DNA damage-inducible transcript 3 protein (GADD153) (GADD153)

DNA damage-inducible transcript 3 protein, commonly referred to as GADD153 or CHOP, is a basic leucine zipper (bZIP) transcription factor that serves as a critical mediator of the endoplasmic reticulum (ER) stress-induced apoptosis pathway [2, 4]. Under physiological conditions, GADD153 is expressed at nearly undetectable levels, but it is rapidly and robustly upregulated in response to stressors such as protein misfolding, DNA damage, hypoxia, and nutrient deprivation [1, 14]. Once activated, the protein functions as a dominant-negative inhibitor of other C/EBP transcription factors or as a direct transcriptional activator of pro-apoptotic genes, leading to the downregulation of Bcl-2 and the promotion of cell death [3, 5, 8]. Due to its central role in deciding cell fate under stress, GADD153 is a significant therapeutic target in oncology, where its induction can be leveraged to kill tumor cells, and in neurodegenerative and metabolic diseases, where its inhibition may protect cells from premature death [6, 11]. For instance, the FUS-DDIT3 fusion protein acts as an oncogenic driver in myxoid liposarcoma, making its regulatory pathway a primary focus for drug development [9, 17]. Clinical interest also extends to its use as a biomarker for cellular stress and treatment efficacy in various cancer therapies, such as those involving temozolomide [2, 13].

Other names

C/EBP homologous proteinCHOPDDIT3Growth arrest and DNA damage-inducible protein 153CHOP-10C/EBP-homologous protein 10CEBPZ

GADD153 acts as a dominant-negative inhibitor or a transcriptional activator by forming heterodimers with C/EBP family transcription factors, leading to the repression of anti-apoptotic genes such as BCL2 and the induction of pro-apoptotic factors and reactive oxygen species during cellular stress [3, 5, 9].