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Gene Review

ATF4  -  activating transcription factor 4

Homo sapiens

Synonyms: Activating transcription factor 4, CREB-2, CREB2, Cyclic AMP-dependent transcription factor ATF-4, Cyclic AMP-responsive element-binding protein 2, ...
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Disease relevance of ATF4


High impact information on ATF4

  • CEP290 (also known as NPHP6) interacts with and modulates the activity of ATF4, a transcription factor implicated in cAMP-dependent renal cyst formation [6].
  • The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4 [6].
  • Molecular analysis revealed that SATB2 directly interacts with and enhances the activity of both Runx2 and ATF4, transcription factors that regulate osteoblast differentiation [7].
  • These results indicate that TRB3 is a novel target of CHOP/ATF4 and downregulates its own induction by repression of CHOP/ATF4 functions, and that it is involved in CHOP-dependent cell death during ER stress [8].
  • Knockdown of endogenous ATF4 or CHOP expression dramatically repressed tunicamycin-induced TRB3 induction [8].

Biological context of ATF4


Anatomical context of ATF4

  • However, induction of ATF4 expression by the endoplasmic reticulum stress pathway does not fully activate the AARE-dependent transcription [10].
  • Interestingly, ATF4 protein level, as reported for its partner RPB3, increases during C2C7 cell line muscle differentiation [13].
  • GABA(B(1)) and ATF4, however, were highly colocalized throughout the cell and displayed a punctate distribution within the dendrites [14].
  • FIAT/gamma-taxilin localizes to the nucleus in osteoblasts and dimerizes with ATF4 to form inactive dimers, because it does not contain a DNA-binding basic domain moiety [5].
  • Molecular interactions involved in the transactivation of the human T-cell leukemia virus type 1 promoter mediated by Tax and CREB-2 (ATF-4) [15].

Associations of ATF4 with chemical compounds

  • ZIP kinase physically binds to ATF4, a member of the activating transcription factor/cyclic AMP-responsive element-binding protein (ATF/CREB) family, through interaction between their leucine zippers [16].
  • However, bortezomib rapidly induced components of the proapoptotic/terminal UPR, including PERK, the ER stress-specific eIF-2alpha kinase; ATF4, an ER stress-induced transcription factor; and its proapoptotic target, CHOP/GADD153 [17].
  • Inactivation or loss of ATF4 greatly diminished the VEGF response to arsenite treatment [11].
  • Expression of ATF4 was found to correlate with cisplatin sensitivity (P = 0.01) [3].
  • The results indicated that ATF4 binds to the NSRE-1 sequence and that the amount of the ATF4 complex was increased when extracts from amino acid-deprived or glucose-deprived cells were tested [18].
  • The microarray study reveals that genes for glutathione metabolism are generally downregulated by the knockdown of ATF4 expression [19].

Physical interactions of ATF4


Regulatory relationships of ATF4

  • Previously, we demonstrated that homocysteine, an endoplasmic reticulum stressor, increases VEGF transcription by a mechanism dependent upon activating transcription factor ATF4 [11].
  • Based on sequence analysis, one of the predicted truncated proteins (ATF3deltaZip3) is likely incapable of binding DNA; and yet, exogenous expression of the cDNA enhanced starvation-induced or ATF4-activated ASNS transcription, possibly by sequestering corepressor proteins [24].
  • Moreover, overexpression of full-length mitosin repressed the transactivation activity of ATF4 in dual luciferase-based reporter assays, while knocking down mitosin expression manifested the opposite effects [12].
  • The F-box-deleted betaTrCP protein behaves as a negative transdominant mutant that inhibits ATF4 ubiquitination and degradation and, subsequently, enhances its activity in cyclic AMP-mediated transcription [25].
  • Thus, this study demonstrates a novel HIF-1alpha-independent anoxic mechanism that regulates ATF-4 induction at the protein stability level in tumor cells [26].
  • This study demonstrates that both CYP2E1 and ethanol induce ATF4 and the integrated stress response, a pathway which coordinates signals from multiple stresses, as well as established risk factors for ALD, and can display detrimental cellular effects upon prolonged activation [27].

Other interactions of ATF4

  • Overexpression of a dominant-negative ATF4 abolished the VEGF response to homocysteine treatment and to amino acid deprivation [9].
  • Overexpression studies established that ATF4, ATF3-FL, and C/EBPbeta-LAP could coordinately modulate the transcription from the human ASNS promoter [28].
  • Characterization of human activating transcription factor 4, a transcriptional activator that interacts with multiple domains of cAMP-responsive element-binding protein (CREB)-binding protein [20].
  • Consistent with its role as a coactivator, CBP potentiates the ability of hATF4 to activate transcription [20].
  • ATF4, whose level is upregulated in the cells exposed to thapsigargin or arsenite, is able to bind to the 33-bp repeat and activate the hNIPK promoter [29].

