Deciphering the mammalian stress response - a stressful task.

Almost any change in cellular homeostasis that results from exogenous or endogenous imbalance is expected to cause stress, which, in turn, will initiate a complex cascade of stress-inducible enzymes and related transcription factors in an attempt to return the cell to its original equilibrium. It is, however, the type and dose of stress that dictates the nature of this cellular response. Cellular rescue from stress is not achieved when damage is too great, or when one or more components of the stress-activated cascade is impaired. It has been a most exciting decade with regard to our understanding of the cellular stress response. Our ability to decipher the components involved in mammalian cells' ability to cope with stress has led to remarkable new developments in our basic understanding of this process, as well as in our ability to design means to alter its regulation. This review issue brings together articles from leading scientists in the ®eld of stress response, which together provide an updated picture of our current knowledge and point to questions yet to be addressed. One of the key questions to understanding the stress response is how does the cell sense stress? Damage to cell surface receptors results in a dierent set of stressactivated kinases than does cytoplasmic or nuclear damage, suggesting that a sensitive array of cellular sensors distinguishes the source and nature of stress. Indeed, the possible existence of stress sensors in dierent cellular compartments has been the target of extensive investigation. Current data allow us to distinguish among three types of stress-related sensors on the basis of their primary cellular localization: nuclear, cytoplasmic and membrane/cell surface receptors. Co-ordinated activation of the stress response could occur in response to activation of one or multiple sensors, depending on the type and magnitude of treatment (Figure 1). Cell surface/membrane-anchored sensors of stress include receptors (e.g., EFGR, PDGFR, IGFR) that dimerize as well as complex arrays of membraneassociated proteins that mediate much of the extracellular signal through interaction with such molecules as upstream components of stress kinases, exempli®ed by ASK1/TRAFs and PI3K. In this issue, Ichijo provides an updated summary of molecular links between in ammatory cytokine receptors and stressactivated kinases and illustrates the complex interplay among upstream stress-regulatory components. Regulation of stress kinases is mediated by several upstream signaling components. These include TRAF2/5, which has been implicated in the regulation of MEKK1, IkB, MEK, and ASK1. It is not clear how a single upstream denominator elicits activation of downstream eectors, which is often seen. These are among the questions for intensive investigation that addresses the co-ordinated regulation of multiple stress kinases as well as the regulation of cross-talk (`wiring') between alternate cascades. Among membrane related stress sensors is phosphoinositol 3 kinase (PI3K), which has been implicated in the regulation of nearly all stress signaling pathways. The 3' phosphorylated lipid products of this enzyme promote activation of PKB, a key player in PI3K's ability to confer cell survival. Further insight into this enzyme's key role comes from mutations (often found in human tumors of lipid phosphatase PTEN), which antagonizes PI3K function. The current understanding of PI3K-dependent regulation of cell survival and death is summarized in the review by Stambolic et al. Many stress stimuli, both endogenous and exogenous, do not involve the membrane. Among the cytoplasmic sensors implicated in the regulation of stress kinases are cysteine-rich molecules that are modulated in response to ROS and altered redox potential. These molecules play key roles in regulating stress kinases, exempli®ed by GSTp and thioredoxin, which make essential contributions to the regulation of JNK and ASK1, respectively. In this issue, Adler et al. review current understanding of ROS-related regulation of stress kinases, an area that has been subject to exponential growth over the past few years. Our better understanding of ROS-mediated regulation of stress kinases is expected to provide fundamental information for understanding the selectivity of a given stress response. For example, it is the regulation of stress kinases by ROS-regulated molecules that is expected to play an important role in determining the nature of the stress kinase to be activated in the cellular response to a particular form of stress. A new aspect of the stress response is pointed out in Williams' review, which summarizes our current understanding of PKR, a protein kinase, which upon activation by cytokines, growth factors and stress signals binds to double-stranded RNA. PKR binding results in inhibition of RNA synthesis via the phosphorylation of eIF2a. PKR also induces the transcription of in ammatory genes by PKR-depen*Correspondence: Z Ronai Oncogene (1999) 18, 6084 ± 6086 a 1999 Stockton Press All rights reserved 0950 ± 9232/99 $15.00