DNA damage-inducible transcript 3 protein (DDIT3)

DNA damage-inducible transcript 3 (DDIT3), also known as CHOP or GADD153, is a stress-responsive transcription factor belonging to the CCAAT/enhancer-binding protein (C/EBP) family (UniProt P35638, GeneCards). It is a critical component of the unfolded protein response (UPR), primarily functioning as a pro-apoptotic mediator when endoplasmic reticulum (ER) stress becomes chronic or irreversible (NIH: PMC10633144). In normal physiology, DDIT3 regulates adipogenesis and erythropoiesis by acting as a dominant-negative inhibitor of other C/EBP proteins (Wikipedia, GeneCards). However, in disease states, particularly myxoid liposarcoma, DDIT3 is involved in pathognomonic chromosomal translocations that create oncogenic fusion proteins like FUS-DDIT3 (PubMed: 38503814). These fusions act as aberrant transcription factors that block cell differentiation and promote tumor growth (MDPI: 10.3390/cells13050435). Therapeutically, DDIT3 is targeted by drugs such as trabectedin, which disrupts the fusion protein's DNA binding, and it serves as a key effector for various anti-cancer drugs that induce ER stress-mediated cell death (PubMed: 31209019). Its complex role as both a tumor suppressor and a potential promoter of survival in certain microenvironments presents both opportunities and challenges for drug development (NIH: PMC10633144).

Other names

C/EBP homologous proteinCHOPGrowth arrest and DNA damage-inducible protein GADD153GADD153C/EBP-homologous protein 10CHOP-10C/EBP zetaCEBPZCCAAT/enhancer-binding protein homologous protein

DDIT3 functions as a transcription factor that regulates genes involved in apoptosis and cell cycle arrest (Wikipedia). In myxoid liposarcoma, the FUS-DDIT3 fusion protein is targeted by trabectedin, which displaces the protein from its DNA binding sites to restore normal differentiation (PubMed: 31209019). Many other chemotherapeutic agents act by inducing DDIT3 expression, which then promotes apoptosis through the upregulation of pro-apoptotic BH3-only proteins and the suppression of anti-apoptotic BCL-2 (NIH: PMC8003732).