Proteins, cellular stress

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. 

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). 

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. 

In this model, cellular stress mediates the release of cytochrome C from the mitochondrion. The proapoptotic proteins Bax and BH3 proteins support the release of cytochrome C, while the antiapoptotic Bcl2 protein has an inhibitory effect. Cytosolic cytochrome C binds to the cofactor Apaf 1, which then associates via its CARD motif with procaspase 9 to a complex termed apopto-some. In this complex, procaspase 9 is processed to the mature caspase which subsequently activates downstream effector caspases and commits the cell to death. 

It is also likely that direct cytotoxicity of halothane metabolites is important in the process, causing cellular stress by lipid peroxidation and covalent binding to target proteins (Fig. 7.77). Then the cytokines produced by this stress cause upregulation of costimulatory molecules, which provides the second signal for the immune response to occur. 

Paracetamol is a widely used analgesic, which causes liver necrosis and sometimes renal failure after overdoses in many species. The half-life is increased after overdoses because of impaired conjugation of the drug. Toxicity is due to metabolic activation and is increased in patients or animals exposed to microsomal enzyme inducers. The reactive metabolite (NAPQI) reacts with GSH, but depletes it after an excessive dose and then binds to liver protein. Cellular target proteins for the reactive metabolite of paracetamol have been detected, some of which are enzymes that are inhibited. Therefore, a number of events occur during which ATP is depleted, Ca levels are deranged, and massive chemical stress switches on the stress response. 

At a stalled bacterial replication fork, there are two avenues for repair. In the absence of a second strand, the information required for accurate repair must come from a separate, homologous chromosome. The repair system thus involves homologous genetic recombination. This re combinational DNA repair is considered in detail in Section 25.3. Under some conditions, a second repair pathway, error-prone translesion DNA synthesis (often abbreviated TLS), becomes available. When this pathway is active, DNA repair becomes significantly less accurate and a high mutation rate can result. In bacteria, error-prone translesion DNA synthesis is part of a cellular stress response to extensive DNA damage known, appropriately enough, as the SOS response. Some SOS proteins, such as the UvrA and UvrB proteins already described (Table 25-6), are normally... 

C-Jun-N-terminal kinases The JNK/Stress-activated protein kinases (SAPKs) do not respond well to mitogens but are strongly activated by agents that induce cellular stress. These kinases phosphorylate C-Jun transcription factor. The sequence of the tripeptide motif for JNK is Thr-Pro-Tyr. The activators of cytokine and tyrosine kinase receptors transduce signal to the upstream MAPKKKs. These... 

HSF3, identified in chicken, is induced by c-Myb in the absence of cellular stress (Nakai and Morimoto, 1993 Kanei-Ishii et al., 1997). Another isoform of HSF found in human cells, HSF4, possesses transcription represser properties in vivo (Frejtag et al., 2001). Comparisons of HSF protein structure in these organisms indicate the presence of conserved DNA binding domain and three hydrophobic heptad repeats that constitute the trimerization domain. These domains are located within the amino-terminal region of the protein. The stress-responsive transcriptional activation domain is located in the carboxyl-terminal region of the molecule. 

The stress or growth pathways modulated by vanadium involve specialized effectors and often can be activated by excess ROS. Cytokines, small proteins that effect communication between cells or cell behavior, can be involved in the cellular stress response. Tumor necrosis factor a (TNFa) is a cytokine stress signal that binds to a membrane receptor (tumor necrosis factor receptor, or TNFR). This interaction stimulates kinase activity that leads to cell injury and inflammation and also to the activation of caspases, a family of cysteine-dependent aspartate-directed proteases that are involved in apoptosis. The mitogen-activated protein (MAP) kinase cascade regulates both mitosis and apoptosis signaling pathways. 

Vanadium compounds are also believed to interact with cellular stress pathways that lead to apoptosis [70], as shown in Figure 11.3. One way vanadium compounds can influence these processes is by catalyzing the formation of intracellular ROS and NOS. All of the phosphorylation/dephosphorylation reactions eventually activate transcription factors that move to the nucleus to initiate the DNA breakdown characteristic of apoptosis. Vanadium is postulated to interfere with the dephosphorylation of some of these proteins by inhibition of various protein phosphatases. The... 

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