Ppp1r15a

Summary

Gene Symbol: Ppp1r15a
Description: protein phosphatase 1, regulatory (inhibitor) subunit 15A
Alias: 9630030H21, Gadd34, Myd116, protein phosphatase 1 regulatory subunit 15A, growth arrest and DNA damage-inducible protein GADD34, growth arrest and DNA-damage-inducible 34, myeloid differentiation primary response gene 116, myeloid differentiation primary response protein MyD116
Species: mouse
Products:     Ppp1r15a

Top Publications

  1. Lord K, Hoffman Liebermann B, Liebermann D. Sequence of MyD116 cDNA: a novel myeloid differentiation primary response gene induced by IL6. Nucleic Acids Res. 1990;18:2823 pubmed
  2. Clavarino G, Cláudio N, Couderc T, Dalet A, Judith D, Camosseto V, et al. Induction of GADD34 is necessary for dsRNA-dependent interferon-? production and participates in the control of Chikungunya virus infection. PLoS Pathog. 2012;8:e1002708 pubmed publisher
    ..We demonstrate that the phosphatase-1 cofactor, growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a), an important component of the unfolded protein response (UPR), is absolutely required for type I-IFN and IL-6 ..
  3. Kojima E, Takeuchi A, Haneda M, Yagi A, Hasegawa T, Yamaki K, et al. The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress: elucidation by GADD34-deficient mice. FASEB J. 2003;17:1573-5 pubmed
    b>GADD34 is a protein that is induced by stresses such as DNA damage. The function of mammalian GADD34 has been proposed by in vitro transfection, but its function in vivo has not yet been elucidated...
  4. Rutkowski D, Arnold S, Miller C, Wu J, Li J, Gunnison K, et al. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol. 2006;4:e374 pubmed
    ..It underscores the contribution of posttranscriptional and posttranslational mechanisms in influencing this outcome. ..
  5. Suraweera A, Münch C, Hanssum A, Bertolotti A. Failure of amino acid homeostasis causes cell death following proteasome inhibition. Mol Cell. 2012;48:242-53 pubmed publisher
    ..These results reveal that cells can tolerate protein waste, but not the amino acid scarcity resulting from proteasome inhibition. ..
  6. Clavarino G, Cláudio N, Dalet A, Terawaki S, Couderc T, Chasson L, et al. Protein phosphatase 1 subunit Ppp1r15a/GADD34 regulates cytokine production in polyinosinic:polycytidylic acid-stimulated dendritic cells. Proc Natl Acad Sci U S A. 2012;109:3006-11 pubmed publisher
    ..during which the transcription factor ATF4 and the growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a), a phosphatase 1 (PP1) cofactor, are expressed...
  7. Harding H, Zhang Y, Scheuner D, Chen J, Kaufman R, Ron D. Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2alpha) dephosphorylation in mammalian development. Proc Natl Acad Sci U S A. 2009;106:1832-7 pubmed publisher
    ..GADD34 and CReP, the products of the related mammalian genes Ppp1r15a and Ppp1r15b, can recruit phosphatase catalytic subunits of the PPP1 class to eIF2(alphaP), but the significance ..
  8. Marciniak S, Yun C, Oyadomari S, Novoa I, Zhang Y, Jungreis R, et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 2004;18:3066-77 pubmed
    ..We find that CHOP directly activates GADD34, which promotes ER client protein biosynthesis by dephosphorylating phospho-Ser 51 of the alpha-subunit of ..
  9. Patterson A, Hollander M, Miller G, Fornace A. Gadd34 requirement for normal hemoglobin synthesis. Mol Cell Biol. 2006;26:1644-53 pubmed
    The protein encoded by growth arrest and DNA damage-inducible transcript 34 (Gadd34) is associated with translation initiation regulation following certain stress responses...

