PubMed  Google Scholar 

  • Menendez D, Shatz M, Azzam K, Garantziotis S, Fessler MB, Resnick MA (2011) The toll-like receptor gene family is integrated into human DNA damage and p53 networks. PLoS Genet 7:e1001360

    PubMed Central  CAS  PubMed  Google Scholar 

  • Menendez D, Shatz M, Resnick MA (2013) Interactions between the tumor suppressor p53 and immune responses. Curr Opin Oncol 25:85–92

    CAS  PubMed  Google Scholar 

  • Morohoshi K, Ohbayashi M, Patel N, Chong V, Bird AC, Ono SJ (2012a) Identification of anti-retinal antibodies in patients with age-related macular degeneration. Exp Mol Pathol 93:193–199

    CAS  PubMed  Google Scholar 

  • Morohoshi K, Patel N, Ohbayashi M, Chong V, Grossniklaus HE, Bird AC, Ono SJ (2012b) Serum autoantibody biomarkers for age-related macular degeneration and possible regulators of neovascularization. Exp Mol Pathol 92:64–73

    CAS  PubMed  Google Scholar 

  • Moser KL, Neas BR, Salmon JE, Yu H, Gray-McGuire C, Asundi N, Bruner GR, Fox J, Kelly J, Henshall S, Bacino D, Dietz M, Hogue R, Koelsch G, Nightingale L, Shaver T, Abdou NI, Albert DA, Carson C, Petri M, Treadwell EL, James JA, Harley JB (1998) Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc Natl Acad Sci USA 95:14869–14874

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mozhui K, Ciobanu DC, Schikorski T, Wang X, Lu L, Williams RW (2008) Dissection of a QTL hotspot on mouse distal chromosome 1 that modulates neurobehavioral phenotypes and gene expression. PLoS Genet 4:e1000260

    PubMed Central  PubMed  Google Scholar 

  • Mullins RF, Aptsiauri N, Hageman GS (2001) Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye (Lond) 15:390–395

    CAS  Google Scholar 

  • Munoz-Fontela C, Macip S, Martinez-Sobrido L, Brown L, Ashour J, Garcia-Sastre A, Lee SW, Aaronson SA (2008) Transcriptional role of p53 in interferon-mediated antiviral immunity. J Exp Med 205:1929–1938

    PubMed Central  CAS  PubMed  Google Scholar 

  • Murinello S, Mullins RF, Lotery AJ, Perry VH, Teeling JL (2014) Fcgamma receptor upregulation is associated with immune complex inflammation in the mouse retina and early age-related macular degeneration. Invest Ophthalmol Vis Sci 55:247–258

    PubMed Central  CAS  PubMed  Google Scholar 

  • Napione L, Strasly M, Meda C, Mitola S, Alvaro M, Doronzo G, Marchio S, Giraudo E, Primo L, Arese M, Bussolino F (2012) IL-12-dependent innate immunity arrests endothelial cells in G0–G1 phase by a p21(Cip1/Waf1)-mediated mechanism. Angiogenesis 15:713–725

    CAS  PubMed  Google Scholar 

  • Nie L, Wu G, Zhang W (2006) Correlation between mRNA and protein abundence in Desulfovibrio vulgaris: a multiple regression to identify sources of variations. Biochem Biophys Res Commun 339:601–610

    Google Scholar 

  • Nimmerjahn F, Ravetch JV (2008) Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 8:34–47

    CAS  PubMed  Google Scholar 

  • Novak N, Bieber T, Peng WM (2010) The immunoglobulin E-toll-like receptor network. Int Arch Allergy Immunol 151:1–7

    CAS  PubMed  Google Scholar 

  • Novakova Z, Hubackova S, Kosar M, Janderova-Rossmeislova L, Dobrovolna J, Vasicova P, Vancurova M, Horejsi Z, Hozak P, Bartek J, Hodny Z (2010) Cytokine expression and signaling in drug-induced cellular senescence. Oncogene 29:273–284

    CAS  PubMed  Google Scholar 

  • Ohtani N, Hara E (2013) Roles and mechanisms of cellular senescence in regulation of tissue homeostasis. Cancer Sci 104:525–530

    CAS  PubMed  Google Scholar 

  • Ouchi M, Ouchi T (2008) Role of IFI16 in DNA damage and checkpoint. Front Biosci 13:236–239

    CAS  PubMed  Google Scholar 

  • Parmeggiani F, Romano MR, Costagliola C, Semeraro F, Incorvaia C, D’Angelo S, Perri P, De Palma P, De Nadai K, Sebastiani A (2012) Mechanism of inflammation in age-related macular degeneration. Mediat Inflamm 2012:546786

    Google Scholar 

  • Patel N, Ohbayashi M, Nugent AK, Ramchand K, Toda M, Chau KY, Bunce C, Webster A, Bird AC, Ono SJ, Chong V (2005) Circulating anti-retinal antibodies as immune markers in age-related macular degeneration. Immunology 115:422–430

    PubMed Central  CAS  PubMed  Google Scholar 

  • Penfold PL, Provis JM, Furby JH, Gatenby PA, Billson FA (1990) Autoantibodies to retinal astrocytes associated with age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 228:270–274

    CAS  PubMed  Google Scholar 

  • Purvis JE, Karhohs KW, Mock C, Batchelor E, Loewer A, Lahav G (2012) p53 dynamics control cell fate. Science 336:1440–1444

    PubMed Central  CAS  PubMed  Google Scholar 

  • Rittirsch D, Flierl MA, Day DE, Nadeau BA, Zetoune FS, Sarma JV, Werner CM, Wanner GA, Simmen HP, Huber-Lang MS, Ward PA (2009) Cross-talk between TLR4 and FcgammaReceptorIII (CD16) pathways. PLoS Pathog 5:e1000464

    PubMed Central  PubMed  Google Scholar 

  • Rozzo SJ, Allard JD, Choubey D, Vyse TJ, Izui S, Peltz G, Kotzin BL (2001) Evidence for an interferon-inducible gene, Ifi202, in the susceptibility to systemic lupus. Immunity 15:435–443

    CAS  PubMed  Google Scholar 

  • Santiago-Raber ML, Amano H, Amano E, Baudino L, Otani M, Lin Q, Nimmerjahn F, Verbeek JS, Ravetch JV, Takasaki Y, Hirose S, Izui S (2009) Fcgamma receptor-dependent expansion of a hyperactive monocyte subset in lupus-prone mice. Arthritis Rheum 60:2408–2417

    CAS  PubMed  Google Scholar 

  • Schmidt RE, Gessner JE (2005) Fc receptors and their interaction with complement in autoimmunity. Immunol Lett 100:56–67

    CAS  PubMed  Google Scholar 

  • Schwartzberg PL, Mueller KL, Qi H, Cannons JL (2009) SLAM receptors and SAP influence lymphocyte interactions, development and function. Nat Rev Immunol 9:39–46

    CAS  PubMed  Google Scholar 

  • Shatz M, Menendez D, Resnick MA (2012) The human TLR innate immune gene family is differentially influenced by DNA stress and p53 status in cancer cells. Cancer Res 72:3948–3957

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shen K, Zheng SS, Park O, Wang H, Sun Z, Gao B (2008) Activation of innate immunity (NK/IFN-gamma) in rat allogeneic liver transplantation: contribution to liver injury and suppression of hepatocyte proliferation. Am J Physiol 294:G1070–1077

    CAS  Google Scholar 

  • Shi X, Liu J, Liu Q, Li M (2014) IFI16 mis-localization can be a contributing factor to hepatocellular carcinoma progression. Med Hypotheses 82:398–400

    CAS  PubMed  Google Scholar 

  • Skokowa J, Ali SR, Felda O, Kumar V, Konrad S, Shushakova N, Schmidt RE, Piekorz RP, Nurnberg B, Spicher K, Birnbaumer L, Zwirner J, Claassens JW, Verbeek JS, van Rooijen N, Kohl J, Gessner JE (2005) Macrophages induce the inflammatory response in the pulmonary Arthus reaction through G alpha i2 activation that controls C5aR and Fc receptor cooperation. J Immunol 174:3041–3050

    CAS  PubMed  Google Scholar 

  • Song LL, Alimirah F, Panchanathan R, Xin H, Choubey D (2008) Expression of an IFN-inducible cellular senescence gene, IFI16, is up-regulated by p53. Mol Cancer Res 6:1732–1741

    CAS  PubMed  Google Scholar 

  • Suzuki HI, Yamagata K, Sugimoto K, Iwamoto T, Kato S, Miyazono K (2009) Modulation of microRNA processing by p53. Nature 460:529–533

