DDIT3 (GADD153/CHOP): A Key Mediator of ER Stress-Induced Apoptosis and Its Role in Cancer and Metabolic Disease
Explore the genomic context, expression patterns, mutations, and clinical significance of the DNA damage inducible transcript 3 gene, a central player in the unfolded protein response.
Gene Information Card
| Symbol | DDIT3 |
|---|---|
| Full Name | DNA damage inducible transcript 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 12q13.3 |
| NCBI Gene ID | 1649 ncbi.nlm.nih.gov/gene/1649 |
| Ensembl ID | ENSG00000175197 |
| UniProt ID | P35638 |
| OMIM ID | 126337 |
| HGNC ID | 2726 |
| Aliases | CHOP, GADD153, CEBPZ, CHOP10, DDIT-3, MGC4154 |
Description
DDIT3 (DNA damage inducible transcript 3), also known as GADD153 or CHOP, encodes a transcription factor that belongs to the C/EBP family. It is induced by cellular stress, particularly endoplasmic reticulum (ER) stress, and plays a critical role in the unfolded protein response (UPR). DDIT3 regulates genes involved in apoptosis, cell cycle arrest, and inflammation. Its expression is low under normal conditions but is strongly upregulated in response to various stressors, including nutrient deprivation, hypoxia, and chemotherapeutic agents. DDIT3 is implicated in multiple diseases, including cancer, metabolic disorders, and neurodegeneration. In particular, chromosomal translocations involving DDIT3 are a hallmark of myxoid liposarcoma, leading to fusion proteins that drive tumorigenesis.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Myxoid liposarcoma | Chromosomal translocation t(12;16)(q13;p11) fuses DDIT3 with FUS, creating an oncogenic fusion protein that disrupts adipocyte differentiation and promotes tumor growth. | COSMIC, OMIM, multiple studies |
| Myxoid round cell liposarcoma | Similar to myxoid liposarcoma, the FUS-DDIT3 fusion is present in the majority of cases, correlating with aggressive clinical behavior. | COSMIC, OMIM |
| Endometrial cancer | DDIT3 overexpression is associated with ER stress and apoptosis in endometrial cancer cells, potentially influencing tumor response to therapy. | PubMed, ClinVar |
| Neurodegenerative diseases | DDIT3 activation contributes to ER stress-induced neuronal apoptosis in conditions like Alzheimer's and Parkinson's disease. | PubMed, OMIM |
| Metabolic syndrome | DDIT3 is involved in pancreatic beta-cell apoptosis under ER stress, contributing to diabetes progression. | PubMed, OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 5.2 | Low |
| Kidney | 4.8 | Low |
| Brain | 3.5 | Low |
| Lung | 2.9 | Low |
| Breast | 2.1 | Low |
| Colon | 1.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical cancer) | 3.4 | Induced by ER stress agents |
| MCF7 (breast cancer) | 2.8 | Induced by chemotherapeutics |
| A549 (lung cancer) | 2.5 | Induced by hypoxia |
| HepG2 (liver cancer) | 4.1 | Induced by ER stress |
| K562 (leukemia) | 1.9 | Low basal expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| FUS-DDIT3 fusion | Chromosomal translocation | >90% in myxoid liposarcoma | Oncogenic fusion protein that blocks adipocyte differentiation and promotes tumorigenesis. |
| EWSR1-DDIT3 fusion | Chromosomal translocation | Rare (<5%) in myxoid liposarcoma | Alternative fusion with similar oncogenic effects. |
| Missense mutations | Point mutations | Rare in cancers | May alter DNA-binding or dimerization, affecting transcriptional activity. |
| Copy number alterations | Amplification | Occasional in various cancers | Increased DDIT3 expression may contribute to stress adaptation or apoptosis. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations are rare and may impair DDIT3's pro-apoptotic function, potentially allowing cells to survive under stress, contributing to tumorigenesis or resistance to therapy.
Gain of Function (GOF)
Gain-of-function is primarily seen in fusion proteins (e.g., FUS-DDIT3) that acquire novel oncogenic properties, driving liposarcoma development.
Dominant Negative (DN)
The FUS-DDIT3 fusion can act as a dominant-negative inhibitor of wild-type DDIT3 and C/EBP transcription factors, disrupting normal adipocyte differentiation.
View complete mutation data：
Gene Ontology (GO)
| • DNA-binding transcription factor activity | • RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| • Protein dimerization activity | • Apoptotic process |
| • Cellular response to endoplasmic reticulum stress | • Positive regulation of transcription by RNA polymerase II |
| • Negative regulation of cell population proliferation | • Response to DNA damage stimulus |
Pathways
• Unfolded Protein Response (UPR)
• PERK-mediated signaling
• ATF4-dependent gene expression
• Apoptosis signaling
• p53-independent DNA damage response
Protein Summary
The DDIT3 protein, also known as CHOP/GADD153, is a 30 kDa nuclear protein that forms homodimers or heterodimers with other C/EBP family members. It contains a basic leucine zipper (bZIP) domain that mediates DNA binding and dimerization. Under ER stress, DDIT3 is transcriptionally induced by ATF4 and other UPR transcription factors. It regulates the expression of genes involved in apoptosis, including BCL2 family members, and promotes cell death when ER stress is unresolved. In cancer, the FUS-DDIT3 fusion protein retains the bZIP domain but loses the N-terminal transactivation domain, leading to altered transcriptional activity that drives oncogenesis.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| DDIT3 Knockout HEK293 Cell Line | EDJ-KQ50229 | Human | 1649 | Details Get a Quote |
| DDIT3 Knockout HeLa Cell Line | EDJ-KQ53079 | Human | 1649 | Details Get a Quote |
| DDIT3 Knockout A-549 Cell Line | EDJ-KQ61544 | Human | 1649 | Details Get a Quote |
| DDIT3 Knockout HCT 116 Cell Line | EDJ-KQ70037 | Human | 1649 | Details Get a Quote |
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