More Information

Publications57

  1. Lee Y, Cevallos R, Jan E. An upstream open reading frame regulates translation of GADD34 during cellular stresses that induce eIF2alpha phosphorylation. J Biol Chem. 2009;284:6661-73 pubmed publisher
    ..in turn induces transcription of downstream stress-induced genes such as growth arrest DNA-inducible gene 34 (GADD34)...
  2. Watanabe R, Tambe Y, Inoue H, Isono T, Haneda M, Isobe K, et al. GADD34 inhibits mammalian target of rapamycin signaling via tuberous sclerosis complex and controls cell survival under bioenergetic stress. Int J Mol Med. 2007;19:475-83 pubmed
    ..Here, we show that the expression of growth arrest and DNA damage protein 34 (GADD34) is induced by energy depletion and that the expression of this protein protects cells from apoptotic cell death...
  3. Hollander M, Zhan Q, Bae I, Fornace A. Mammalian GADD34, an apoptosis- and DNA damage-inducible gene. J Biol Chem. 1997;272:13731-7 pubmed
    ..Induction of the human DNA damage- and growth arrest-inducible gene, GADD34, by ionizing radiation was only seen in certain cell lines and correlated with apoptosis following ionizing ..
  4. D Antonio M, Musner N, Scapin C, Ungaro D, Del Carro U, Ron D, et al. Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice. J Exp Med. 2013;210:821-38 pubmed publisher
    ..Here, we show that Gadd34 is a detrimental effector of CHOP that reactivates translation too aggressively in myelinating Schwann cells...
  5. Uddin M, Ito S, Nishio N, Suganya T, Isobe K. Gadd34 induces autophagy through the suppression of the mTOR pathway during starvation. Biochem Biophys Res Commun. 2011;407:692-8 pubmed publisher
    Several types of cellular stress induce expression of growth arrest and DNA damage protein 34 (Gadd34). Autophagy occurs under both basal conditions and conditions of stress, such as starvation...
  6. Lin W, Kunkler P, Harding H, Ron D, Kraig R, Popko B. Enhanced integrated stress response promotes myelinating oligodendrocyte survival in response to interferon-gamma. Am J Pathol. 2008;173:1508-17 pubmed publisher
    ..In this study, we found that growth arrest and DNA damage 34 (GADD34), a stress-inducible regulatory subunit of a phosphatase complex that dephosphorylates eIF2alpha, was selectively ..
  7. Minami K, Tambe Y, Watanabe R, Isono T, Haneda M, Isobe K, et al. Suppression of viral replication by stress-inducible GADD34 protein via the mammalian serine/threonine protein kinase mTOR pathway. J Virol. 2007;81:11106-15 pubmed
    b>GADD34 is a protein that is induced by a variety of stressors, including DNA damage, heat shock, nutrient deprivation, energy depletion, and endoplasmic reticulum stress...
  8. Novoa I, Zeng H, Harding H, Ron D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol. 2001;153:1011-22 pubmed
    ..eIF2alpha kinases PERK (also known as PEK) and GCN2, phospho-eIF2alpha levels were markedly diminished in GADD34-overexpressing cells...
  9. Novoa I, Zhang Y, Zeng H, Jungreis R, Harding H, Ron D. Stress-induced gene expression requires programmed recovery from translational repression. EMBO J. 2003;22:1180-7 pubmed
    ..b>GADD34 is a stress-inducible regulatory subunit of a holophosphatase complex that dephosphorylates eIF2alpha, and has ..
  10. Zhou W, Jeyaraman K, Yusoff P, Shenolikar S. Phosphorylation at tyrosine 262 promotes GADD34 protein turnover. J Biol Chem. 2013;288:33146-55 pubmed publisher
    ..Subsequent transcriptional activation of GADD34 assembles an eIF2? phosphatase that feeds back to restore mRNA translation...
  11. Lin Y, Jamison S, Lin W. Interferon-? activates nuclear factor-? B in oligodendrocytes through a process mediated by the unfolded protein response. PLoS ONE. 2012;7:e36408 pubmed publisher
  12. Kim J, Park S, Kim T, Park H, Park J, Kim B, et al. Testicular hyperthermia induces Unfolded Protein Response signaling activation in spermatocyte. Biochem Biophys Res Commun. 2013;434:861-6 pubmed publisher
    ..In the present study, we verified that UPR signaling via phospho-eIF2?/ATF4/GADD34, p90ATF6, and phospho-IRE1?/XBP-1 is activated with testicular hyperthermia (43 °C, 15 min/day) and induced ER ..
  13. Ohri S, Mullins A, Hetman M, Whittemore S. Inhibition of GADD34, the stress-inducible regulatory subunit of the endoplasmic reticulum stress response, does not enhance functional recovery after spinal cord injury. PLoS ONE. 2014;9:e109703 pubmed publisher
    ..Here, we investigated the contribution of stress-inducible PPP1R15A/GADD34, an ERSR signaling effector downstream of CHOP that dephosphorylates eIF2α, in the pathogenesis of SCI...
  14. Chen R, Rato C, Yan Y, Crespillo Casado A, Clarke H, Harding H, et al. G-actin provides substrate-specificity to eukaryotic initiation factor 2α holophosphatases. elife. 2015;4: pubmed publisher
    ..synthesis at the waning of stress responses and requires a PP1 catalytic subunit and a regulatory subunit, PPP1R15A/GADD34 or PPP1R15B/CReP...
  15. Krokowski D, Jobava R, Guan B, Farabaugh K, Wu J, Majumder M, et al. Coordinated Regulation of the Neutral Amino Acid Transporter SNAT2 and the Protein Phosphatase Subunit GADD34 Promotes Adaptation to Increased Extracellular Osmolarity. J Biol Chem. 2015;290:17822-37 pubmed publisher
    ..response to mild hyperosmotic stress involves regulation of the phosphorylation of eIF2α by increased levels of GADD34, a regulatory subunit of protein phosphatase 1 (PP1)...
  16. Tanaka Y, Ito S, Oshino R, Chen N, Nishio N, Isobe K. Effects of growth arrest and DNA damage-inducible protein 34 (GADD34) on inflammation-induced colon cancer in mice. Br J Cancer. 2015;113:669-79 pubmed publisher
    Growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a) is a family of GADD proteins that are induced by DNA damage. GADD34 protein has been suggested to regulate inflammation or host defense systems...
  17. Reid D, Tay A, Sundaram J, Lee I, Chen Q, George S, et al. Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2? Phosphatases during the Unfolded Protein Response. Mol Cell Biol. 2016;36:1868-80 pubmed publisher
    ..Two eIF2? phosphatases, containing GADD34 and CReP, catalyze P-eIF2? dephosphorylation...
  18. Ito S, Tanaka Y, Oshino R, Okado S, Hori M, Isobe K. GADD34 suppresses lipopolysaccharide-induced sepsis and tissue injury through the regulation of macrophage activation. Cell Death Dis. 2016;7:e2219 pubmed publisher
    Growth arrest and DNA damage inducible protein 34 (GADD34) is induced by various cellular stresses, such as DNA damage, endoplasmic reticulum stress, and amino-acid deprivation...
  19. Stone S, Ho Y, Li X, Jamison S, Harding H, Ron D, et al. Dual role of the integrated stress response in medulloblastoma tumorigenesis. Oncotarget. 2016;7:64124-64135 pubmed publisher
    ..eIF2α is quickly dephosphorylated by the protein phosphatase 1 and growth arrest and DNA damage 34 (GADD34) complex. Data indicate that the ISR can either promote or suppress tumor development...
  20. Dalet A, Argüello R, Combes A, Spinelli L, Jaeger S, Fallet M, et al. Protein synthesis inhibition and GADD34 control IFN-β heterogeneous expression in response to dsRNA. EMBO J. 2017;36:761-782 pubmed publisher
    ..and then overcome this inhibition by decreasing eIF2α phosphorylation through phosphatase 1c cofactor GADD34 (Ppp1r15a) expression...
  21. Wu H, Wei L, Fan F, Ji S, Zhang S, Geng J, et al. Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis. Nat Commun. 2015;6:6239 pubmed publisher
    ..kinase-eIF2α axis activates Yap, while prolonged ER stress-induced Hippo signalling triggers assembly of the GADD34/PP1 complex in a negative feedback loop to inhibit Yap and promote apoptosis...
  22. Liu L, Nishio N, Ito S, Tanaka Y, Isobe K. Negative regulation of GADD34 on myofibroblasts during cutaneous wound healing. Biomed Res Int. 2014;2014:137049 pubmed publisher
    The growth arrest and DNA damage-inducible protein, GADD34, has been proved to be involved in TGF-β signaling pathway and correlates with cell death, which are two important mechanisms in regulating myofibroblast differentiation and ..
  23. McCabe C, White F, Brown S, Macrae I. GADD34 gene restores virulence in viral vector used in experimental stroke study. J Cereb Blood Flow Metab. 2008;28:747-51 pubmed
    b>GADD34 is expressed in the ischaemic brain and reverses protein synthesis shutdown. Consequently, GADD34 could have neuroprotective potential in stroke...
  24. Yagi A, Hasegawa Y, Xiao H, Haneda M, Kojima E, Nishikimi A, et al. GADD34 induces p53 phosphorylation and p21/WAF1 transcription. J Cell Biochem. 2003;90:1242-9 pubmed
    Recently, others and we have shown that one of the functions of GADD34 is a recovery from a shutoff of protein synthesis induced by endoplasmic reticulum stress. GADD34 has been shown to induce growth arrest and apoptosis...
  25. Hasegawa T, Yagi A, Isobe K. Interaction between GADD34 and kinesin superfamily, KIF3A. Biochem Biophys Res Commun. 2000;267:593-6 pubmed
    b>GADD34 is one of a subset of proteins induced after DNA damage or cell growth arrest. To examine the function of GADD34, we used the yeast two-hybrid system to clone the protein that interacts with the murine GADD34...
  26. Tanaka C, Ito S, Nishio N, Kodera Y, Sakurai H, Suzuki H, et al. GADD34 suppresses wound healing by upregulating expression of myosin IIA. Transgenic Res. 2010;19:637-45 pubmed publisher
    ..In order to analyze the potential function of growth arrest and DNA damage inducible protein 34 (GADD34) in tissue repair, we performed in vitro and in vivo wound healing experiments...
  27. Perego J, Mendes A, Bourbon C, Camosseto V, Combes A, Liu H, et al. Guanabenz inhibits TLR9 signaling through a pathway that is independent of eIF2? dephosphorylation by the GADD34/PP1c complex. Sci Signal. 2018;11: pubmed publisher
    ..Upon the resolution of ER stress, the inducible phosphatase 1 cofactor GADD34 promotes the dephosphorylation of the initiation factor eIF2?, thereby enabling protein translation to resume...
  28. Farook J, Shields J, Tawfik A, Markand S, Sen T, Smith S, et al. GADD34 induces cell death through inactivation of Akt following traumatic brain injury. Cell Death Dis. 2013;4:e754 pubmed publisher
    ..Here we show that upregulation of a pro-apototic protein, GADD34, attenuates TRAF6-mediated Akt activation in a controlled cortical impact model of TBI in mice...
  29. Adolph T, Tomczak M, Niederreiter L, Ko H, Böck J, Martínez Naves E, et al. Paneth cells as a site of origin for intestinal inflammation. Nature. 2013;503:272-6 pubmed publisher
  30. Nishio N, Ito S, Isobe K. Loss of GADD34 induces early age-dependent deviation to the myeloid lineage. Immunol Cell Biol. 2014;92:170-80 pubmed publisher
    ..Upon aging, myeloid-biased HSCs are maintained, whereas lymphoid-biased HSCs are lost. GADD34 protein is expressed in myeloid-lineage cells and has been cloned from them...
  31. Jiang W, Jiang C, Pei H, Wang L, Zhang J, Hu H, et al. In vivo molecular mediators of cancer growth suppression and apoptosis by selenium in mammary and prostate models: lack of involvement of gadd genes. Mol Cancer Ther. 2009;8:682-91 pubmed publisher
    ..The mRNA levels of growth arrest-DNA damage inducible 34 (gadd34), gadd45, and gadd153 genes were, contrary to expectation, not higher in the Se-treated carcinomas than in the ..
  32. Young S, Shao Y, Bidwell J, Wek R. Nuclear Matrix Protein 4 Is a Novel Regulator of Ribosome Biogenesis and Controls the Unfolded Protein Response via Repression of Gadd34 Expression. J Biol Chem. 2016;291:13780-8 pubmed publisher
    ..also induces a feedback mechanism through enhanced transcriptional and translational expression of Gadd34 (Ppp1r15A),which targets type 1 protein phosphatase for dephosphorylation of eIF2?-P to restore protein synthesis...
  33. Cheng G, Gross M, Brett M, He B. AlaArg motif in the carboxyl terminus of the gamma(1)34.5 protein of herpes simplex virus type 1 is required for the formation of a high-molecular-weight complex that dephosphorylates eIF-2alpha. J Virol. 2001;75:3666-74 pubmed
    ..5 is functionally active in the absence of any other HSV proteins. In addition to a PP1 binding domain, the carboxyl terminus of gamma(1)34.5 contains an effector domain that is required to form a functional complex. ..
  34. Chen N, Nishio N, Ito S, Tanaka Y, Sun Y, Isobe K. Growth arrest and DNA damage-inducible protein (GADD34) enhanced liver inflammation and tumorigenesis in a diethylnitrosamine (DEN)-treated murine model. Cancer Immunol Immunother. 2015;64:777-89 pubmed publisher
    Growth arrest and DNA damage-inducible protein (GADD34/Ppp1r15a) is induced by various stimuli including DNA damage and ER stress...
  35. Liu L, Ito S, Nishio N, Sun Y, Chen N, Tanaka Y, et al. GADD34 Facilitates Cell Death Resulting from Proteasome Inhibition. Anticancer Res. 2015;35:5317-24 pubmed
    ..To investigate the role of GADD34 in cell death following proteasome inhibition, we treated WT MEF and GADD34 KO MEF with MG132 and various analyses ..
  36. Grigaravicius P, Kaminska E, Hübner C, McKinnon P, von Deimling A, Frappart P. Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain. Cell Death Differ. 2016;23:454-68 pubmed publisher
    ..Altogether, our findings highlight the crucial roles of Rint1 in vivo in genomic stability maintenance, as well as in prevention of ER stress and autophagy. ..
  37. Nishio N, Isobe K. GADD34-deficient mice develop obesity, nonalcoholic fatty liver disease, hepatic carcinoma and insulin resistance. Sci Rep. 2015;5:13519 pubmed publisher
    ..DNA damage-inducible protein 34 (GADD34/Ppp1r15a), originally isolated from UV-inducible transcripts in Chinese hamster ovary (CHO) cells, dephosphorylates ..
  38. Posey K, Coustry F, Veerisetty A, Liu P, Alcorn J, Hecht J. Chop (Ddit3) is essential for D469del-COMP retention and cell death in chondrocytes in an inducible transgenic mouse model of pseudoachondroplasia. Am J Pathol. 2012;180:727-37 pubmed publisher
    ..Taken together, these results suggest that there may be an optimal window before the induction of significant D469del-COMP retention during which endoplasmic reticulum stress could be targeted. ..