Analytical, diagnostic and therapeutic context of ATF4


  1. Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. He, C.H., Gong, P., Hu, B., Stewart, D., Choi, M.E., Choi, A.M., Alam, J. J. Biol. Chem. (2001) [Pubmed]
  2. Latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) binds ATF4/CREB2 and inhibits its transcriptional activation activity. Lim, C., Sohn, H., Gwack, Y., Choe, J. J. Gen. Virol. (2000) [Pubmed]
  3. Activating transcription factor 4 increases the cisplatin resistance of human cancer cell lines. Tanabe, M., Izumi, H., Ise, T., Higuchi, S., Yamori, T., Yasumoto, K., Kohno, K. Cancer Res. (2003) [Pubmed]
  4. Functional interaction of the HTLV-1 transactivator Tax with activating transcription factor-4 (ATF4). Reddy, T.R., Tang, H., Li, X., Wong-Staal, F. Oncogene (1997) [Pubmed]
  5. Inhibition of ATF4 transcriptional activity by FIAT/gamma-taxilin modulates bone mass accrual. Yu, V.W., Gauthier, C., St-Arnaud, R. Ann. N. Y. Acad. Sci. (2006) [Pubmed]
  6. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Sayer, J.A., Otto, E.A., O'Toole, J.F., Nurnberg, G., Kennedy, M.A., Becker, C., Hennies, H.C., Helou, J., Attanasio, M., Fausett, B.V., Utsch, B., Khanna, H., Liu, Y., Drummond, I., Kawakami, I., Kusakabe, T., Tsuda, M., Ma, L., Lee, H., Larson, R.G., Allen, S.J., Wilkinson, C.J., Nigg, E.A., Shou, C., Lillo, C., Williams, D.S., Hoppe, B., Kemper, M.J., Neuhaus, T., Parisi, M.A., Glass, I.A., Petry, M., Kispert, A., Gloy, J., Ganner, A., Walz, G., Zhu, X., Goldman, D., Nurnberg, P., Swaroop, A., Leroux, M.R., Hildebrandt, F. Nat. Genet. (2006) [Pubmed]
  7. SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation. Dobreva, G., Chahrour, M., Dautzenberg, M., Chirivella, L., Kanzler, B., Fariñas, I., Karsenty, G., Grosschedl, R. Cell (2006) [Pubmed]
  8. TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. Ohoka, N., Yoshii, S., Hattori, T., Onozaki, K., Hayashi, H. EMBO J. (2005) [Pubmed]
  9. Homocysteine increases the expression of vascular endothelial growth factor by a mechanism involving endoplasmic reticulum stress and transcription factor ATF4. Roybal, C.N., Yang, S., Sun, C.W., Hurtado, D., Vander Jagt, D.L., Townes, T.M., Abcouwer, S.F. J. Biol. Chem. (2004) [Pubmed]
  10. Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation. Averous, J., Bruhat, A., Jousse, C., Carraro, V., Thiel, G., Fafournoux, P. J. Biol. Chem. (2004) [Pubmed]
  11. The oxidative stressor arsenite activates vascular endothelial growth factor mRNA transcription by an ATF4-dependent mechanism. Roybal, C.N., Hunsaker, L.A., Barbash, O., Vander Jagt, D.L., Abcouwer, S.F. J. Biol. Chem. (2005) [Pubmed]
  12. Mitosin/CENP-F as a negative regulator of activating transcription factor-4. Zhou, X., Wang, R., Fan, L., Li, Y., Ma, L., Yang, Z., Yu, W., Jing, N., Zhu, X. J. Biol. Chem. (2005) [Pubmed]
  13. Functional interaction of the subunit 3 of RNA polymerase II (RPB3) with transcription factor-4 (ATF4). De Angelis, R., Iezzi, S., Bruno, T., Corbi, N., Di Padova, M., Floridi, A., Fanciulli, M., Passananti, C. FEBS Lett. (2003) [Pubmed]
  14. GABA(B) receptors couple directly to the transcription factor ATF4. Vernon, E., Meyer, G., Pickard, L., Dev, K., Molnar, E., Collingridge, G.L., Henley, J.M. Mol. Cell. Neurosci. (2001) [Pubmed]
  15. Molecular interactions involved in the transactivation of the human T-cell leukemia virus type 1 promoter mediated by Tax and CREB-2 (ATF-4). Gachon, F., Thebault, S., Peleraux, A., Devaux, C., Mesnard, J.M. Mol. Cell. Biol. (2000) [Pubmed]
