ATF4

ATF4 Background

The ATF4 gene codes for activating transcription factor 4 (ATF4) that belongs to the ATF subfamily of the basic leucine zipper (bZIP) transcription factor superfamily ^[1]. ATF4 is induced and expressed by stress signals such as anoxic insult, endoplasmic reticulum (ER) stress, oxidative stress, nutrition deprivation, and other cellular stresses. Upon binding to C/EBP-ATF Response Element (CARE) sequences of a subset of specific target genes, ATF4 induces increased transcription of these genes ^[2][3][4]. The expression of these adaptive genes allows cells to endure periods of stress. Whereas, under prolonged stress conditions, ATF4 promotes the induction of apoptosis. ATF4 expression is regulated transcriptionally and translationally via the PERK pathway of eIF2alpha phosphorylation, and then posttranslationally by phosphorylation. The eventual result is ATF4 degradation by proteasomal. ATF4 also mediates the induction of the Integrated Stress Response (ISR) and is involved in amino acid metabolism, differentiation, metastasis, angiogenesis ^[5], and drug resistanc ^[6]. Transgenic studies have demonstrated ATF4 to be involved in hematopoiesis, lens ＆ skeletal development, fertility, proliferation, differentiation, and long-term memory. ATF4 expression is upregulated in cancer. ATF4 reduces tumor burden by controlling the expression of target genes implicated in the induction of apoptosis. Since ATF4 is induced by tumor microenvironmental factors and regulates processes relevant to cancer progression, it might serve as a potential therapeutic target in cancer. Jie Luo et al. demonstrated that ATF4 plays a crucial role in blocking the progression and resistance response in RET/GRP78-positive human osteosarcoma ^[7]. Evidence shows ATF4 activation is responsible for proteasome inhibitor bortezomib (BTZ)-induced osteosarcoma (OS) cell death ^[7].

[1] Ameri K, Harris AL. Activating transcription factor 4 [J]. Int. J. Biochem. Cell Biol. 2008;40:14-21.
[2] Siu F, Bain PJ, et al. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene [J]. J. Biol. Chem., 2002, vol. 277 (pg. 24120-24127).
[3] Averous J, Bruhat A, et al. Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation [J]. J. Biol. Chem., 2004, vol. 279 (pg. 5288-5297).
[4] Bruhat A, Cherasse Y, et al. Amino acids as regulators of gene expression in mammals: molecular mechanisms [J]. Biofactors, 2009, vol. 35 (pg. 249-257).
[5] Harding HP, Zhang Y, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress [J]. Mol. Cell, 2003, vol. 11 (pg. 619-633).
[6] Rzymski T, Milani M, et al. Role of ATF4 in regulation of autophagy and resistance to drugs and hypoxia [J]. Cell Cycle, 2009, vol. 8 (pg. 3838-3847).
[7] Jie Luo, Yuanzheng Xia, et al. ATF4 Destabilizes RET Through Nonclassical GRP78 Inhibition to Enhance Chemosensitivity to Bortezomib in Human Osteosarcoma. [J] Theranostics, 2019 Aug, 9 (21), 6334-6353.