ATF4 activates genes in response to endoplasmic reticulum stress (Homo sapiens)

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1, 4, 5, 8, 12...3, 1411259, 10, 13, 15, 17415cytosolendoplasmic reticulum lumennucleoplasmNF-YEXOSC1 NFYB CCL2IGFPB1 geneHERPUD1 geneEXOSC3 DDIT3ATF6(1-379)EXOSC2 EXOSC4 ASNSCCL2 geneIL8 GeneATF3EXOSC6 ATF4DIS3 ATF3 geneNFYC EXOSC8 KSRP PARN IL8ASNS geneEXOSC9 EXOSC5 NFYA DCP2 EXOSC7 IGFBP1mRNA Transcript Targeted by KSRP KSRP:mRNADegradation ComplexDDIT3 geneHERPUD1162, 6, 7, 11


Description

ATF4 is a transcription factor and activates expression of IL-8, MCP1, IGFBP-1, CHOP, HERP1 and ATF3. View original pathway at:Reactome.

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Bibliography

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  1. Balasubramanian MN, Shan J, Kilberg MS.; ''Dynamic changes in genomic histone association and modification during activation of the ASNS and ATF3 genes by amino acid limitation.''; PubMed Europe PMC Scholia
  2. Hayner JN, Shan J, Kilberg MS.; ''Regulation of the ATF3 gene by a single promoter in response to amino acid availability and endoplasmic reticulum stress in human primary hepatocytes and hepatoma cells.''; PubMed Europe PMC Scholia
  3. Armstrong JL, Flockhart R, Veal GJ, Lovat PE, Redfern CP.; ''Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells.''; PubMed Europe PMC Scholia
  4. Chen H, Pan YX, Dudenhausen EE, Kilberg MS.; ''Amino acid deprivation induces the transcription rate of the human asparagine synthetase gene through a timed program of expression and promoter binding of nutrient-responsive basic region/leucine zipper transcription factors as well as localized histone acetylation.''; PubMed Europe PMC Scholia
  5. Mukaida N, Shiroo M, Matsushima K.; ''Genomic structure of the human monocyte-derived neutrophil chemotactic factor IL-8.''; PubMed Europe PMC Scholia
  6. Sikalidis AK, Lee JI, Stipanuk MH.; ''Gene expression and integrated stress response in HepG2/C3A cells cultured in amino acid deficient medium.''; PubMed Europe PMC Scholia
  7. Yamaguchi Y, Larkin D, Lara-Lemus R, Ramos-Castañeda J, Liu M, Arvan P.; ''Endoplasmic reticulum (ER) chaperone regulation and survival of cells compensating for deficiency in the ER stress response kinase, PERK.''; PubMed Europe PMC Scholia
  8. Kowalski J, Denhardt DT.; ''Regulation of the mRNA for monocyte-derived neutrophil-activating peptide in differentiating HL60 promyelocytes.''; PubMed Europe PMC Scholia
  9. Averous J, Bruhat A, Jousse C, Carraro V, Thiel G, Fafournoux P.; ''Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation.''; PubMed Europe PMC Scholia
  10. Gjymishka A, Su N, Kilberg MS.; ''Transcriptional induction of the human asparagine synthetase gene during the unfolded protein response does not require the ATF6 and IRE1/XBP1 arms of the pathway.''; PubMed Europe PMC Scholia
  11. Gargalovic PS, Imura M, Zhang B, Gharavi NM, Clark MJ, Pagnon J, Yang WP, He A, Truong A, Patel S, Nelson SF, Horvath S, Berliner JA, Kirchgessner TG, Lusis AJ.; ''Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids.''; PubMed Europe PMC Scholia
  12. Gargalovic PS, Gharavi NM, Clark MJ, Pagnon J, Yang WP, He A, Truong A, Baruch-Oren T, Berliner JA, Kirchgessner TG, Lusis AJ.; ''The unfolded protein response is an important regulator of inflammatory genes in endothelial cells.''; PubMed Europe PMC Scholia
  13. Pan YX, Chen H, Thiaville MM, Kilberg MS.; ''Activation of the ATF3 gene through a co-ordinated amino acid-sensing response programme that controls transcriptional regulation of responsive genes following amino acid limitation.''; PubMed Europe PMC Scholia
  14. Li H, Chen W, Zhou Y, Abidi P, Sharpe O, Robinson WH, Kraemer FB, Liu J.; ''Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements.''; PubMed Europe PMC Scholia
  15. Suswam EA, Nabors LB, Huang Y, Yang X, King PH.; ''IL-1beta induces stabilization of IL-8 mRNA in malignant breast cancer cells via the 3' untranslated region: Involvement of divergent RNA-binding factors HuR, KSRP and TIAR.''; PubMed Europe PMC Scholia
  16. Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi M, Mori K.; ''ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response.''; PubMed Europe PMC Scholia
  17. Matsushima K, Morishita K, Yoshimura T, Lavu S, Kobayashi Y, Lew W, Appella E, Kung HF, Leonard EJ, Oppenheim JJ.; ''Molecular cloning of a human monocyte-derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin 1 and tumor necrosis factor.''; PubMed Europe PMC Scholia
  18. Marchand A, Tomkiewicz C, Magne L, Barouki R, Garlatti M.; ''Endoplasmic reticulum stress induction of insulin-like growth factor-binding protein-1 involves ATF4.''; PubMed Europe PMC Scholia
