DDIT4_MOUSE
ID DDIT4_MOUSE Reviewed; 229 AA.
AC Q9D3F7;
DT 23-OCT-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 134.
DE RecName: Full=DNA damage-inducible transcript 4 protein;
DE AltName: Full=Dexamethasone-induced gene 2 protein;
DE AltName: Full=HIF-1 responsive protein RTP801;
DE AltName: Full=Protein regulated in development and DNA damage response 1;
DE Short=REDD-1;
GN Name=Ddit4; Synonyms=Dig2, Redd1, Rtp801;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RC STRAIN=C57BL/6J; TISSUE=Thymus;
RX PubMed=12736248; DOI=10.1074/jbc.m303723200;
RA Wang Z., Malone M.H., Thomenius M.J., Zhong F., Xu F., Distelhorst C.W.;
RT "Dexamethasone-induced gene 2 (dig2) is a novel pro-survival stress gene
RT induced rapidly by diverse apoptotic signals.";
RL J. Biol. Chem. 278:27053-27058(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Cerebellum, and Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP IDENTIFICATION, DEVELOPMENTAL STAGE, AND INDUCTION.
RX PubMed=12453409; DOI=10.1016/s1097-2765(02)00706-2;
RA Ellisen L.W., Ramsayer K.D., Johannessen C.M., Yang A., Beppu H., Minda K.,
RA Oliner J.D., McKeon F., Haber D.A.;
RT "REDD1, a developmentally regulated transcriptional target of p63 and p53,
RT links p63 to regulation of reactive oxygen species.";
RL Mol. Cell 10:995-1005(2002).
RN [5]
RP INDUCTION.
RX PubMed=11884613; DOI=10.1128/mcb.22.7.2283-2293.2002;
RA Shoshani T., Faerman A., Mett I., Zelin E., Tenne T., Gorodin S.,
RA Moshel Y., Elbaz S., Budanov A., Chajut A., Kalinski H., Kamer I.,
RA Rozen A., Mor O., Keshet E., Leshkowitz D., Einat P., Skaliter R.,
RA Feinstein E.;
RT "Identification of a novel hypoxia-inducible factor 1-responsive gene,
RT RTP801, involved in apoptosis.";
RL Mol. Cell. Biol. 22:2283-2293(2002).
RN [6]
RP INDUCTION, AND FUNCTION.
RX PubMed=15545625; DOI=10.1101/gad.1256804;
RA Brugarolas J., Lei K., Hurley R.L., Manning B.D., Reiling J.H., Hafen E.,
RA Witters L.A., Ellisen L.W., Kaelin W.G. Jr.;
RT "Regulation of mTOR function in response to hypoxia by REDD1 and the
RT TSC1/TSC2 tumor suppressor complex.";
RL Genes Dev. 18:2893-2904(2004).
RN [7]
RP INDUCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=15452091; DOI=10.1167/iovs.04-0052;
RA Brafman A., Mett I., Shafir M., Gottlieb H., Damari G., Gozlan-Kelner S.,
RA Vishnevskia-Dai V., Skaliter R., Einat P., Faerman A., Feinstein E.,
RA Shoshani T.;
RT "Inhibition of oxygen-induced retinopathy in RTP801-deficient mice.";
RL Invest. Ophthalmol. Vis. Sci. 45:3796-3805(2004).
RN [8]
RP DISRUPTION PHENOTYPE, FUNCTION, AND INDUCTION.
RX PubMed=15988001; DOI=10.1128/mcb.25.14.5834-5845.2005;
RA Sofer A., Lei K., Johannessen C.M., Ellisen L.W.;
RT "Regulation of mTOR and cell growth in response to energy stress by
RT REDD1.";
RL Mol. Cell. Biol. 25:5834-5845(2005).
RN [9]
RP INDUCTION.
RX PubMed=17005863; DOI=10.1523/jneurosci.3292-06.2006;
RA Malagelada C., Ryu E.J., Biswas S.C., Jackson-Lewis V., Greene L.A.;
RT "RTP801 is elevated in Parkinson brain substantia nigral neurons and
RT mediates death in cellular models of Parkinson's disease by a mechanism
RT involving mammalian target of rapamycin inactivation.";
RL J. Neurosci. 26:9996-10005(2006).
RN [10]
RP DISRUPTION PHENOTYPE, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=20176937; DOI=10.1073/pnas.0907705107;
RA Horak P., Crawford A.R., Vadysirisack D.D., Nash Z.M., DeYoung M.P.,
RA Sgroi D., Ellisen L.W.;
RT "Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses
RT tumorigenesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:4675-4680(2010).
RN [11]
RP FUNCTION, INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=21383064; DOI=10.1128/mcb.01393-10;
RA Wolff N.C., Vega-Rubin-de-Celis S., Xie X.J., Castrillon D.H., Kabbani W.,
RA Brugarolas J.;
RT "Cell-type-dependent regulation of mTORC1 by REDD1 and the tumor
RT suppressors TSC1/TSC2 and LKB1 in response to hypoxia.";
RL Mol. Cell. Biol. 31:1870-1884(2011).
RN [12]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=21896779; DOI=10.1128/mcb.05541-11;
RA Vadysirisack D.D., Baenke F., Ory B., Lei K., Ellisen L.W.;
RT "Feedback control of p53 translation by REDD1 and mTORC1 limits the p53-
RT dependent DNA damage response.";
RL Mol. Cell. Biol. 31:4356-4365(2011).
RN [13]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=21909097; DOI=10.1038/nchembio.645;
RA Mata M.A., Satterly N., Versteeg G.A., Frantz D., Wei S., Williams N.,
RA Schmolke M., Pena-Llopis S., Brugarolas J., Forst C.V., White M.A.,
RA Garcia-Sastre A., Roth M.G., Fontoura B.M.;
RT "Chemical inhibition of RNA viruses reveals REDD1 as a host defense
RT factor.";
RL Nat. Chem. Biol. 7:712-719(2011).
CC -!- FUNCTION: Regulates cell growth, proliferation and survival via
CC inhibition of the activity of the mammalian target of rapamycin complex
CC 1 (mTORC1). Inhibition of mTORC1 is mediated by a pathway that involves
CC DDIT4/REDD1, AKT1, the TSC1-TSC2 complex and the GTPase RHEB. Plays an
CC important role in responses to cellular energy levels and cellular
CC stress, including responses to hypoxia and DNA damage. Regulates
CC p53/TP53-mediated apoptosis in response to DNA damage via its effect on
CC mTORC1 activity. Its role in the response to hypoxia depends on the
CC cell type; it mediates mTORC1 inhibition in fibroblasts and thymocytes,
CC but not in hepatocytes. Inhibits neuronal differentiation and neurite
CC outgrowth mediated by NGF via its effect on mTORC1 activity. Required
CC for normal neuron migration during embryonic brain development. Plays a
CC role in neuronal cell death. Required for mTORC1-mediated defense
CC against viral protein synthesis and virus replication.
CC {ECO:0000269|PubMed:15545625, ECO:0000269|PubMed:15988001,
CC ECO:0000269|PubMed:20176937, ECO:0000269|PubMed:21383064,
CC ECO:0000269|PubMed:21896779, ECO:0000269|PubMed:21909097}.
CC -!- SUBUNIT: Monomer. Interacts with BTRC. Identified in a complex with
CC CUL4A, DDB1 and BTRC. Interacts with TXNIP; this inhibits the
CC proteasomal degradation of DDIT4 (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:20176937}.
CC Cytoplasm, cytosol {ECO:0000269|PubMed:20176937}.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC {ECO:0000269|PubMed:12736248, ECO:0000269|PubMed:21383064}.
CC -!- DEVELOPMENTAL STAGE: Expressed at 7 dpc. At 11 dpc, expressed in the
CC apical ectodermal ridge. At 13.5 dpc, expressed in the whisker pad,
CC eyelid, breast primordia and developing limb. At 14.5 dpc, expressed in
CC supraorbital and suborbital follicles, whisker pad, limbs and patches
CC of developing epidermis. {ECO:0000269|PubMed:12453409,
CC ECO:0000269|PubMed:12736248}.
CC -!- INDUCTION: By dexamethasone, heat-shock or osmotic stress. Up-regulated
CC by hypoxia, in a HIF1A-dependent but TP53-independent mechanism. Up-
CC regulated upon energy stress. Up-regulated in brain from MPTP-
CC intoxicated mice, a model for Parkinson disease (at protein level). Up-
CC regulated by hypoxia in bowel, liver, spleen, heart, lung, brain and
CC kidney. {ECO:0000269|PubMed:11884613, ECO:0000269|PubMed:12453409,
CC ECO:0000269|PubMed:15452091, ECO:0000269|PubMed:15545625,
CC ECO:0000269|PubMed:15988001, ECO:0000269|PubMed:17005863,
CC ECO:0000269|PubMed:21383064}.
CC -!- PTM: Phosphorylated by GSK3B; this promotes proteasomal degradation.
CC {ECO:0000250}.
CC -!- PTM: Polyubiquitinated by a DCX (DDB1-CUL4A-RBX1) E3 ubiquitin-protein
CC ligase complex with BTRC as substrate-recognition component, leading to
CC its proteasomal degradation. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: No visible phenotype. Mice are normal and less
CC sensitive to oxygen-induced retinopathy. Mitochondria show increased
CC production of reactive oxygen species. Newborn mice show increased
CC radiation-induced apoptosis in brain and thymus, due to increased
CC levels of TP53 and increased TP53 activity. Likewise, cultured
CC embryonic fibroblasts are highly sensitive to DNA damage caused by UV
CC irradiation or doxomycin and display increased levels of TP53 and
CC increased TP53 activity, leading to increased apoptosis. Cultured
CC embryonic fibroblasts are more susceptible to cell death caused by
CC influenza virus infection and produce about 200 times more virus
CC particles than wild-type. {ECO:0000269|PubMed:15452091,
CC ECO:0000269|PubMed:15988001, ECO:0000269|PubMed:20176937,
CC ECO:0000269|PubMed:21896779, ECO:0000269|PubMed:21909097}.
CC -!- SIMILARITY: Belongs to the DDIT4 family. {ECO:0000305}.
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DR EMBL; AY260552; AAP13851.1; -; mRNA.
DR EMBL; AK017926; BAB31006.1; -; mRNA.
DR EMBL; AK081046; BAC38121.1; -; mRNA.
DR EMBL; BC131992; AAI31993.1; -; mRNA.
DR EMBL; BC132645; AAI32646.1; -; mRNA.
DR CCDS; CCDS23868.1; -.
DR RefSeq; NP_083359.1; NM_029083.2.
DR AlphaFoldDB; Q9D3F7; -.
DR SMR; Q9D3F7; -.
DR STRING; 10090.ENSMUSP00000020308; -.
DR iPTMnet; Q9D3F7; -.
DR PhosphoSitePlus; Q9D3F7; -.
DR PaxDb; Q9D3F7; -.
DR PRIDE; Q9D3F7; -.
DR ProteomicsDB; 279897; -.
DR Antibodypedia; 29243; 334 antibodies from 37 providers.
DR DNASU; 74747; -.
DR Ensembl; ENSMUST00000020308; ENSMUSP00000020308; ENSMUSG00000020108.
DR GeneID; 74747; -.
DR KEGG; mmu:74747; -.
DR UCSC; uc007fee.1; mouse.
DR CTD; 54541; -.
DR MGI; MGI:1921997; Ddit4.
DR VEuPathDB; HostDB:ENSMUSG00000020108; -.
DR eggNOG; ENOG502RB72; Eukaryota.
DR GeneTree; ENSGT00530000063652; -.
DR HOGENOM; CLU_086145_1_0_1; -.
DR InParanoid; Q9D3F7; -.
DR OMA; EQGKGCH; -.
DR OrthoDB; 1588396at2759; -.
DR PhylomeDB; Q9D3F7; -.
DR TreeFam; TF105007; -.
DR Reactome; R-MMU-5628897; TP53 Regulates Metabolic Genes.
DR BioGRID-ORCS; 74747; 6 hits in 73 CRISPR screens.
DR ChiTaRS; Ddit4; mouse.
DR PRO; PR:Q9D3F7; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; Q9D3F7; protein.
DR Bgee; ENSMUSG00000020108; Expressed in aortic valve and 262 other tissues.
DR ExpressionAtlas; Q9D3F7; baseline and differential.
DR Genevisible; Q9D3F7; MM.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; IDA:MGI.
DR GO; GO:0071889; F:14-3-3 protein binding; IDA:MGI.
DR GO; GO:0006915; P:apoptotic process; ISO:MGI.
DR GO; GO:0007420; P:brain development; ISS:UniProtKB.
DR GO; GO:0071549; P:cellular response to dexamethasone stimulus; IDA:MGI.
DR GO; GO:0051607; P:defense response to virus; ISO:MGI.
DR GO; GO:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; IMP:UniProtKB.
DR GO; GO:0045820; P:negative regulation of glycolytic process; IMP:MGI.
DR GO; GO:1902532; P:negative regulation of intracellular signal transduction; ISS:UniProtKB.
DR GO; GO:0033137; P:negative regulation of peptidyl-serine phosphorylation; ISS:UniProtKB.
DR GO; GO:0010801; P:negative regulation of peptidyl-threonine phosphorylation; ISS:UniProtKB.
DR GO; GO:0032007; P:negative regulation of TOR signaling; IMP:MGI.
DR GO; GO:0030182; P:neuron differentiation; ISS:UniProtKB.
DR GO; GO:0001764; P:neuron migration; ISS:UniProtKB.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:1901216; P:positive regulation of neuron death; ISS:UniProtKB.
DR GO; GO:0032984; P:protein-containing complex disassembly; IMP:MGI.
DR GO; GO:0072593; P:reactive oxygen species metabolic process; IMP:MGI.
DR GO; GO:0032006; P:regulation of TOR signaling; IBA:GO_Central.
DR GO; GO:0001666; P:response to hypoxia; IMP:MGI.
DR Gene3D; 3.90.470.40; -; 1.
DR InterPro; IPR012918; RTP801-like.
DR InterPro; IPR038281; RTP801-like_C_sf.
DR PANTHER; PTHR12478; PTHR12478; 1.
DR Pfam; PF07809; RTP801_C; 1.
PE 1: Evidence at protein level;
KW Antiviral defense; Apoptosis; Cytoplasm; Mitochondrion; Phosphoprotein;
KW Reference proteome; Ubl conjugation.
FT CHAIN 1..229
FT /note="DNA damage-inducible transcript 4 protein"
FT /id="PRO_0000307198"
FT REGION 1..68
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..23
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 49..64
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 16
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9NX09"
FT MOD_RES 20
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9NX09"
FT MOD_RES 118
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9NX09"
SQ SEQUENCE 229 AA; 24871 MW; FE7EA24D3FF63949 CRC64;
MPSLWDRFSS SSSSSSSSRT PAADRPPRSA WGSAAREEGL DRCASLESSD CESLDSSNSG
FGPEEDSSYL DGVSLPDFEL LSDPEDEHLC ANLMQLLQES LSQARLGSRR PARLLMPSQL
VSQVGKELLR LAYSEPCGLR GALLDVCVEQ GKSCHSVAQL ALDPSLVPTF QLTLVLRLDS
RLWPKIQGLL SSANSSLVPG YSQSLTLSTG FRVIKKKLYS SEQLLIEEC
