Surviving Stress: Modulation of ATF4-Mediated Stress Responses in Normal and Malignant Cells

Abstract

Activating transcription factor 4 (ATF4) is a stress-induced transcription factor that is frequently upregulated in cancer cells. ATF4 controls the expression of a wide range of adaptive genes that allow cells to endure periods of stress, such as hypoxia or amino acid limitation. However, under persistent stress conditions, ATF4 promotes the induction of apoptosis. Recent advances point to a role for post-translational modifications (PTMs) and epigenetic mechanisms in balancing these pro- and anti-survival effects of ATF4. We review here how PTMs and epigenetic modifiers associated with ATF4 may be exploited by cancer cells to cope with cellular stress conditions that are intrinsically associated with tumor growth. Identification of mechanisms that modulate ATF4-mediated transcription and its effects on cellular metabolism may uncover new targets for cancer treatment.

A Lipophilic 4‐Phenylbutyric Acid Derivative That Prevents Aggregation and Retention of Misfolded Proteins

“…[19] ATF4 belongs to theP ERK-eIF2a pathway and regulates the expression of dozens of genes involved in the anti-stress response:a mino acid biosynthesis, the expression of antioxidant enzymes/proteins, and apoptosis-related proteins. [20] ER stress and UPR activates both transcription factors, in direct correlation with the level of the stress.…”

METTL5, an 18S rRNA-specific m6A methyltransferase, modulates expression of stress response genes

“…If an upstream open reading frame (uORF) is short, a portion of the small ribosomal subunit remains attached to mRNA following termination of uORF translation, then resumes scanning the same mRNA and re-initiates translation at a downstream site. The translational re-initiation is highly regulated and represents an important mechanism for controlling translation of stress response genes, such as the ATF4 transcription factor (14)(15)(16). Indeed, ATF4 is at the nexus of multiple signaling pathways that regulate responses of cells to various types of stress, emanating from "sensor" kinases to phosphorylation of translational regulators such as eIF2α, which leads to activation of ATF4 expression at the translational level (17).…”

A stress response that allows highly mutated eukaryotic cells to survive and proliferate

“…This is consistent with Gcn4 functioning to activate EMBR in yeast. ATF4 is known to promote survival under stress while carefully balancing induction of apoptosis (Wortel et al, 2017). Based on these observations we propose that an additional role could be activation of hEMBR in high mutation burden cancers.…”