Adaptive posttranslational control in cellular stress response pathways and its relationship to toxicity testing and safety assessment

Qiang Zhang, Sudin Bhattacharya, Jingbo Pi, Rebecca A. Clewell, Paul L. Carmichael, Melvin E. Andersen

Research output: Contribution to journalArticle

  • 8 Citations

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.

Original languageEnglish (US)
Article numberkfv130
Pages (from-to)302-316
Number of pages15
JournalToxicological Sciences
Volume147
Issue number2
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

Profile

Safety
Genes
Addison Disease
Blood Flow Velocity
Heat-Shock Proteins
Homeostasis
Cyclic AMP Receptor Protein
Metabolomics
Gene Regulatory Networks
Proteomics
DNA Damage
Anoxia
Oxidative Stress
Hot Temperature
Metals
Cell Proliferation
Apoptosis
Proteins
Blood Stains
Acrodermatitis

Keywords

  • Feedback
  • Pathway
  • Posttranslational
  • Stress
  • Transcriptional

ASJC Scopus subject areas

  • Toxicology

Cite this

Adaptive posttranslational control in cellular stress response pathways and its relationship to toxicity testing and safety assessment. / Zhang, Qiang; Bhattacharya, Sudin; Pi, Jingbo; Clewell, Rebecca A.; Carmichael, Paul L.; Andersen, Melvin E.

In: Toxicological Sciences, Vol. 147, No. 2, kfv130, 01.10.2015, p. 302-316.

Research output: Contribution to journalArticle

Zhang, Qiang; Bhattacharya, Sudin; Pi, Jingbo; Clewell, Rebecca A.; Carmichael, Paul L.; Andersen, Melvin E. / Adaptive posttranslational control in cellular stress response pathways and its relationship to toxicity testing and safety assessment.

In: Toxicological Sciences, Vol. 147, No. 2, kfv130, 01.10.2015, p. 302-316.

Research output: Contribution to journalArticle

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