Cellular stress

Macario AJL, Conway de Macario E (2005) Sick chaperones, cellular stress, and disease. New Engl J Med 353 1489-1501... 

Inflammatory caspases (caspase-1, -4, -5,-11 and -12) constitute a subgroup of the caspase family. Caspase-1 is the best characterized member and is responsible for the proteolytic maturation and release of the pro-inflammatory cytokines pro-interleukin (IL)-1 (3 and pro-IL-18. Caspase-1 gets activated in inflammasome complexes upon cellular stress, cellular damage and infection. 

A sequence stretch 300 base pairs upstream of the transcriptional start site suffices for most of the transcriptional regulation of the IL-6 gene (Fig. 1). Within this sequence stretch several transcription factors find their specific recognition sites. In 5 to 3 direction, AP-1, CREB, C/EBP 3/NF-IL6, SP-1 and NF-kB can bind to the promoter followed by TATA and its TATA binding protein TBP. Most enhancer factors become active in response to one or several different stimuli and the active factors can trigger transcription individually or in concert. For example, AP-1 is active upon cellular stress, or upon stimuli that tell cells to proliferate CREB becomes also active if cells experience growth signals, but also upon elevation of intracellular levels of cyclic adenosine monophosphate (cAMP), which occurs upon stimulation if so called hormone-activated G protein-coupled receptors. 

The human HS cycle can be considered broadly as a period which leads to the dramatic shift in activities of the transcriptional and translational machinery followed by eventual recovery and resumption of original activities preceding stress. Figure 1 depicts many of the key events in the HS cycle for a typical human cell line such as cervical carcinoma-derived HeLa cells. Most cells respond in an identical fashion, but some cell types that have distinctive HS responses. These differences are manifested by shifts in the relative concentrations of accumulated HS proteins and possibly in the pattern of posttranslational modifications. In all cases, however, the cellular stress response is heralded by induction of a specific transcription factor whose DNA binding activity facilitates increased expression of one or more of the stress-inducible genes. 

As more is learned about the chromosomal effects on HS gene expression, it is important to point out that these genes are actually a subset of inducible responses to cellular stress. Not all of these inducible responses involve HSF, and this indicates that cells have diversified transcriptional responses to cope with different types of stress. This diversification is manifested by glucose regulated genes (grp), as well as the metallothionein and oxidant-injury genes (Watswich, 1988 Storz et al., 1990 Devary et al., 1992 Skroch et al., 1993 Xu, 1993). 

J9. Jolliet, P Slosman, D. 0., and Polla, B. S., Heat shock proteins in critical illness Markers of cellular stress or more In Yearbook of Intensive Care and Emergency Medicine (J.L. Vincent, ed.) Springer-Verlag, Berlin, 24-34 (1994). 

Signal transduction (control of cellular stress responses and MAP-kinase pathways)... 

Svendsen, C. and Weeks, J. M. (1995). The use of a lysosome assay for the rapid assessment of cellular stress from copper to the fresh water snail Viviparus contectus (Millet), Mar. Poll. Bull., 31, 139-142. 

Cytochrome c is thought to be an essential component of the apoptopic pathway responsive to DNA damage and other forms of cellular stress. This notion is based on studies with cell lines from mice having the gene disrupted (Li et al., 2000). These cell lines are refractory to apoptosis induced by stimuli that affect mitochondria. 

How does PARP-Fs role as a nucleosome-binding protein and modulator of chromatin structure, which is evident under normal physiological conditions, impact PARP-1-dependent DNA repair, cell death, and inflammatory response pathways, which occur under pathophysiological conditions A number of different scenarios are possible. For example, PARP-l s chromatin-dependent activities may be critical for its function as a DNA repair protein, since the repair of genomic DNA must occur in the context of chromatin. In addition, nucleosome-stimulated autoPARylation may play a role in depleting cellular NAD+ pools in response to cellular stresses. Furthermore, PARP-Fs chromatin-dependent activities may help to regulate the expression of immune and inflammatory response genes. These possibilities will need to be examined in the future. 

Thermal and chemical cellular stresses result in the rapid disappearance of ubiquitinated histones [258,259]. The levels of ubiquitinated histones drops precipitously after human tumor cells are treated with proteasome inhibitors [260,261]. Deubiquitination of uH2A also occurs during apoptosis, with its lose coinciding with nuclear pyknosis and chromatin condensation [262,263]. 

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