  16. ZIP kinase, a novel serine/threonine kinase which mediates apoptosis. Kawai, T., Matsumoto, M., Takeda, K., Sanjo, H., Akira, S. Mol. Cell. Biol. (1998) [Pubmed]
  17. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Obeng, E.A., Carlson, L.M., Gutman, D.M., Harrington, W.J., Lee, K.P., Boise, L.H. Blood (2006) [Pubmed]
  18. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. Siu, F., Bain, P.J., LeBlanc-Chaffin, R., Chen, H., Kilberg, M.S. J. Biol. Chem. (2002) [Pubmed]
  19. Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines. Igarashi, T., Izumi, H., Uchiumi, T., Nishio, K., Arao, T., Tanabe, M., Uramoto, H., Sugio, K., Yasumoto, K., Sasaguri, Y., Wang, K.Y., Otsuji, Y., Kohno, K. Oncogene (2007) [Pubmed]
  20. Characterization of human activating transcription factor 4, a transcriptional activator that interacts with multiple domains of cAMP-responsive element-binding protein (CREB)-binding protein. Liang, G., Hai, T. J. Biol. Chem. (1997) [Pubmed]
  21. ATF4 regulates gamma-secretase activity during amino acid imbalance. Mitsuda, T., Hayakawa, Y., Itoh, M., Ohta, K., Nakagawa, T. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  22. p300 modulates ATF4 stability and transcriptional activity independently of its acetyltransferase domain. Lassot, I., Estrabaud, E., Emiliani, S., Benkirane, M., Benarous, R., Margottin-Goguet, F. J. Biol. Chem. (2005) [Pubmed]
  23. Expression of the bZIP transcription factor TCF11 and its potential dimerization partners during development. Murphy, P., Kolstø, A. Mech. Dev. (2000) [Pubmed]
  24. Amino acid deprivation and endoplasmic reticulum stress induce expression of multiple activating transcription factor-3 mRNA species that, when overexpressed in HepG2 cells, modulate transcription by the human asparagine synthetase promoter. Pan, Y., Chen, H., Siu, F., Kilberg, M.S. J. Biol. Chem. (2003) [Pubmed]
  25. ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase. Lassot, I., Ségéral, E., Berlioz-Torrent, C., Durand, H., Groussin, L., Hai, T., Benarous, R., Margottin-Goguet, F. Mol. Cell. Biol. (2001) [Pubmed]
  26. Anoxic induction of ATF-4 through HIF-1-independent pathways of protein stabilization in human cancer cells. Ameri, K., Lewis, C.E., Raida, M., Sowter, H., Hai, T., Harris, A.L. Blood (2004) [Pubmed]
  27. ATF4 and the integrated stress response are induced by ethanol and cytochrome P450 2E1 in human hepatocytes. Magne, L., Blanc, E., Legrand, B., Lucas, D., Barouki, R., Rouach, H., Garlatti, M. J. Hepatol. (2011) [Pubmed]
  28. 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. Chen, H., Pan, Y.X., Dudenhausen, E.E., Kilberg, M.S. J. Biol. Chem. (2004) [Pubmed]
  29. Characterization of human NIPK (TRB3, SKIP3) gene activation in stressful conditions. Ord, D., Ord, T. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  30. Amino-acid limitation induces transcription from the human C/EBPbeta gene via an enhancer activity located downstream of the protein coding sequence. Chen, C., Dudenhausen, E., Chen, H., Pan, Y.X., Gjymishka, A., Kilberg, M.S. Biochem. J. (2005) [Pubmed]
  31. Assignment of the gene for cyclic AMP-response element binding protein 2 (CREB2) to human chromosome 2q24.1-q32. Diep, A., Li, C., Klisak, I., Mohandas, T., Sparkes, R.S., Gaynor, R., Lusis, A.J. Genomics (1991) [Pubmed]
  32. Presence of activating transcription factor 4 (ATF4) in the porcine anterior pituitary. Kato, Y., Koike, Y., Tomizawa, K., Ogawa, S., Hosaka, K., Tanaka, S., Kato, T. Mol. Cell. Endocrinol. (1999) [Pubmed]
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