  19. Ma Y, Hendershot LM.; ''Herp is dually regulated by both the endoplasmic reticulum stress-specific branch of the unfolded protein response and a branch that is shared with other cellular stress pathways.''; PubMed Europe PMC Scholia
  20. Gherzi R, Trabucchi M, Ponassi M, Ruggiero T, Corte G, Moroni C, Chen CY, Khabar KS, Andersen JS, Briata P.; ''The RNA-binding protein KSRP promotes decay of beta-catenin mRNA and is inactivated by PI3K-AKT signaling.''; PubMed Europe PMC Scholia
  21. Chou CF, Mulky A, Maitra S, Lin WJ, Gherzi R, Kappes J, Chen CY.; ''Tethering KSRP, a decay-promoting AU-rich element-binding protein, to mRNAs elicits mRNA decay.''; PubMed Europe PMC Scholia
  22. Lee SH, Min KW, Zhang X, Baek SJ.; ''3,3'-diindolylmethane induces activating transcription factor 3 (ATF3) via ATF4 in human colorectal cancer cells.''; PubMed Europe PMC Scholia
  23. Takayanagi S, Fukuda R, Takeuchi Y, Tsukada S, Yoshida K.; ''Gene regulatory network of unfolded protein response genes in endoplasmic reticulum stress.''; PubMed Europe PMC Scholia
  24. Lee JI, Dominy JE, Sikalidis AK, Hirschberger LL, Wang W, Stipanuk MH.; ''HepG2/C3A cells respond to cysteine deprivation by induction of the amino acid deprivation/integrated stress response pathway.''; PubMed Europe PMC Scholia
  25. Schmidt N, Pautz A, Art J, Rauschkolb P, Jung M, Erkel G, Goldring MB, Kleinert H.; ''Transcriptional and post-transcriptional regulation of iNOS expression in human chondrocytes.''; PubMed Europe PMC Scholia
  26. Fu L, Kilberg MS.; ''Elevated cJUN expression and an ATF/CRE site within the ATF3 promoter contribute to activation of ATF3 transcription by the amino acid response.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114726view16:20, 25 January 2021ReactomeTeamReactome version 75
113170view11:23, 2 November 2020ReactomeTeamReactome version 74
112398view15:33, 9 October 2020ReactomeTeamReactome version 73
101302view11:19, 1 November 2018ReactomeTeamreactome version 66
100839view20:50, 31 October 2018ReactomeTeamreactome version 65
100380view19:24, 31 October 2018ReactomeTeamreactome version 64
99927view16:08, 31 October 2018ReactomeTeamreactome version 63
99482view14:40, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99135view12:40, 31 October 2018ReactomeTeamreactome version 62
93981view13:49, 16 August 2017ReactomeTeamreactome version 61
93583view11:28, 9 August 2017ReactomeTeamreactome version 61
87088view14:26, 18 July 2016MkutmonOntology Term : 'transcription pathway' added !
87087view14:25, 18 July 2016MkutmonOntology Term : 'PW:0001756' removed !
87086view14:25, 18 July 2016MkutmonOntology Term : 'peptide and protein metabolic process' added !
86689view09:24, 11 July 2016ReactomeTeamreactome version 56
83046view09:46, 18 November 2015ReactomeTeamVersion54
81769view10:15, 26 August 2015ReactomeTeamVersion53
76999view08:29, 17 July 2014ReactomeTeamFixed remaining interactions
76704view12:07, 16 July 2014ReactomeTeamFixed remaining interactions
76030view10:09, 11 June 2014ReactomeTeamRe-fixing comment source
75739view11:22, 10 June 2014ReactomeTeamReactome 48 Update
75089view14:04, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74736view08:49, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ASNS geneGeneProductENSG00000070669 (Ensembl)
ASNSProteinP08243 (Uniprot-TrEMBL)
ATF3 geneGeneProductENSG00000162772 (Ensembl)
ATF3ProteinP18847 (Uniprot-TrEMBL)
ATF4ProteinP18848 (Uniprot-TrEMBL)
ATF6(1-379)ProteinP18850 (Uniprot-TrEMBL)
CCL2 geneGeneProductENSG00000108691 (Ensembl)
CCL2ProteinP13500 (Uniprot-TrEMBL)
DCP2 ProteinQ8IU60 (Uniprot-TrEMBL)
DDIT3 geneGeneProductENSG00000175197 (Ensembl)
DDIT3ProteinP35638 (Uniprot-TrEMBL)
DIS3 ProteinQ9Y2L1 (Uniprot-TrEMBL)
EXOSC1 ProteinQ9Y3B2 (Uniprot-TrEMBL)
EXOSC2 ProteinQ13868 (Uniprot-TrEMBL)
EXOSC3 ProteinQ9NQT5 (Uniprot-TrEMBL)
EXOSC4 ProteinQ9NPD3 (Uniprot-TrEMBL)
EXOSC5 ProteinQ9NQT4 (Uniprot-TrEMBL)
EXOSC6 ProteinQ5RKV6 (Uniprot-TrEMBL)
EXOSC7 ProteinQ15024 (Uniprot-TrEMBL)
EXOSC8 ProteinQ96B26 (Uniprot-TrEMBL)
EXOSC9 ProteinQ06265 (Uniprot-TrEMBL)
HERPUD1 geneGeneProductENSG00000051108 (Ensembl)
HERPUD1ProteinQ15011 (Uniprot-TrEMBL)
IGFBP1ProteinP08833 (Uniprot-TrEMBL)
IGFPB1 geneGeneProductENSG00000146678 (Ensembl)
IL8 GeneGeneProductENSG00000169429 (Ensembl)
IL8ProteinP10145 (Uniprot-TrEMBL)
KSRP ProteinQ92945 (Uniprot-TrEMBL)
KSRP:mRNA Degradation ComplexComplexR-HSA-450479 (Reactome)
NF-YComplexR-HSA-381204 (Reactome) NF-Y is a ubiquitous heterotrimeric transcription factor comprising subunits NF-Y A, NF-Y B, and NF-Y C. It binds the sequence CCAAT.
NFYA ProteinP23511 (Uniprot-TrEMBL)
NFYB ProteinP25208 (Uniprot-TrEMBL)
NFYC ProteinQ13952 (Uniprot-TrEMBL)
PARN ProteinO95453 (Uniprot-TrEMBL)
mRNA Transcript Targeted by KSRP R-NUL-450386 (Reactome) KSRP binds AU-rich elements in the following mRNAs: IL-8, LDLR, and NOS2 (iNOS). Binding of KSRP to the mRNA encoding Beta-catenin is inferred from mouse.

