ATF2 (activating transcription factor 2) is a member of the ATF/CREB (cAMP response element binding protein) family of basic region leucine zipper proteins. Alternative names for ATF2 include: CREB2, cAMP responsive element binding protein 2, and CRE-BP1. The gene for human ATF2 maps to chromosome 2 (band 2q32). Human ATF2 is 94% homologous with mouse ATF2 and 38% homologous with the Y54E10A.6 protein in C. elegans. Three isoforms of human ATF2 are observed, designated CRE BP-1, -2, and -3, that result from differential splicing of a single transcript. The full length human ATF2 (CRE-BP1) is a protein with MW = 60 kDa, comprised of 487 amino acid residues. ATF2 localizes to the nucleus. Tissues that express the highest levels of ATF2 include brain, lung, liver, and kidney. ATF2 is a transcription factor that regulates expression of genes containing a cAMP response element (CRE; 5'gtgacgt(a/c)(a/g)3'), contained in the promoter region of regulated genes, including TNF-α, TGF-β, cyclin A, E-selectin, DNA polymerase β, and c-Jun. ATF2 also possesses histone acyltransferase activity, with histones H2B and H4 serving as its substrates. As with Fos, Jun, and CREB, ATF2 contains a C-terminal leucine zipper dimerization motif and a C-terminal basic stretch of amino acids that mediate binding to specific DNA sequences. The N-terminal region of ATF2 contains a transactivation domain. Within this transactivation domain is a putative MAPK docking site, similar to the docking site found in other MAPK substrates (designated the DEJL sequence [46KHKHEMTL53]) that mediates interaction of ATF2 with D313 and D316 of p38 α MAPK. Under resting conditions, ATF2 possesses low levels of transcriptional activity, because of an intramolecular inhibitory interaction in which the C-terminal DNA binding domain is bound to the N-terminal transactivation domain. This intramolecular inhibition can be relieved through protein:protein interactions, including ATF2's interaction with normal cell proteins (pRb, the high mobility group HMG, NF-κB, and c-Jun) and ATF2's interaction with viral proteins (adenovirus E1A, hepatitis B virus protein X, or human T-cell leukemia virus type I protein Tax). Intramolecular inhibition is also relieved through phosphorylation of ATF2 at threonine residues 69 and 71. Phosphorylation of these sites is also correlated with enhanced stability of ATF2. These phosphorylation events afford the protein resistance from ubiquitination and subsequent targeting to the 26S proteasome. Phosphorylation of ATF2 at Thr69/71 is catalyzed by several protein kinases. In response to treatment with proinflammatory cytokines, UV irradiation, and B-cell and T-cell receptor engagement, both Thr69 and Thr71 are phosphorylated by JNK and p38 MAPK by a two step mechanism in which the MAPK dissociates from the ATF2 after each phosphorylation event. ATF2 is also observed to be phosphorylated in response to stimuli which do not activate JNK or p38 MAPK, including treatment with insulin, epidermal growth factor, and serum. The sequential phosphorylation of ATF2 at 71 by ERK in the Raf/MEK/ERK cascade, followed by phosphorylation of Thr69 by p38 MAPK in a signaling pathway that includes Ral-RalGDS-Src-p38 MAPK in response to these other stimuli is currently under investigation. Activated ATF2 forms homodimers with other members of the ATF family or heterodimers with members of the c-Jun family of transcription factors. These ATF2 containing dimers bind to the the cAMP response element and with several other proteins including p300/CBP, p50/p65 NF-κB, SMAD3, SMAD4, NFAT family members, and the interferon regulatory factor 1 (IRF1). These ATF-containing protein complexes recruit RNA Pol II, and enhance the transcription of the responsive genes. Activation of ATF2 is observed in cellular responses to various types of stress and apoptotic signals, and is currently under investigation in studies of growth factor independent cell growth, cell cycle progression, differentiation, cytokine production in response to B-cell and T-cell receptor engagement, and inflammation. ATF2 appears to be especially important in cancer. ATF2 has recently been shown to render melanoma cells resistant to irradiation. A peptide that contains that ATF2 sequence corresponding to amino acid residues 50 through 100 (containing both the phosphorylated threonines and possibly a site for interaction with p300) has been shown to enhance sensitivity of melanoma to chemotherapeutic drugs. The interaction of ATF2 with v-Jun (the avian sarcoma virus 17 transforming protein, a viral homolog of the c-Jun protein) is also implicated in the development of fibrosarcoma.
CRE-BP1; CREB2; HB16; TREB7; CREB-2; activating transcription factor 2 splice variant ATF2-var2; cAMP response element-binding protein CRE-BP1; cAMP responsive element binding protein 2, formerly; cAMP-dependent transcription factor ATF-2; cAMP-responsive element-binding protein 2; cyclic AMP-dependent transcription factor ATF-2; cyclic AMP-responsive element-binding protein 2; ATF2; activating transcription factor 2; cAMP responsive element binding protein 2 , CREB2; CRE BP1; MGC111558