ATF4

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Mammalian protein found in Homo sapiens

title: "ATF4" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["transcription-factors"] description: "Mammalian protein found in Homo sapiens" topic_path: "arts/film" source: "https://en.wikipedia.org/wiki/ATF4" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Mammalian protein found in Homo sapiens ::

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.

Function

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.

ATF4 is an established effector of the Integrated Stress Response in animal cells, coupling the stress-induced phosphorylation of the α subunit of translation initiation factor 2 (eIF2α) to activation of downstream gene expression programs. Unique features of the ATF4 mRNA subordinate its translation to changing levels of phosphorylated eIF2α (as described below).

ATF4 transcription factor is also known to play role in osteoblast differentiation along with RUNX2 and osterix. 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. IMPACT protein regulates ATF4 in C. elegans to promote lifespan.

ATF4 is also involved in the cannabinoid Δ9-tetrahydrocannabinol–induced apoptosis in cancer cells, by the proapoptotic role of the stress protein p8 via its upregulation of the endoplasmic reticulum stress-related genes ATF4, CHOP, and TRB3.

Translation

The translation of ATF4 is dependent on upstream open reading frames located in the 5'UTR. 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.

References

References

  1. (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.
  2. (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.
  3. "Entrez Gene: ATF4 activating transcription factor 4 (tax-responsive enhancer element B67)".
  4. (November 2000). "Regulated translation initiation controls stress-induced gene expression in mammalian cells". Molecular Cell.
  5. (March 2003). "An integrated stress response regulates amino acid metabolism and resistance to oxidative stress". Molecular Cell.
  6. (2009). "Transcriptional regulation of osteoblasts". Cells, Tissues, Organs.
  7. (March 2009). "JNK activity is essential for Atf4 expression and late-stage osteoblast differentiation". Journal of Bone and Mineral Research.
  8. (October 2016). "IMPACT is a GCN2 inhibitor that limits lifespan in Caenorhabditis elegans". BMC Biology.
  9. (July 2006). "Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes". Cancer Research.
  10. (April 2006). "The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells". Cancer Cell.
  11. (August 2013). "A perspective on mammalian upstream open reading frame function". The International Journal of Biochemistry & Cell Biology.
  12. (August 2004). "Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells". Proceedings of the National Academy of Sciences of the United States of America.
  13. (October 2004). "Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response". The Journal of Cell Biology.

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transcription-factors