ATF4

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]

ATF4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesATF4, CREB-2, CREB2, TAXREB67, TXREB, activating transcription factor 4
External IDsOMIM: 604064 MGI: 88096 HomoloGene: 1266 GeneCards: ATF4
Orthologs
SpeciesHumanMouse
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 MbChr 15: 80.14 – 80.14 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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

References
  1. GRCh38: Ensembl release 89: ENSG00000128272 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000042406 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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): 1420–1426. doi:10.1128/JVI.65.3.1420-1426.1991. PMC 239921. PMID 1847461.
  6. 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): 4820–4824. Bibcode:1992PNAS...89.4820K. doi:10.1073/pnas.89.11.4820. PMC 49179. PMID 1534408.
  7. Ebert SM, Rasmussen BB, Judge AR, Judge SM, Larsson L, Wek RC, et al. (April 2022). "Biology of Activating Transcription Factor 4 (ATF4) and Its Role in Skeletal Muscle Atrophy". The Journal of Nutrition. 152 (4): 926–938. doi:10.1093/jn/nxab440. PMC 8970988. PMID 34958390.
  8. "Entrez Gene: ATF4 activating transcription factor 4 (tax-responsive enhancer element B67)".
  9. Franceschi RT, Ge C, Xiao G, Roca H, Jiang D (2009). "Transcriptional regulation of osteoblasts". Cells Tissues Organs. 189 (1–4): 144–152. doi:10.1159/000151747. PMC 3512205. PMID 18728356.
  10. 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. 24 (3): 398–410. doi:10.1359/jbmr.081107. PMID 19016586. S2CID 13111270.
  11. Ferraz RC, Camara H, De-Souza EA, Pinto S, Pinca AP, Silva RC, et al. (October 2016). "IMPACT is a GCN2 inhibitor that limits lifespan in Caenorhabditis elegans". BMC Biology. 14 (1): 87. doi:10.1186/s12915-016-0301-2. PMC 5054600. PMID 27717342.
  12. Carracedo A, Gironella M, Lorente M, Garcia S, Guzmán M, Velasco G, Iovanna JL (July 2006). "Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes". Cancer Research. 66 (13): 6748–6755. doi:10.1158/0008-5472.CAN-06-0169. PMID 16818650.
  13. Carracedo A, Lorente M, Egia A, Blázquez C, García S, Giroux V, et al. (April 2006). "The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells". Cancer Cell. 9 (4): 301–312. doi:10.1016/j.ccr.2006.03.005. PMID 16616335.
  14. Somers J, Pöyry T, Willis AE (August 2013). "A perspective on mammalian upstream open reading frame function". The International Journal of Biochemistry & Cell Biology. 45 (8): 1690–1700. doi:10.1016/j.biocel.2013.04.020. PMC 7172355. PMID 23624144.

Further reading

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