ATF4

ATF4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1CI6
Identifiers
Aliases	ATF4, CREB-2, CREB2, TAXREB67, TXREB, activating transcription factor 4
External IDs	OMIM: 604064 MGI: 88096 HomoloGene: 1266 GeneCards: ATF4
Gene location (Human) Chr. Chromosome 22 (human)[1] Band 22q13.1 Start 39,519,695 bp[1] End 39,522,683 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15 E1|15 37.85 cM Start 80,139,385 bp[2] End 80,141,742 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in popliteal artery body of stomach subcutaneous adipose tissue fundus right coronary artery body of pancreas left coronary artery prostate ascending aorta gastric mucosa Top expressed in ankle joint calvaria lacrimal gland plantaris muscle temporal muscle islet of Langerhans triceps brachii muscle parotid gland extensor digitorum longus muscle superior surface of tongue More reference expression data BioGPS n/a
Gene ontology Molecular function DNA binding sequence-specific DNA binding DNA-binding transcription factor activity DNA-binding transcription activator activity, RNA polymerase II-specific transcription factor binding RNA polymerase II cis-regulatory region sequence-specific DNA binding core promoter sequence-specific DNA binding protein C-terminus binding protein binding leucine zipper domain binding protein heterodimerization activity protein kinase binding DNA-binding transcription factor activity, RNA polymerase II-specific RNA polymerase II transcription regulatory region sequence-specific DNA binding Cellular component cytoplasm ATF1-ATF4 transcription factor complex ATF4-CREB1 transcription factor complex transcription regulator complex dendrite membrane nucleus Lewy body core nuclear periphery membrane plasma membrane nucleoplasm microtubule organizing center neuron projection cytoskeleton CHOP-ATF4 complex centrosome protein-containing complex RNA polymerase II transcription regulator complex Biological process gamma-aminobutyric acid signaling pathway gluconeogenesis regulation of transcription, DNA-templated positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress regulation of transcription by RNA polymerase II negative regulation of oxidative stress-induced neuron death cellular response to amino acid starvation mRNA transcription by RNA polymerase II circadian regulation of gene expression response to endoplasmic reticulum stress PERK-mediated unfolded protein response response to manganese-induced endoplasmic reticulum stress positive regulation of transcription, DNA-templated positive regulation of neuron apoptotic process intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress positive regulation of gene expression positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress circadian rhythm negative regulation of potassium ion transport positive regulation of transcription by RNA polymerase II positive regulation of transcription from RNA polymerase II promoter in response to arsenic-containing substance cellular response to glucose starvation negative regulation of translational initiation in response to stress rhythmic process cellular response to UV positive regulation of transcription from RNA polymerase II promoter in response to stress cellular amino acid metabolic process transcription by RNA polymerase II transcription, DNA-templated positive regulation of apoptotic process positive regulation of vascular endothelial growth factor production positive regulation of transcription by RNA polymerase I cellular response to dopamine response to toxic substance neuron differentiation cellular response to oxygen-glucose deprivation positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway cellular calcium ion homeostasis positive regulation of biomineral tissue development negative regulation of cold-induced thermogenesis positive regulation of vascular associated smooth muscle cell apoptotic process positive regulation of sodium-dependent phosphate transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 468 11911 Ensembl ENSG00000128272 ENSMUSG00000042406 UniProt P18848 Q06507 RefSeq (mRNA) NM_182810 NM_001675 NM_001287180 NM_009716 RefSeq (protein) NP_001666 NP_877962 NP_001274109 NP_033846 Location (UCSC) Chr 22: 39.52 – 39.52 Mb Chr 15: 80.14 – 80.14 Mb PubMed search [3] [4]
Wikidata
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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.^[5][6]

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). ATF4 is not a functional transcription factor by itself but one-half of many possible heterodimeric transcription factors. Because ATF4 can simultaneously participate in multiple distinct heterodimers, the overall set of genes that require ATF4 for maximal expression in a specific context (ATF4-dependent genes) can be a mixture of genes that are regulated by different ATF4 heterodimers, with some ATF4-dependent genes activated by one ATF4 heterodimer and other ATF4-dependent genes activated by other ATF4 heterodimers.^[7]

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.^[8]

ATF4 transcription factor is also known to play role in osteoblast differentiation along with RUNX2 and osterix.^[9] 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.^[10] IMPACT protein regulates ATF4 in C. elegans to promote lifespan.^[11]

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.^[12][13]

Translation

The translation of ATF4 is dependent on upstream open reading frames located in the 5'UTR.^[14] 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.^[14]

See also

• Activating transcription factor

References

Further reading

External links

• ATF4+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human ATF4 genome location and ATF4 gene details page in the UCSC Genome Browser.
• PDBe-KB provides an overview of all the structure information available in the PDB for Human Cyclic AMP-dependent transcription factor ATF-4
• ATF4 (activating transcription factor 4)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.