ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67))

2009-10-01   Kurosh Ameri , Adrian L Harris 





ATF4 gene is transcribed at very high levels (according to ACEview). Several stress conditions such as hypoxia, anoxia, and glucose deprivation result in endoplasmic reticulum stress (ER stress), initiating the unfolded protein response pathway (UPR pathway) that increases the synthesis (increased mRNA translation) of ATF4.
Atlas Image


The mouse ATF4 mRNA contains two upstream open reading frames, uORF1 and uORF2, and the human ATF4 contains three open reading frames, uORF1 (uO1), uORF2 (uO2), and uORF3 (uO3) that are located 5 to the ATF4 coding sequence. These uORFs are translated in non-stressed conditions, which result in exclusion of ATF4 translation. In mouse, uORF2, or in humans, uORF3 overlap ATF4 ORF in an out of frame manner. After translation of uORF1, sufficient eIF2-GTP makes it possible to reinitiate translation from the uORF2 in mouse, and uORF3 in human, and therefore ATF4 synthesis is minimized. During ER stress, PERK phosphorylates eIF2alpha resulting in a decrease of functional eIF2 complex. Stress-induced p-elF2alpha leads to limited eIF2-GTP and prolongs the duration for the scanning ribosome to reinitiate following uORF1, 2, and 3. Consequently ribosome scanning bypasses the mouse uORF2 or human uORF3, and translation re-initiation occurs at the ATF4 ORF (initiation at the ATF4 coding region is increased). Therefore, translation of ATF4 is increased in response to stress including hypoxia, anoxia, nutrition deprivation, including amino acid limitation and glucose deprivation.



ATF4 protein consists of 351 amino acids and is 38,590 Da. The protein is structured into several domains/motifs.
Atlas Image


ATF4 protein consists of 351 amino acids. The protein is unstable and structured into several domains/motifs that are essential for ATF4 homo/heterodimerization, DNA binding, and the regulation of ATF4 at the protein stability level. The organization of the motifs modulating ATF4 protein stability is potentially essential for the regulation of ATF4 stability in response to stress, including hypoxic and anoxic insult. ATF4 has an oxygen dependent degradation domain (ODDD) motif which is recognized by the orthologs of C. elegans Egl-9, designated as PH (prolyl hydroxylase) domain containing enzymes (PHD) [also called HIF Prolyl Hydroxylase, HPH], specifically PHD3. The betaTrCP recognition motif is another degradation motif, which when phosphorylated, is recognized by betaTrCP and targeted for proteasomal degradation.


ATF4 mRNA is transcribed ubiquitously, but protein expression and level is increased in cells that are exposed to various stress factors such as hypoxia, anoxia, lack of nutrition, as well as during development.


ATF4 protein is targeted to the nucleus. Single point mutations of basic amino acids within the basic region of ATF4 identified the sequence KKLKK (amino acids 280 to 284) as important for nuclear targeting.


