TOXICOLOGICAL SCIENCES, 147(2), 2015, 302–316 doi: 10.1093/toxsci/kfv130 Contemporary Review CONTEMPORARY REVIEW Adaptive Posttranslational Control in Cellular Stress Response Pathways and Its Relationship to Toxicity Testing and Safety Assessment Downloaded from Qiang Zhang,*,1 Sudin Bhattacharya,* Jingbo Pi,† Rebecca A. Clewell,* Paul L. Carmichael,‡ and Melvin E. Andersen* *Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, http://toxsci.oxfordjournals.org/ North Carolina 27709; †School of Public Health, China Medical University, Shenyang, China; and ‡Unilever, Safety and Environmental Assurance Centre, Colworth Science Park, Sharnbrook, Bedfordshire, UK 1To whom correspondence should be addressed at Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709. Fax: 1-919-558-1300. E-mail:
[email protected] ABSTRACT at CIIT Library on September 25, 2015 Although transcriptional induction of stress genes constitutes a major cellular defense program against a variety of stressors, posttranslational control directly regulating the activities of preexisting stress proteins provides a faster-acting alternative response. We propose that posttranslational control is a general adaptive mechanism operating in many stress pathways. Here with the aid of computational models, we first show that posttranslational control fulfills two roles: (1) handling small, transient stresses quickly and (2) stabilizing the negative feedback transcriptional network. We then review the posttranslational control pathways for major stress responses—oxidative stress, metal stress, hyperosmotic stress, DNA damage, heat shock, and hypoxia. Posttranslational regulation of stress protein activities occurs by reversible covalent modifications, allosteric or non-allosteric enzymatic regulations, and physically induced protein structural changes.