title: Adaptive Posttranslational Control in Cellular Stress Response Pathways and Its Relationship to Toxicity Testing and Safety Assessment.
abstract: 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. Acting in feedback or feedforward networks, posttranslational control may establish a threshold level of cellular stress. Sub-threshold stresses are handled adequately by posttranslational control without invoking gene transcription. With supra-threshold stress levels, cellular homeostasis cannot be maintained and transcriptional induction of stress genes and other gene programs, eg, those regulating cell metabolism, proliferation, and apoptosis, takes place. The loss of homeostasis with consequent changes in cellular function may lead to adverse cellular outcomes. Overall, posttranslational and transcriptional control pathways constitute a stratified cellular defense system, handling stresses coherently across time and intensity. As cell-based assays become a focus for chemical testing anchored on toxicity pathways, examination of proteomic and metabolomic changes as a result of posttranslational control occurring in the absence of transcriptomic alterations deserves more attention.
authors.affiliation: *Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, 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 qzhang@thehamner.org.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: *Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, 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.
authors.forename: Sudin
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: *Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, 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.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
authors.affiliation: *Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, 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.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Clewell
authors.affiliation: *Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, 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.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Carmichael
authors.affiliation: *Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, 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.
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
mesh_terms: D000818:Animals; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013312:Stress, Physiological / Q000187:drug effects* / Q000502:physiology; D018675:Toxicity Tests
keywords: feedback; pathway; posttranslational; stress; transcriptional