ATF4 protein can function as a transcriptional activator, as well as a repressor. It is also a protective gene regulating the adaptation of cells to stress factors such as anoxic insult, endoplasmic reticulum stress and oxidative stress. ATF4 plays an essential role in development, and is particularly required for proper skeletal and eye development as well as haematopoiesis. ATF4 is also involved in proper function of memory. Furthermore, ATF4 is also a major factor in nutrition sensing, and has also been recently implicated in extreme hypoxia/anoxia mediated metastasis.
Metabolism: ATF4 is a conserved regulator of metabolism and carbohydrate homeostasis, and provides a mechanistic link between nutrients, insulin resistance, and diabetes, and has been described as a major mediator of nutrition-sensing response pathway, regulating the expression of asparagine synthetase (ASNS). In addition to regulating the expression of ASNS during lack of nutrition, ATF4 also regulates several aspects of mammalian metabolism, such as fat storage, energy expenditure, and glycemic control. The TOR pathway regulates invertebrate and vertebrate metabolism, and ATF4 mutant mice have reduced TOR signaling, and consequently reduced expression of genes important in the intracellular concentration of amino acids. Therefore, lack of ATF4 results in reduced concentration of amino acids, attributed to reduced TOR input. Thus, there is a close relationship between ATF4 function, the TOR pathway, and metabolism. This function of ATF4 also explains why type I collagen synthesis is specifically reduced in primary osteoblast cultures lacking ATF4, which can be rescued by adding nonessential amino acids to the culture. Thus, ATF4 is required for efficient amino acid import into osteoblasts.
Bone Metabolism: ATF4 is being considered as a global regulator of osteoblast biology and bone metabolism and formation. ATF4 supports bone formation through two mechanisms, which depend on its phosphorylation by RSK2. ATF4 regulates osteoblast-specific gene transcription and the synthesis of type I collagen, the main component of the bone extracellular matrix (ECM). ATF4 does this by favoring amino acid import, and therefore is a critical determinant of the synthesis of proteins in osteoblasts. Type I collagen is the most abundant protein of the bone ECM, and therefore, ATF4 is a major regulator of bone formation and of bone ECM mineralization. Consequently, ATF4-deficient mice are runted and harbor low bone mass, reduced osteoblast activity, decreased type I collagen synthesis, and inhibited osteocalcin and bone sialoprotein gene transcription.
Skeletogenesis: ATF4 plays an important role in assuring that osteoblasts fulfill their function. Rsk2-deficient mice display decreased bone mass due to impaired bone formation. ATF4 is more strongly phosphorylated by Rsk2 than any other proposed substrate. ATF4-deficient mice have revealed that this transcription factor plays several crucial roles in osteoblast differentiation and function. ATF4-deficient mice display a delayed skeletal development and result in a severe low-bone-mass phenotype caused by decreased bone formation.
Osteoclast differentiation: ATF4 regulates osteoclast differentiation and ultimately bone resorption through its expression in osteoblasts. ATF4 binds to the promoter of the receptor activator of nuclear factor-KappaB ligand (RankL) gene, which encodes a factor secreted by osteoblasts that promotes osteoclast differentiation. Accordingly, ATF4-deficient mice have decreased osteoclast numbers owing to reduced RankL expression.
Fetal liver hematopoiesis: A knockout mutation of ATF4 has demonstrated severe fetal anemia in mice. ATF4-/- Fetal livers are pale and hypoplastic, and the number of hematopoietic progenitors of multiple lineages is decreased more than 2 fold. Therefore, ATF4 is essential for the normal, high-level proliferation required for fetal-liver hematopoiesis.
Memory: ATF4 is a memory repressor that blocks the new expression of genes needed for memories, which appears to be a conserved mechanism. Decreasing the activity of ATF4 in mice or ApCREB2 (the ortholog of ATF4) in the sea slug Aplysia lowers the threshold for long-lasting changes and memory.


Drosophila: Cryptocephal (CRC) gene.
C. elegans: According to WormBase, the C. elegans homologue of the human ATF4 gene is atf-5 (T04C10.4). The binding site of C. elegans ATF-5 is uncharacterized.



A frameshift mutation is present in one allele of the ATF4 gene in F9 embryonal carcinoma stem cells. The mutation gives rise to the fusion of a short 5 open reading frame to the coding sequence of ATF4. Overexpression of mutant ATF4 suppresses ras-induced transformation.

