The slight unfolding of proteins triggers distinct, secondary cellular responses, which target: (1) transcription factor activation leading to altered physiological processes; (2) gene expression leading to metabolic adjustments; (3) rapid production of protective metabolites; or (4) signaling systems triggering tertiary responses. (1) Inhibitors,research,lifescience,medical Effects of protein unfolding on transcription factor activation leading to altered physiological

processes. Of particular prominence, the Lonafarnib concentration pathway associated with heat shock factor 1 (HSF1) is activated in response to heat (Figure 1). Hsf1p is a transcription factor that recognizes and binds to the heat shock element HSE (5′-NGAAN-3′) [8]. Under normal conditions, Hsf1p exists in two states, namely free or bound to HSEs. In both states, Hsf1p is kept repressed through

the association with repressor proteins like Cpr7p, Hsc82p, or Sse1p. Heat-unfolded proteins affect the response system through sequestration of these repressor proteins, which thereby permit the Inhibitors,research,lifescience,medical activation of Hsf1p [9]. Thus, unfolded proteins free a regulatory protein, HSF1, whose pathway is responsible for Inhibitors,research,lifescience,medical the production of protein chaperones, such as HSP82, SSAs and SSBs. HSF1 is also involved in cell cycle regulation and in protein turnover by regulating the expression of the genes UBC4 and CUP1. Figure 1 Modeling heat shock factor 1 (HSF1) activation. Free HSF1 protein binds to the heat shock element (HSE) and helps elicit the heat shock response, by inhibiting cell cycle progression and leading to the expression of chaperonins. In the absence of heat-unfolded … (2) Effects of protein unfolding on gene expression leading to metabolic adjustments. Heat-induced protein unfolding also targets the zinc-finger transcription Inhibitors,research,lifescience,medical factors MSN2/MSN4, which control a large number of genes that appear to be associated

with metabolic stress responses (Figure 2). MSN2 and MSN4, collectively called MSN, respond to heat stress and protein kinase A (PKA) Inhibitors,research,lifescience,medical in an antagonistic fashion [10]. As long as PKA is active, MSN is kept in the cytosol, where it is inactive. Sufficient heat induction inactivates the PKA pathway and causes MSN to relocate to the nucleus, where it becomes active [11]. Once in the nucleus, the transcription factors bind to specific Stress Response Elements (STRE; 5′-CCCCT-3′) and thereby activate Etomidate the transcription of downstream genes [12,13]. Genes under the control of MSN code for protein chaperons, proteins involved in protective metabolic pathways (Hxk1p, Tps1p, Nth1p, Gpd1p) and proteins involved in antioxidant defenses (Ctt1p, Sod2p) [9]. Figure 2 Heat stress affects the localization of MSN protein. The MSN protein (Msnp) is produced from its corresponding mRNA (MSN), which in turn is transcriptionally activated by heat stress (HS). Heat stress promotes a nuclear localization of the MSN protein …