ATF6 and ER Stress: Potential Cancer BioMarker?

ATF6 is a constitutively expressed, endoplasmic reticulum (ER) membrane-anchored transcription factor. ATF6 is a key transcriptional activator of the unfolded protein response (UPR), which allows mammalian cells to maintain cellular homeostasis when they are subjected to environmental and physiological stresses that target the ER (reviewed in Shen and Prywes, and Groenendyk and Michalak). The C-terminus of ATF6 is located in the ER lumen and its N-terminal DNA binding domain faces the cytosol. AFT6 plays a key role in the ER stress response by transmitting the ER stress signal across the ER membrane into the nucleus. The induction of new gene expression by ATF6 is an important aspect of the ER stress response. In response to stress, ATF6 translocates from the ER to the Golgi. The 90 kDa full-length ATF6 is processed within the Golgi to its active 50 kDa form through sequential cleavage by site-1 and site-2 proteases (S1P and S2P). Proteolytic activation of ATF6 in the ER stress response is a mechanism to regulate membrane-bound factors, and is referred to as regulated intramembrane proteolysis. The N-terminal active ATF6 translocates to the nucleus where it binds to ER stress-response elements in ER stress-response genes (ERSRGs). ATF6 is a potent transcriptional activator of ERSRGs. Active ATF6 is implicated in a number of disease states including myocardial infarction, atherosclerosis, neurodegenerative diseases (i.e. Alzheimer's), Charcot-Marie Tooth Disease, Cystic Fibrosis, and cancer.  The significance of over-expression of active (nuclear) ATF6 in a subset of immune system cancers remains to be elucidated. Further studies should help elucidate the potential role of active ATF6 in immune cell tumors and other cancers.  Research may also demonstrate the utility of ATF6 as a novel biomarker for disease, or as part of a panel of antibodies that could be employed to discover and validate new protein BioMarkers. IMGENEX offers a number of related reagents including ATF antibodies,  including full-length and cleaved ATF6 (citations), a complete suite of apoptosis tools, lysates and formalin-fixed & frozen tissues.

Unfolded Proteins in the ER Induce Stress

ER-resident transmembrane proteins together with the ER molecular chaperone BiP/GRP78, are important in ER stress. Unfolded proteins trigger activation of the UPR mechanism which involves gene transcription activation and protein synthesis and leads to an overall increase in the size of the ER.  The ER environment is monitored by at least three molecules including ATF6, IRE1, and PERK.

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