Endoplasmic Reticulum Stress Response, the Future of Cancer Research and a New Designated Journal

Abstract

The Endoplasmic Reticulum Stress Response (ERSR), the understanding of its mechanisms, and its contribution to the numerous vital functions of the cell are both the most avantgarde and highest priority in basic and clinical biomedical research fields. Like many other important fields in biology, ERSR started completely as basic research, with the most important discoveries made in yeast, immunoglobulin assembly and metabolic cellular studies [1,2]. Protein chaperones, such as Grp78 and Grp94, were indeed discovered in glucose starvation experiments between the mid-seventies and eighties by Pastan’s lab [3]. Gething and Sambrook understood the importance of chaperone up-regulation and discovered common elements in their promoters that govern chaperones’ transcriptional control. It was in 1992 when the term “Unfolded Protein Response” (UPR) was first used [4]. The yeast IRE1 trans-membrane kinase and ribonuclease was the first sensor of the accumulation of unfolded proteins in ER cloned in 1998 by two labs, Sambrook and Walter [5,6]. IRE1 is the most evolutionary conserved branch of UPR and the only one present in yeast. The rescue of IRE1 -/yeast cells by over-expression of Hac1p transcription factor revealed the unique mode of action of IREα ref., thus connecting the sensing of ERS and the massive transcriptional program initiated by UPR signaling. Beautifully surprising and somehow expected is the story of mammalian UPR sensors’ identification [7-11]. As compared to that of the yeast, the mammalian system shows much more complexity and redundancy due to contributions from at least 3 major pathways of UPR: IRE1α and IREα, PERK and ATF6. PERK added extra release to the stressed ER by translational attenuation of new protein synthesis. Before XBP1 was identified and connected to UPR, it was thought that ATF6 fulfilled Hac1 function in higher eukaryotes [12,13]. Slowly, the primary components of UPR have been unveiled; experiments implementing “classical” and artificial UPR inducers, such as Tunicamycin and Thapsigargin, have helped to delineate the core mechanisms of UPR induction as well as Endoplasmic Reticulum Stress Response, the Future of Cancer Research and a New Designated Journal. Editorial • DOI: 10.2478/ersc-2012-0001 • ERSC • 201 • 1-3