ATF4: Activating Transcription Factor 4
A key stress-responsive transcription factor regulating amino acid metabolism, redox homeostasis, and the integrated stress response.
Gene Information Card
| Symbol | ATF4 |
|---|---|
| Full Name | Activating transcription factor 4 |
| Gene Type | Protein coding |
| Chromosomal Location | 22q13.1 |
| NCBI Gene ID | 468 ncbi.nlm.nih.gov/gene/468 |
| Ensembl ID | ENSG00000128274 |
| UniProt ID | P18848 |
| OMIM ID | 604064 |
| HGNC ID | 786 |
| Aliases | CREB2, TAXREB67, cAMP-dependent transcription factor ATF-4 |
Description
ATF4 (Activating transcription factor 4) encodes a basic leucine zipper (bZIP) transcription factor that belongs to the ATF/CREB family. It is a master regulator of the integrated stress response (ISR), induced by various cellular stresses including endoplasmic reticulum (ER) stress, amino acid deprivation, hypoxia, and oxidative stress. ATF4 controls the expression of genes involved in amino acid transport and metabolism, redox balance, autophagy, and apoptosis. It plays critical roles in bone development, hematopoiesis, and cancer progression.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Osteogenesis imperfecta (OI) | ATF4 mutations disrupt osteoblast differentiation and collagen synthesis, leading to bone fragility. | ClinVar, OMIM |
| Coffin-Lowry syndrome (CLS) | Dysregulation of ATF4 signaling via RPS6KA3 mutations impairs bone and cognitive development. | OMIM |
| Cancer (multiple types) | ATF4 overexpression promotes tumor survival under hypoxia and nutrient stress; contributes to chemoresistance. | COSMIC, NCBI |
| Diabetes | ATF4-mediated ER stress response contributes to pancreatic beta-cell dysfunction and insulin resistance. | NCBI, OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Bone marrow | 15.2 | Medium |
| Liver | 12.8 | Medium |
| Kidney | 10.5 | Medium |
| Brain | 8.3 | Low |
| Heart | 6.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 18.4 | Cervical cancer cell line; high ATF4 expression under ER stress |
| HEK293 | 14.7 | Embryonic kidney cells; moderate baseline expression |
| MCF7 | 12.1 | Breast cancer cell line; induced by hypoxia |
| HepG2 | 11.3 | Hepatocellular carcinoma; responsive to amino acid deprivation |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1A>G (p.Met1?) | Missense | Rare | Loss of start codon; predicted loss of function |
| c.137C>T (p.Pro46Leu) | Missense | <0.01% | Reduced transcriptional activity; associated with osteogenesis imperfecta |
| c.340G>A (p.Glu114Lys) | Missense | <0.01% | Impaired DNA binding; dominant negative effect |
Mutation functional classification
Loss of Function (LOF)
Mutations that disrupt ATF4 translation or DNA-binding domain reduce its ability to activate target genes, impairing stress responses and bone development.
Gain of Function (GOF)
Amplification or overexpression of wild-type ATF4 in cancers enhances survival under stress and promotes metastasis.
Dominant Negative (DN)
Certain missense mutations (e.g., p.Glu114Lys) produce a protein that dimerizes with wild-type ATF4 but fails to bind DNA, inhibiting normal function.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Integrated stress response (ISR) - Reactome R-HSA-9634638
• Unfolded protein response (UPR) - KEGG hsa04141
• ATF4 activates genes in response to amino acid deprivation - Reactome R-HSA-9634600
• PERK-mediated signaling - Reactome R-HSA-381042
Protein Summary
ATF4 is a 351-amino acid transcription factor with a C-terminal bZIP domain that mediates dimerization and DNA binding. It is ubiquitously expressed but tightly regulated at the translational level via upstream open reading frames (uORFs) in its mRNA. Under stress, eIF2α phosphorylation allows bypass of inhibitory uORFs, enabling ATF4 translation. Once translated, ATF4 forms homodimers or heterodimers with other bZIP proteins (e.g., C/EBPβ, NRF2) to regulate genes such as CHOP, GADD34, and ASNS. Its activity is critical for adaptation to stress, but chronic activation can trigger apoptosis.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| ATF4 Knockout HEK293 Cell Line | EDJ-KQ611 | Human | 468 | Details Get a Quote |
| ATF4 Knockout A-549 Cell Line | EDJ-KQ18171 | Human | 468 | Details Get a Quote |
| ATF4 Knockout HCT 116 Cell Line | EDJ-KQ19071 | Human | 468 | Details Get a Quote |
| ATF4 Knockout HeLa Cell Line | EDJ-KQ19072 | Human | 468 | Details Get a Quote |
| ATF4 Knockout HaCaT Cell Line | EDC07706 | Human | 468 | Details Get a Quote |
