ATF3 (activating transcription factor 3)

Description	The ATF3 gene spans a region of 55 Kb and has two major transcription start sites, each designated P1 and P2, respectively. The P1 and P2 transcripts differ in the first exon but share common exons 2, 3, and 4 encoding the same protein sequence.
Transcription	Transcribed from centromere to telomere orientation. The P1 and P2 promoters are differentially activated by growth and stress stimuli.
Pseudogene	Unknown.

Note	atf3 protein represents one of the 53 basic leucine zipper (b-Zip) transcription factors in human and is composed of 181 amino acids with putative basic leucine zipper structure. The leucine zipper region is responsible for homo- or heterodimer formation with other member of bZip family proteins. One study reported that transcriptional activation or repression activity is located at both N- or C-terminal region, but the detailed mechanism of those activity remains elusive.
Description	The P1 and P2 transcripts give rise to atf3 proteins of an identical sequence. These transcripts, however, are differentially spliced to give rise to full length and deltaZip or deltaZip2 proteins lacking the C-terminal dimerization domain.
Expression	ATF3 is expressed ubiquitously but its level is maintained low in the absence of cellular stresses. Upon exposure to various conditions, such as hypoxia, DNA damaging agents (MMS, 5-FU, etoposide, ionizing radiation, UV irradiation), heat shock, cold shock, nutrient starvation, and serum stimulation, ATF3 is rapidly induced by transcriptional activation. Known upstream regulators of ATF3 include ATF4, HIF-1a, C/EBPb, and p53.
Localisation	ATF3 proteins are localized in the nucleus.
Function	ATF3 is a member of the CREB/ATF family of transcription factors and both homodimerize and heterodimerize with other members of CREB/ATF family, including C/EBPg, CHOP/DDIT3, ATF2, Jun, JunB, p21SNFT/JDP1, and Nrf2/NFE2L2. ATF3 and various heterodimers containing ATF3 has been shown to bind to a consensus cAMP response element (5'-GTGACGT[AC][AG]-3') with varying affinities in vitro. ATF3 also interacts with other DNA binding proteins such as Elk1, Sp1, and Egr1 which might recruit ATF3 to promoters indirectly. Increasing number of genes have been shown to be regulated by ATF3 (currently about 40 target genes are known). ATF3 plays an important role in repressing IL-6, IL-12, and other cytokine genes downstream of Toll-like receptor 4 (TLR4) thereby providing a negative feedback to contain excessive inflammatory responses. A splice variant of ATF3 (dZip2) forms complex with p65 subunit of NF-kB and inhibits recruitment of CBP, thus repressing inhibitors of apoptosis (IAPs) genes. ATF3 can also interfere with Nrf2-mediated gene activation by causing dissociation of CBP from Nrf2. Thus, it is likely that ATF3 is a regulator of stress response. ATF3 is one of immediate early response genes and plays role in determining cell fate. However, its biological function of ATF3 in vivo remains largely elusive since targeted disruption of the ATF3 gene causes no obvious phenotype. Studies mostly carried out in vitro using established cancer cell lines show that ATF3 has dual functions in promoting either cell death or cell survival under different conditions. On one hand, the ATF3 gene is overexpressed in a large fraction of cancers including solid tumors in the breast, lungs, prostate, colon or Hodgkin Reed-Sternberg cells, suggesting that ATF3 may promote proliferation and/or survival of cancer cells. On the other, expression of ATF3 has been shown to cause cell death of various cancer cell lines in response to DNA damage, UV, or various anti-cancer drugs. ATF3 is also proposed to be a causative gene in hypospadia.
Homology	ATF3 share a highly homologous leucine zipper domain with other CREB/ATF family members. ATF3 has been found widely in vertebrates and there is also a paralogue of ATF3 called JDP2 which differ from ATF3 in the C-terminal region. Higher vertebrates have both ATF3 and JDP2 homologues, whereas Ciona intestinalis has only one copy of either ATF3 or JDP2 (it is not clear which). Drosophila melanogaster A3-3 share 55% identity with aa 81-149 of human ATF3 and is thought to be a fly homologue of ATF3/JDP2.

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