    CAS  PubMed  Google Scholar 

  • Syed SN, Konrad S, Wiege K, Nieswandt B, Nimmerjahn F, Schmidt RE, Gessner JE (2009) Both FcgammaRIV and FcgammaRIII are essential receptors mediating type II and type III autoimmune responses via FcRgamma-LAT-dependent generation of C5a. Eur J Immunol 39:3343–3356

    CAS  PubMed  Google Scholar 

  • Templeton JP, Freeman NE, Nickerson JM, Jablonski MM, Rex TS, Williams RW, Geisert EE (2013a) Innate immune network in the retina activated by optic nerve crush. Invest Ophthalmol Vis Sci 54:2599–2606

    PubMed Central  CAS  PubMed  Google Scholar 

  • Templeton JP, Wang X, Freeman NE, Ma Z, Lu A, Hejtmancik F, Geisert EE (2013b) A crystallin gene network in the mouse retina. Exp Eye Res 116:129–140

    PubMed Central  CAS  PubMed  Google Scholar 

  • Tian Q, Stepaniants SB, Mao M, Weng L, Feetham MC, Doyle MJ, Yi EC, Dia H, Thorsson V, Eng J, Goodlett D, Berger JP, Gunter B, Linseley PS, Stoughton RB, Aebersold R, Collins SJ, Hanlon WA, Hood LE (2004) Integrated genomic and proteomic analysis of gene expression in mammalian cells. Mol Cell Proteomics 3:960–969

    CAS  PubMed  Google Scholar 

  • Tordella L, Koch S, Salter V, Pagotto A, Doondeea JB, Feller SM, Ratnayaka I, Zhong S, Goldin RD, Lozano G, McKeon FD, Tavassoli M, Fritzsche F, Huber GF, Rossle M, Moch H, Lu X (2013) ASPP2 suppresses squamous cell carcinoma via RelA/p65-mediated repression of p63. Proc Natl Acad Sci USA 110:17969–17974

    PubMed Central  CAS  PubMed  Google Scholar 

  • Valente LJ, Strasser A (2013) Distinct target genes and effector processes appear to be critical for p53-activated responses to acute DNA damage versus p53-mediated tumor suppression. BioDiscovery 8:1–16

    Google Scholar 

  • Valente LJ, Gray DH, Michalak EM, Pinon-Hofbauer J, Egle A, Scott CL, Janic A, Strasser A (2013) p53 efficiently suppresses tumor development in the complete absence of its cell-cycle inhibitory and proapoptotic effectors p21, Puma, and Noxa. Cell Rep 3:1339–1345

    CAS  PubMed  Google Scholar 

  • Veeranki S, Duan X, Panchanathan R, Liu H, Choubey D (2011) IFI16 protein mediates the anti-inflammatory actions of the type-I interferons through suppression of activation of caspase-1 by inflammasomes. PLoS One 6:e27040

    PubMed Central  CAS  PubMed  Google Scholar 

  • Vogel H, Scherneck S, Kanzleiter T, Benz V, Kluge R, Stadion M, Kryvych S, Bluher M, Kloting N, Joost HG, Schurmann A (2012) Loss of function of Ifi202b by a microdeletion on chromosome 1 of C57BL/6J mice suppresses 11beta-hydroxysteroid dehydrogenase type 1 expression and development of obesity. Hum Mol Genet 21:3845–3857

    CAS  PubMed  Google Scholar 

  • Vogel H, Montag D, Kanzleiter T, Jonas W, Matzke D, Scherneck S, Chadt A, Tole J, Kluge R, Joost HG, Schurmann A (2013) An interval of the obesity QTL Nob3.38 within a QTL hotspot on chromosome 1 modulates behavioral phenotypes. PLoS One 8:e53025

    PubMed Central  CAS  PubMed  Google Scholar 

  • Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137:413–431

    CAS  PubMed  Google Scholar 

  • Vuong L, Conley SM, Al-Ubaidi MR (2012) Expression and role of p53 in the retina. Invest Ophthalmol Vis Sci 53:1362–1371

    CAS  PubMed  Google Scholar 

  • Vyse TJ, Rozzo SJ, Drake CG, Izui S, Kotzin BL (1997) Control of multiple autoantibodies linked with a lupus nephritis susceptibility locus in New Zealand black mice. J Immunol 158:5566–5574

    CAS  PubMed  Google Scholar 

  • Wakeland EK, Liu K, Graham RR, Behrens TW (2001) Delineating the genetic basis of systemic lupus erythematosus. Immunity 15:397–408

    CAS  PubMed  Google Scholar 

  • Whitcup SM, Sodhi A, Atkinson JP, Holers VM, Sinha D, Rohrer B, Dick AD (2013) The role of the immune response in age-related macular degeneration. Int J Inflam 2013:348092

    PubMed Central  PubMed  Google Scholar 

  • Whitney IE, Raven MA, Lu L, Williams RW, Reese BE (2011) A QTL on chromosome 10 modulates cone photoreceptor number in the mouse retina. Invest Ophthalmol Vis Sci 52:3228–3236

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wilson AM, Morquette B, Abdouh M, Unsain N, Barker PA, Feinstein E, Bernier G, Di Polo A (2013) ASPP1/2 regulate p53-dependent death of retinal ganglion cells through PUMA and Fas/CD95 activation in vivo. J Neurosci 33:2205–2216

    CAS  PubMed  Google Scholar 

  • Xaus J, Cardo M, Valledor AF, Soler C, Lloberas J, Celada A (1999) Interferon gamma induces the expression of p21waf-1 and arrests macrophage cell cycle, preventing induction of apoptosis. Immunity 11:103–113

    CAS  PubMed  Google Scholar 

  • Xin H, Pereira-Smith OM, Choubey D (2004) Role of IFI 16 in cellular senescence of human fibroblasts. Oncogene 23:6209–6217

    CAS  PubMed  Google Scholar 

  • Xu H, Chen M, Forrester JV (2009) Para-inflammation in the aging retina. Prog Retin Eye Res 28:348–368

    PubMed  Google Scholar 

  • Yamada K, Ono M, Bensaddek D, Lamond AI, Rocha S (2013a) FMN2 is a novel regulator of the cyclin-dependent kinase inhibitor p21. Cell Cycle 12:2348–2354

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yamada K, Ono M, Perkins ND, Rocha S, Lamond AI (2013b) Identification and functional characterization of FMN2, a regulator of the cyclin-dependent kinase inhibitor p21. Mol Cell 49:922–933

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zipfel PF, Lauer N, Skerka C (2010) The role of complement in AMD. Adv Exp Med Biol 703:9–24

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

These studies were supported in part by an unrestricted UTHSC departmental grant from Research to Prevent Blindness, New York, NY, the Plough Foundation, Memphis, TN, The Lions of Arkansas Foundation Inc., and the UTHSC Hamilton Eye Institute NEI Core Grant for Vision Research (P30 EY013080). The authors would also like to thank Dr. Rob Williams for his comments and review of the manuscript.

Author information

Authors and Affiliations

  1. Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Edward Chaum, Christina S. Winborn & Sujoy Bhattacharya

  2. Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Edward Chaum

  3. Hamilton Eye Institute, 930 Madison Ave. Suite 731, Memphis, TN, 38163, USA

    Edward Chaum

Authors
  1. Edward Chaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christina S. Winborn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sujoy Bhattacharya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward Chaum.

Electronic supplementary material

Below is the link to the electronic supplementary material.

335_2015_9568_MOESM1_ESM.tif

Fig. S1. Expression of Cdkn1a, Cdkn2a and Cdkn2b in the retina of BXD mice. Data illustrates variable expression in BXD mouse retinas for (A) Cdkn1a, (B) Cdkn2a and (C) Cdkn2b. Mean expression and range (expression fold change) for Cdkn1a, Cdkn2a and Cdkn2b are 7.86 (±3.32), 7.19 (±1.6) and 7.29 (±2.65), respectively. Supplementary material 1 (TIFF 8997 kb)

335_2015_9568_MOESM2_ESM.tif

Fig. S2. Expression of candidate genes in the Qrr1 locus in the retina of BXD mice. Data illustrates varied expression of (A) Fcer1γ, (B) Fcgr3, (C) Fmn2 and (D) Ifi205 in BXD mice retinas. Mean expression and rage (fold) for these candidate genes are 7.64 (±6.28), 7.31 (±2.44), 9.18 (±2.91) and 6.811 (±2.19), respectively. Supplementary material 2 (TIFF 8305 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chaum, E., Winborn, C.S. & Bhattacharya, S. Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium. Mamm Genome 26, 210–221 (2015). https://doi.org/10.1007/s00335-015-9568-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-015-9568-9

Keywords

Search

Navigation