  39. Weiss R, Enoch T, Leder P. Inactivation of mouse Hus1 results in genomic instability and impaired responses to genotoxic stress. Genes Dev. 2000;14:1886-98 pubmed
    ..Taken together, these results indicate that mouse Hus1 functions in the maintenance of genomic stability and additionally identify an evolutionarily-conserved role for Hus1 in mediating cellular responses to genotoxins. ..
  40. Zhang B, Zheng C, Zhu M, Tao J, Vasievich M, Baines A, et al. Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of ?1-antitrypsin. Blood. 2011;118:3384-91 pubmed publisher
  41. Majumder M, Huang C, Snider M, Komar A, Tanaka J, Kaufman R, et al. A novel feedback loop regulates the response to endoplasmic reticulum stress via the cooperation of cytoplasmic splicing and mRNA translation. Mol Cell Biol. 2012;32:992-1003 pubmed publisher
    ..We propose a model in which eIF2? phosphorylation-mediated control of mRNA turnover is a molecular switch that regulates the stress response transcription program and the ER's capacity for protein folding during stress. ..
  42. Ito S, Tanaka Y, Oshino R, Aiba K, Thanasegaran S, Nishio N, et al. GADD34 inhibits activation-induced apoptosis of macrophages through enhancement of autophagy. Sci Rep. 2015;5:8327 pubmed publisher
    ..The process is induced by depletion of nutrients including amino acids. GADD34 is expressed following DNA damage, ER stresses and amino acid deprivation...
  43. Tao J, Zhu M, Wang H, Afelik S, Vasievich M, Chen X, et al. SEC23B is required for the maintenance of murine professional secretory tissues. Proc Natl Acad Sci U S A. 2012;109:E2001-9 pubmed publisher
  44. Gu M, Ouyang C, Lin W, Zhang T, Cao X, Xia Z, et al. Phosphatase holoenzyme PP1/GADD34 negatively regulates TLR response by inhibiting TAK1 serine 412 phosphorylation. J Immunol. 2014;192:2846-56 pubmed publisher
    ..DNA damage-inducible protein 34 (GADD34) specifies PP1 to dephosphorylate TAK1 at Ser412...
  45. Latreille M, Larose L. Nck in a complex containing the catalytic subunit of protein phosphatase 1 regulates eukaryotic initiation factor 2alpha signaling and cell survival to endoplasmic reticulum stress. J Biol Chem. 2006;281:26633-44 pubmed
    ..of eIF2alphaSer51 is accomplished by protein phosphatase 1 (PP1c) complexes containing either the protein CReP or GADD34, which target PP1c to eIF2...
  46. Kimball S, Jefferson L. Induction of REDD1 gene expression in the liver in response to endoplasmic reticulum stress is mediated through a PERK, eIF2? phosphorylation, ATF4-dependent cascade. Biochem Biophys Res Commun. 2012;427:485-9 pubmed publisher
    ..Moreover, the induction of REDD1 gene expression was shown to require the protein kinase PERK and enhanced phosphorylation of its substrate, the ?-subunit of eukaryotic initiation factor 2. ..
  47. Zhu M, Tao J, Vasievich M, Wei W, Zhu G, Khoriaty R, et al. Neural tube opening and abnormal extraembryonic membrane development in SEC23A deficient mice. Sci Rep. 2015;5:15471 pubmed publisher
    ..Our results suggest that mammalian SEC23A and SEC23B transport overlapping yet distinct spectra of cargo in vivo. ..
  48. Minami K, Inoue H, Terashita T, Kawakami T, Watanabe R, Haneda M, et al. GADD34 induces p21 expression and cellular senescence. Oncol Rep. 2007;17:1481-5 pubmed
    We previously identified GADD34 (growth arrest and DNA damage protein 34) by screening for genes involved in oncogenic-transformation and/or cellular senescence in Ras-transformed rat F2408 fibroblasts (7EJ-Ras), which exhibit anchorage-..