Meta-Biol

• Pathways

Attenuation of the heat shock transcriptional response occurs during continuous exposure to intermediate heat shock conditions or upon recovery from stress (Abravaya et al. 1991). The attenuation phase of HSF1 cycle involves the transcriptional silencing of HSF1 bound to HSE, the release of HSF1 trimers from HSE and dissociation of HSF1 trimers to monomers. HSF1-driven heat stress associated transcription was shown to depend on inducible and reversible acetylation of HSF1 at Lys80, which negatively regulates DNA binding activity of HSF1 (Westerheide SD et al. 2009). In addition, the attenuation of HSF1 activation takes place when enough HSP70/HSP40 is produced to saturate exposed hydrophobic regions of proteins damaged as a result of heat exposure. The excess HSP70/HSP40 binds to HSF1 trimer, which leads to its dissociation from the promoter and conversion to the inactive monomeric form (Abravaya et al. 1991; Shi Y et al. 1998). Interaction of HSP70 with the transcriptional corepressor repressor element 1-silencing transcription factor corepressor (CoREST) assists in terminating heat-shock response (Gomez AV et al. 2008). HSF1 DNA-binding and transactivation activity were also inhibited upon interaction of HSF1-binding protein (HSBP1) with active trimeric HSF1(Satyal SH et al. 1998).

Cells are subject to external molecular and physical stresses such as foreign molecules that perturb metabolic or signaling processes, and changes in temperature or pH. Cells are also subject to internal molecular stresses such as production of reactive metabolic byproducts. The ability of cells and tissues to modulate molecular processes in response to such stresses is essential to the maintenance of tissue homeostasis (Kultz 2005). Specific stress-related processes annotated here are cellular response to hypoxia, cellular response to heat stress, cellular senescence, HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand, response of EIF2AK1 (HRI) to heme deficiency, heme signaling, cellular response to chemical stress, cellular response to starvation, and unfolded protein response.

Individual cells detect and respond to diverse external molecular and physical signals. Appropriate responses to these signals are essential for normal development, maintenance of homeostasis in mature tissues, and effective defensive responses to potentially noxious agents (Kultz 2005). It is convenient, if somewhat arbitrary, to distinguish responses to signals involved in development and homeostasis from ones involved in stress responses, and that classification is followed here, with macroautophagy and responses to metal ions classified as responses to normal external stimuli, while responses to hypoxia, reactive oxygen species, and heat, and the process of cellular senescence are classified as stress responses. Signaling cascades are integral components of all of these response mechanisms but because of their number and diversity, they are grouped in a separate signal transduction superpathway in Reactome.