Activating transcription factor 4 (ATF4) (ATF4)

Activating transcription factor 4 (ATF4) is a master regulator of the Integrated Stress Response (ISR), a conserved signaling pathway that allows cells to adapt to various environmental stressors such as nutrient deprivation, hypoxia, and endoplasmic reticulum (ER) stress (UniProt P18848). Under homeostatic conditions, ATF4 expression is minimal due to inhibitory upstream open reading frames (uORFs) in its mRNA; however, stress-induced phosphorylation of eIF2alpha leads to its preferential translation (PubMed: 25076037). Once synthesized, ATF4 translocates to the nucleus where it coordinates the expression of genes involved in amino acid transport, antioxidant defenses, and protein folding to restore cellular balance. In the context of cancer, many tumors exploit the ATF4 pathway to survive the metabolic stress of the tumor microenvironment and develop resistance to therapy (Nature Reviews Drug Discovery: 10.1038/nrd.2017.108). Conversely, prolonged ATF4 activation can trigger apoptosis through the induction of CHOP, contributing to neuronal loss in neurodegenerative diseases like Alzheimer's and Parkinson's. Therapeutic strategies include small molecules like ISRIB that block the ISR or repurposed drugs like Trazodone that mitigate the downstream effects of eIF2alpha phosphorylation (PubMed: 28429704).

Other names

CREB-2TAXREB67DNA-binding protein TAXREB67Cyclic AMP-responsive element-binding protein 2Tax-responsive enhancer-binding protein 67

Inhibition of the Integrated Stress Response (ISR) signaling to prevent the selective translation of ATF4 mRNA or direct inhibition of ATF4 transcriptional activity.