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ASNS geneR-HSA-1791118 (Reactome)
ASNSArrowR-HSA-1791118 (Reactome)
ATF3 geneR-HSA-1791173 (Reactome)
ATF3ArrowR-HSA-1791173 (Reactome)
ATF4ArrowR-HSA-1791056 (Reactome)
ATF4ArrowR-HSA-1791095 (Reactome)
ATF4ArrowR-HSA-1791107 (Reactome)
ATF4ArrowR-HSA-1791118 (Reactome)
ATF4ArrowR-HSA-1791173 (Reactome)
ATF4ArrowR-HSA-1791180 (Reactome)
ATF4ArrowR-HSA-517731 (Reactome)
ATF6(1-379)ArrowR-HSA-1791107 (Reactome)
CCL2 geneR-HSA-1791056 (Reactome)
CCL2ArrowR-HSA-1791056 (Reactome)
DDIT3 geneR-HSA-1791107 (Reactome)
DDIT3ArrowR-HSA-1791107 (Reactome)
HERPUD1 geneR-HSA-1791095 (Reactome)
HERPUD1ArrowR-HSA-1791095 (Reactome)
IGFBP1ArrowR-HSA-1791180 (Reactome)
IGFPB1 geneR-HSA-1791180 (Reactome)
IL8 GeneR-HSA-517731 (Reactome)
IL8ArrowR-HSA-517731 (Reactome)
KSRP:mRNA Degradation ComplexTBarR-HSA-517731 (Reactome)
NF-YArrowR-HSA-1791107 (Reactome)
R-HSA-1791056 (Reactome) The CCL2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-1791095 (Reactome) The HERPUD gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-1791107 (Reactome) The CHOP (DDIT3) gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-1791118 (Reactome) The Aspariagine Synthetase (ASNS) gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-1791173 (Reactome) The ATF3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-1791180 (Reactome) The IGFBP1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-517731 (Reactome) The IL-8 gene is transcribed to yield mRNA which is translated to yield protein.
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