Implicated in

Entity name
Various cancers
ATF4 is a major factor induced by tumor hypoxia and anoxia, as well as lack of nutrition including low glucose levels. The expression of ATF4 has been noted to be greater in patient cancer compared to paired normal tissue. ATF4 is important for cellular survival under conditions of extreme hypoxia, including anoxia. Recently it has been shown that antiangiogenic treatment with avastin results in induction of ATF4 in vivo.
ATF4 renders cells resistant to multiple anti-cancer drugs and it has been implicated to be a multidrug resistant gene in cancer, and is involved in metastasis, by regulating the expression of the metastasis associated gene LAMP3.
ATF4 is a major factor in regulating the expression of asparagine synthetase (ASNS) during hypoxia and nutritional deprivation (lack of amino acids and glucose). ASNS is associated with drug resistance in leukemia and oncogenesis triggered by mutated p53.
Entity name
Skeletal abnormalities of neurofibromatosis
There has been a link between increased Rsk2-dependent phosphorylation of ATF4 and the development of the skeletal abnormalities in human patients suffering from neurofibromatosis. This disease of tumor development in the nervous system, is caused by inactivating mutations of the neurofibromatosis 1 (NF 1), which plays a major physiological role in bone remodeling. The Nf1ob-/- (NF knockout specifically in osteoblasts) mice display a high bone mass phenotype. NF1 induces an increased production of type I collagen, attributed to Rsk2-dependent activation of ATF4. Thus, transgenic mice overexpressing ATF4 in osteoblasts display a phenotype similar to the Nf1ob-/- mice.
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In human brains, ATF4 and phospho-eIF2alpha levels are tightly correlated and up-regulated in Alzheimer disease, most probably representing an adaptive response against disease-related cellular stress rather than a correlate of neurodegeneration.
Entity name
Coffin-lowry syndrome
Coffin-Lowry Syndrome (CLS) is an X-linked mental retardation condition associated with skeletal abnormalities. ATF4 has been identified as a critical regulator of osteoblast differentiation and function, and lack of ATF4 phosphorylation by RSK2 may contribute to the skeletal phenotype of CLS.
Entity name
Vascular disease
ATF4 can be induced by both vascular injury and fibroblast growth factor-2 (FGF-2) and can serves as a conduit for the inducible expression of one growth factor by another during the process of intimal thickening.
Entity name
Joubert syndrome
The centrosomal protein, nephrocystin-6 (NPHP6), is disrupted in Joubert syndrome. NPHP6 interacts physically with and activates ATF4 as a signaling component on the level of transcriptional regulation in this disease group.
Entity name
Lack of ATF4 results in severe microphthalmia due to complete aphakia (absence of the eye lens). The affects of lack of ATF4 is attributed to p53 mediated apoptosis of anterior lens epithelial cells.


Pubmed IDLast YearTitleAuthors
174665662008Activating transcription factor 4.Ameri K et al
146049722004Anoxic induction of ATF-4 through HIF-1-independent pathways of protein stabilization in human cancer cells.Ameri K et al
85215211995Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change.Bartsch D et al
161489482005ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth.Bi M et al
129252792003Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins.Chen A et al
105353061999Nuclear targeting of cAMP response element binding protein 2 (CREB2).Cibelli G et al
179816872008Regulation of osteogenic differentiation during skeletal development.Deng ZL et al
171416282006ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae.Elefteriou F et al
126674462003An integrated stress response regulates amino acid metabolism and resistance to oxidative stress.Harding HP et al
108857502000Microphthalmia due to p53-mediated apoptosis of anterior lens epithelial cells in mice lacking the CREB-2 transcription factor.Hettmann T et al
109244692000The cryptocephal gene (ATF4) encodes multiple basic-leucine zipper proteins controlling molting and metamorphosis in Drosophila.Hewes RS et al
172974412007Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines.Igarashi T et al
176841562007Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor.Köditz J et al
162197722005p300 modulates ATF4 stability and transcriptional activity independently of its acetyltransferase domain.Lassot I et al
112389522001ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase.Lassot I et al
190176412009Basal levels of eIF2alpha phosphorylation determine cellular antioxidant status by regulating ATF4 and xCT expression.Lewerenz J et al
186176962008Activation transcription factor-4 induced by fibroblast growth factor-2 regulates vascular endothelial growth factor-A transcription in vascular smooth muscle cells and mediates intimal thickening in rat arteries following balloon injury.Malabanan KP et al
118069722002Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice.Masuoka HC et al
89209551996Mutated Atf4 suppresses c-Ha-ras oncogene transcript levels and cellular transformation in NIH3T3 fibroblasts.Mielnicki LM et al
194171382009The role of ATF4 stabilization and autophagy in resistance of breast cancer cells treated with Bortezomib.Milani M et al
197260952009Hypoxic activation of the unfolded protein response (UPR) induces expression of the metastasis-associated gene LAMP3.Mujcic H et al
166829732006The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4.Sayer JA et al
150771942004Tumor-derived p53 mutants induce oncogenesis by transactivating growth-promoting genes.Scian MJ et al
196900632009Atf4 regulates obesity, glucose homeostasis, and energy expenditure.Seo J et al
119609872002ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene.Siu F et al
152776802004Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells.Vattem KM et al
151094982004ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome.Yang X et al

