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Q9D3F7 (DDIT4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 86. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
DNA damage-inducible transcript 4 protein
Alternative name(s):
Dexamethasone-induced gene 2 protein
HIF-1 responsive protein RTP801
Protein regulated in development and DNA damage response 1
Short name=REDD-1
Gene names
Name:Ddit4
Synonyms:Dig2, Redd1, Rtp801
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length229 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Regulates cell growth, proliferation and survival via inhibition of the activity of the mammalian target of rapamycin complex 1 (mTORC1). Inhibition of mTORC1 is mediated by a pathway that involves DDIT4/REDD1, AKT1, the TSC1-TSC2 complex and the GTPase RHEB. Plays an important role in responses to cellular energy levels and cellular stress, including responses to hypoxia and DNA damage. Regulates p53/TP53-mediated apoptosis in response to DNA damage via its effect on mTORC1 activity. Its role in the response to hypoxia depends on the cell type; it mediates mTORC1 inhibition in fibroblasts and thymocytes, but not in hepatocytes. Inhibits neuronal differentiation and neurite outgrowth mediated by NGF via its effect on mTORC1 activity. Required for normal neuron migration during embryonic brain development. Plays a role in neuronal cell death. Required for mTORC1-mediated defense against viral protein synthesis and virus replication. Ref.6 Ref.8 Ref.10 Ref.11 Ref.12 Ref.13

Subunit structure

Monomer. Interacts with BTRC. Identified in a complex with CUL4A, DDB1 and BTRC. Interacts with TXNIP; this inhibits the proteasomal degradation of DDIT4 By similarity.

Subcellular location

Mitochondrion. Cytoplasmcytosol Ref.10.

Tissue specificity

Ubiquitously expressed. Ref.1 Ref.11

Developmental stage

Expressed at E7. At E11, expressed in the apical ectodermal ridge. At E13.5, expressed in the whisker pad, eyelid, breast primordia and developing limb. At E14.5, expressed in supraorbital and suborbital follicles, whisker pad, limbs and patches of developing epidermis. Ref.1 Ref.4

Induction

By dexamethasone, heat-shock or osmotic stress. Up-regulated by hypoxia, in a HIF1A-dependent but TP53-independent mechanism. Up-regulated upon energy stress. Up-regulated in brain from MPTP-intoxicated mice, a model for Parkinson disease (at protein level). Up-regulated by hypoxia in bowel, liver, spleen, heart, lung, brain and kidney. Ref.4 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.11

Post-translational modification

Phosphorylated by GSK3B; this promotes proteasomal degradation By similarity.

Polyubiquitinated by a DCX (DDB1-CUL4A-RBX1) E3 ubiquitin-protein ligase complex with BTRC as substrate-recognition component, leading to its proteasomal degradation By similarity.

Disruption phenotype

No visible phenotype. Mice are normal and less sensitive to oxygen-induced retinopathy. Mitochondria show increased production of reactive oxygen species. Newborn mice show increased radiation-induced apoptosis in brain and thymus, due to increased levels of TP53 and increased TP53 activity. Likewise, cultured embryonic fibroblasts are highly sensitive to DNA damage caused by UV irradiation or doxomycin and display increased levels of TP53 and increased TP53 activity, leading to increased apoptosis. Cultured embryonic fibroblasts are more susceptible to cell death caused by influenza virus infection and produce about 200 times more virus particles than wild-type. Ref.7 Ref.8 Ref.10 Ref.12 Ref.13

Sequence similarities

Belongs to the DDIT4 family.

Ontologies

Keywords
   Biological processAntiviral defense
Apoptosis
   Cellular componentCytoplasm
Mitochondrion
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processbrain development

Inferred from sequence or structural similarity. Source: UniProtKB

cell proliferation

Inferred from sequence or structural similarity. Source: UniProtKB

defense response to virus

Inferred from electronic annotation. Source: UniProtKB-KW

intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator

Inferred from mutant phenotype Ref.12. Source: UniProtKB

negative regulation of TOR signaling

Inferred from mutant phenotype PubMed 18198340. Source: MGI

negative regulation of glycolytic process

Inferred from mutant phenotype Ref.10. Source: MGI

negative regulation of intracellular signal transduction

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of peptidyl-serine phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of peptidyl-threonine phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

neuron differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

neuron migration

Inferred from sequence or structural similarity. Source: UniProtKB

neurotrophin TRK receptor signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of neuron death

Inferred from sequence or structural similarity. Source: UniProtKB

protein complex disassembly

Inferred from mutant phenotype PubMed 18198340. Source: MGI

reactive oxygen species metabolic process

Inferred from mutant phenotype Ref.10. Source: MGI

response to hypoxia

Inferred from mutant phenotype PubMed 18198340. Source: MGI

   Cellular_componentcytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

cytosol

Inferred from electronic annotation. Source: UniProtKB-SubCell

mitochondrion

Inferred from direct assay Ref.10. Source: MGI

   Molecular_function14-3-3 protein binding

Inferred from direct assay PubMed 18198340. Source: MGI

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 229229DNA damage-inducible transcript 4 protein
PRO_0000307198

Amino acid modifications

Modified residue161Phosphoserine By similarity
Modified residue201Phosphothreonine By similarity
Modified residue1181Phosphoserine By similarity

Sequences

Sequence LengthMass (Da)Tools
Q9D3F7 [UniParc].

Last modified June 1, 2001. Version 1.
Checksum: FE7EA24D3FF63949

FASTA22924,871
        10         20         30         40         50         60 
MPSLWDRFSS SSSSSSSSRT PAADRPPRSA WGSAAREEGL DRCASLESSD CESLDSSNSG 

        70         80         90        100        110        120 
FGPEEDSSYL DGVSLPDFEL LSDPEDEHLC ANLMQLLQES LSQARLGSRR PARLLMPSQL 

       130        140        150        160        170        180 
VSQVGKELLR LAYSEPCGLR GALLDVCVEQ GKSCHSVAQL ALDPSLVPTF QLTLVLRLDS 

       190        200        210        220 
RLWPKIQGLL SSANSSLVPG YSQSLTLSTG FRVIKKKLYS SEQLLIEEC 

« Hide

References

« Hide 'large scale' references
[1]"Dexamethasone-induced gene 2 (dig2) is a novel pro-survival stress gene induced rapidly by diverse apoptotic signals."
Wang Z., Malone M.H., Thomenius M.J., Zhong F., Xu F., Distelhorst C.W.
J. Biol. Chem. 278:27053-27058(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
Strain: C57BL/6.
Tissue: Thymus.
[2]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: C57BL/6J.
Tissue: Cerebellum and Thymus.
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Brain.
[4]"REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species."
Ellisen L.W., Ramsayer K.D., Johannessen C.M., Yang A., Beppu H., Minda K., Oliner J.D., McKeon F., Haber D.A.
Mol. Cell 10:995-1005(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION, DEVELOPMENTAL STAGE, INDUCTION.
[5]"Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis."
Shoshani T., Faerman A., Mett I., Zelin E., Tenne T., Gorodin S., Moshel Y., Elbaz S., Budanov A., Chajut A., Kalinski H., Kamer I., Rozen A., Mor O., Keshet E., Leshkowitz D., Einat P., Skaliter R., Feinstein E.
Mol. Cell. Biol. 22:2283-2293(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION.
[6]"Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex."
Brugarolas J., Lei K., Hurley R.L., Manning B.D., Reiling J.H., Hafen E., Witters L.A., Ellisen L.W., Kaelin W.G. Jr.
Genes Dev. 18:2893-2904(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION, FUNCTION.
[7]"Inhibition of oxygen-induced retinopathy in RTP801-deficient mice."
Brafman A., Mett I., Shafir M., Gottlieb H., Damari G., Gozlan-Kelner S., Vishnevskia-Dai V., Skaliter R., Einat P., Faerman A., Feinstein E., Shoshani T.
Invest. Ophthalmol. Vis. Sci. 45:3796-3805(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION, DISRUPTION PHENOTYPE.
[8]"Regulation of mTOR and cell growth in response to energy stress by REDD1."
Sofer A., Lei K., Johannessen C.M., Ellisen L.W.
Mol. Cell. Biol. 25:5834-5845(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE, FUNCTION, INDUCTION.
[9]"RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson's disease by a mechanism involving mammalian target of rapamycin inactivation."
Malagelada C., Ryu E.J., Biswas S.C., Jackson-Lewis V., Greene L.A.
J. Neurosci. 26:9996-10005(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION.
[10]"Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis."
Horak P., Crawford A.R., Vadysirisack D.D., Nash Z.M., DeYoung M.P., Sgroi D., Ellisen L.W.
Proc. Natl. Acad. Sci. U.S.A. 107:4675-4680(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE, FUNCTION, SUBCELLULAR LOCATION.
[11]"Cell-type-dependent regulation of mTORC1 by REDD1 and the tumor suppressors TSC1/TSC2 and LKB1 in response to hypoxia."
Wolff N.C., Vega-Rubin-de-Celis S., Xie X.J., Castrillon D.H., Kabbani W., Brugarolas J.
Mol. Cell. Biol. 31:1870-1884(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INDUCTION, TISSUE SPECIFICITY.
[12]"Feedback control of p53 translation by REDD1 and mTORC1 limits the p53-dependent DNA damage response."
Vadysirisack D.D., Baenke F., Ory B., Lei K., Ellisen L.W.
Mol. Cell. Biol. 31:4356-4365(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[13]"Chemical inhibition of RNA viruses reveals REDD1 as a host defense factor."
Mata M.A., Satterly N., Versteeg G.A., Frantz D., Wei S., Williams N., Schmolke M., Pena-Llopis S., Brugarolas J., Forst C.V., White M.A., Garcia-Sastre A., Roth M.G., Fontoura B.M.
Nat. Chem. Biol. 7:712-719(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AY260552 mRNA. Translation: AAP13851.1.
AK017926 mRNA. Translation: BAB31006.1.
AK081046 mRNA. Translation: BAC38121.1.
BC131992 mRNA. Translation: AAI31993.1.
BC132645 mRNA. Translation: AAI32646.1.
CCDSCCDS23868.1.
RefSeqNP_083359.1. NM_029083.2.
UniGeneMm.21697.

3D structure databases

ProteinModelPortalQ9D3F7.
SMRQ9D3F7. Positions 86-219.
ModBaseSearch...
MobiDBSearch...

PTM databases

PhosphoSiteQ9D3F7.

Proteomic databases

PRIDEQ9D3F7.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000020308; ENSMUSP00000020308; ENSMUSG00000020108.
GeneID74747.
KEGGmmu:74747.
UCSCuc007fee.1. mouse.

Organism-specific databases

CTD54541.
MGIMGI:1921997. Ddit4.

Phylogenomic databases

eggNOGNOG78982.
GeneTreeENSGT00530000063652.
HOGENOMHOG000082523.
HOVERGENHBG104439.
InParanoidQ9D3F7.
KOK08270.
OMADEHLCAS.
OrthoDBEOG7P2XTF.
PhylomeDBQ9D3F7.
TreeFamTF105007.

Gene expression databases

ArrayExpressQ9D3F7.
BgeeQ9D3F7.
CleanExMM_DDIT4.
GenevestigatorQ9D3F7.

Family and domain databases

InterProIPR012918. RTP801-like.
[Graphical view]
PANTHERPTHR12478. PTHR12478. 1 hit.
PfamPF07809. RTP801_C. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSDDIT4. mouse.
NextBio341548.
PROQ9D3F7.
SOURCESearch...

Entry information

Entry nameDDIT4_MOUSE
AccessionPrimary (citable) accession number: Q9D3F7
Entry history
Integrated into UniProtKB/Swiss-Prot: October 23, 2007
Last sequence update: June 1, 2001
Last modified: July 9, 2014
This is version 86 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot