Roles of the heat shock transcription factors in regulation of the heat shock response and beyond

The heat shock response, characterized by increased expression of heat shoc k proteins (Hsps) is induced by exposure of cells and tissues to extreme co nditions that cause acute or chronic stress. Hsps function as molecular cha perones in regulating cellular homeostasis and promoting survival. If the s tress is too severe, a signal that leads to programmed cell death, apoptosi s, is activated, thereby providing a finely tuned balance between survival and death, In addition to extracellular stimuli, several nonstressful condi tions induce Hsps during normal cellular growth and development. The enhanc ed heat shock gene expression in response to various stimuli is regulated b y heat shock transcription factors (HSFs), After the discovery of the famil y of HSFs (i.e., murine and human HSF1, 2, and 4 and a unique avian HSF3), the functional relevance of distinct HSFs is now emerging. HSF1, an HSF pro totype, and HSF3 are responsible for heat-induced Hsp expression, whereas H SF2 is refractory to classical stressors, HSF4 is expressed in a tissue-spe cific manner; similar to HSF1 and HSF2, alternatively spliced isoforms add further complexity to its regulation. Recently developed powerful genetic m odels have provided evidence for both cooperative and specific functions of HSFs that expand beyond the heat shock response. Certain specialized funct ions of HSFs may even include regulation of novel target genes in response to distinct stimuli.