Other Information

Locus ID:

NCBI: 468
MIM: 604064
HGNC: 786
Ensembl: ENSG00000128272


dbSNP: 468
ClinVar: 468
TCGA: ENSG00000128272


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
Long-term potentiationKEGGko04720
GnRH signaling pathwayKEGGko04912
Prostate cancerKEGGko05215
MAPK signaling pathwayKEGGhsa04010
Long-term potentiationKEGGhsa04720
GnRH signaling pathwayKEGGhsa04912
Prostate cancerKEGGhsa05215
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
Protein processing in endoplasmic reticulumKEGGko04141
Protein processing in endoplasmic reticulumKEGGhsa04141
Cholinergic synapseKEGGhsa04725
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Dopaminergic synapseKEGGko04728
Dopaminergic synapseKEGGhsa04728
Cocaine addictionKEGGhsa05030
Cocaine addictionKEGGko05030
Amphetamine addictionKEGGhsa05031
Amphetamine addictionKEGGko05031
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Hepatitis BKEGGhsa05161
Insulin secretionKEGGhsa04911
Estrogen signaling pathwayKEGGhsa04915
Estrogen signaling pathwayKEGGko04915
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Thyroid hormone synthesisKEGGhsa04918
Thyroid hormone synthesisKEGGko04918
Non-alcoholic fatty liver disease (NAFLD)KEGGhsa04932
Non-alcoholic fatty liver disease (NAFLD)KEGGko04932
Adrenergic signaling in cardiomyocytesKEGGhsa04261
Adrenergic signaling in cardiomyocytesKEGGko04261
cGMP-PKG signaling pathwayKEGGhsa04022
cGMP-PKG signaling pathwayKEGGko04022
Glucagon signaling pathwayKEGGhsa04922
Glucagon signaling pathwayKEGGko04922
Metabolism of proteinsREACTOMER-HSA-392499
Unfolded Protein Response (UPR)REACTOMER-HSA-381119
ATF6 (ATF6-alpha) activates chaperonesREACTOMER-HSA-381033
ATF6 (ATF6-alpha) activates chaperone genesREACTOMER-HSA-381183
PERK regulates gene expressionREACTOMER-HSA-381042
ATF4 activates genesREACTOMER-HSA-380994
Aldosterone synthesis and secretionKEGGhsa04925
Aldosterone synthesis and secretionKEGGko04925
Longevity regulating pathwayKEGGhsa04211
Mitophagy - animalKEGGko04137
Mitophagy - animalKEGGhsa04137

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
166829732006The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4.244
204732722010The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation.205
186358912008Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis.190
194171382009The role of ATF4 stabilization and autophagy in resistance of breast cancer cells treated with Bortezomib.127
153141572004Activating transcription factor 4 is translationally regulated by hypoxic stress.125
231535362012ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation.121
198553862009Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling.117
211131452011Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress.115
285663242017Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals.113
181950132008Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions.112


Kurosh Ameri ; Adrian L Harris

ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67))

Atlas Genet Cytogenet Oncol Haematol. 2009-10-01

Online version: