Meta-Biol

• Pathways

Acquisition of DNA binding activity by HSF1 is necessary but insufficient for transcriptional activation (Cotto JJ et al. 1996; Trinklein ND et al. 2004). In addition to having a sequence-specific DNA binding domain, HSF1 contains a C-terminal region which is involved in activating the transcription of the target genes (Green M et al. 1995). However, the transactivating ability of the transactivation domain itself is not stress sensitive. Rather, it's controled by a regulatory domain of HSF1 (amino acids 221-310), which represses the transactivating ability under normal physiological conditions (Green M et al. 1995; Zuo J et al. 1995; Newton EM et al. 1996). The HSF1 transactivation domain can be divided into two distinct regions, activation domain 1 (AD1) and activation domain 2 (AD2) (Brown SA et al. 1998). AD1 and AD2 each contain residues that are important for both transcriptional initiation and elongation. Mutations in acidic residues in both AD1 and AD2 preferentially affect the ability of HSF1 to stimulate transcriptional initiation, while mutations in phenylalanine residues preferentially affect stimulation of elongation (Brown SA et al. 1998).

Activation of the DNA-bound but transcriptionally incompetent HSF1 is thought to occur upon stress induced HSF1 phosphorylation at several serine residues (Ding XZ et al. 1997; Holmberg CI et al. 2001; Guettouche T et al. 2005). In cells exposed to heat, acquisition of HSE DNA-binding activity was observed to precede phosphorylation of HSF1 (Cotto JJ et al. 1996; Kline MP & Morimoto RI 1997). While there is a sufficient evidence to suggest that phosphorylation of HSF1 is essential to modulate HSF1 transactiviting capacity, mechanisms behind stress stimuli and kinases/phosphatases involved have not been clearly established.

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.