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Subject: Integrated stress response, NeuroD, EMX homeogene, Transcription factors, NOBOX
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Activating transcription factor 4

PDB rendering based on 1ci6.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols  ; CREB-2; CREB2; TAXREB67; TXREB
External IDs GeneCards:
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

Activating transcription factor 4 (tax-responsive enhancer element B67), also known as ATF4, is a protein that in humans is encoded by the ATF4 gene.[1][2]


This gene encodes a transcription factor that was originally identified as a widely expressed mammalian DNA binding protein that could bind a tax-responsive enhancer element in the LTR of HTLV-1. The encoded protein was also isolated and characterized as the cAMP-response element binding protein 2 (CREB-2). The protein encoded by this gene belongs to a family of DNA-binding proteins that includes the AP-1 family of transcription factors, cAMP-response element binding proteins (CREBs) and CREB-like proteins. These transcription factors share a leucine zipper region that is involved in protein–protein interactions, located C-terminal to a stretch of basic amino acids that functions as a DNA-binding domain. Two alternative transcripts encoding the same protein have been described. Two pseudogenes are located on the X chromosome at q28 in a region containing a large inverted duplication.[3]

ATF4 transcription factor is also known to play role in osteoblast differentiation along with RUNX2 and osterix.[4] Terminal osteoblast differentiation, represented by matrix mineralization, is significantly inhibited by the inactivation of JNK. JNK inactivation downregulates expression of ATF-4 and, subsequently, matrix mineralization.[5]


The translation of ATF4 is dependent on upstream open reading frames located in the 5'UTR.[6] The location of the second uORF, aptly named uORF2, overlaps with the ATF4 open-reading frame. During normal conditions, the uORF1 is translated, and then translation of uORF2 occurs only after eIF2-TC has been reacquired. Translation of the uORF2 requires that the ribosomes pass by the ATF4 ORF, whose start codon is located within uORF2. This leads to its repression. However, during stress conditions, the 40S ribosome will bypass uORF2 because of a decrease in concentration of eIF2-TC, which means the ribosome does not acquire one in time to translate uORF2. Instead ATF4 is translated.[6]


Kir2.1 has been shown to interact with:

See also


  1. ^ Tsujimoto A, Nyunoya H, Morita T, Sato T, Shimotohno K (March 1991). "Isolation of cDNAs for DNA-binding proteins which specifically bind to a tax-responsive enhancer element in the long terminal repeat of human T-cell leukemia virus type I". Journal of Virology 65 (3): 1420–6.  
  2. ^ Karpinski BA, Morle GD, Huggenvik J, Uhler MD, Leiden JM (June 1992). "Molecular cloning of human CREB-2: an ATF/CREB transcription factor that can negatively regulate transcription from the cAMP response element". Proceedings of the National Academy of Sciences of the United States of America 89 (11): 4820–4.  
  3. ^ "Entrez Gene: ATF4 activating transcription factor 4 (tax-responsive enhancer element B67)". 
  4. ^ Franceschi RT, Ge C, Xiao G, Roca H, Jiang D (2009). "Transcriptional regulation of osteoblasts". Cells, Tissues, Organs 189 (1–4): 144–52.  
  5. ^ Matsuguchi T, Chiba N, Bandow K, Kakimoto K, Masuda A, Ohnishi T (March 2009). "JNK activity is essential for Atf4 expression and late-stage osteoblast differentiation". Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research 24 (3): 398–410.  
  6. ^ a b Somers J, Pöyry T, Willis AE (August 2013). "A perspective on mammalian upstream open reading frame function". Int. J. Biochem. Cell Biol. 45 (8): 1690–700.  
  7. ^ Nehring RB, Wischmeyer E, Döring F, Veh RW, Sheng M, Karschin A (2000). "Neuronal inwardly rectifying K(+) channels differentially couple to PDZ proteins of the PSD-95/SAP90 family". J. Neurosci. 20 (1): 156–62.  
  8. ^ Kurschner C, Yuzaki M (1999). "Neuronal interleukin-16 (NIL-16): a dual function PDZ domain protein". J. Neurosci. 19 (18): 7770–80.  
  9. ^ Grishin A, Li H, Levitan ES, Zaks-Makhina E (2006). "Identification of gamma-aminobutyric acid receptor-interacting factor 1 (TRAK2) as a trafficking factor for the K+ channel Kir2.1". J. Biol. Chem. 281 (40): 30104–11.  

Further reading

External links

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