Novel regulatory factors of HSF-1 activation: facts and perspectives regarding their involvement in the age-associated attenuation of the heat shock response

An attenuated response to stress is characteristic of senescence. Heat shock (HS), a significant form of stress, is delayed and reduced in aging organisms. In the response to heat shock, heat shock factor 1 (HSF-1) is activated by trimerization of its monomeric subunits. This then initiates the transcription of a series of heat shock genes (hsp genes) that encode chaperone proteins protective against heat stress. Using a promoter binding electromobility shift assay (EMSA), we have found no activation of this transcription factor in the brains of old (36 months) rats in response to exposure to 41 degreesC for I h while strong activation is elicited in young (6 months) animals. Since brains of young and old rats had approximately the same amount of HSF- 1 subunits, we anticipated the presence of auxiliary regulatory factors essential for the activation of HSF-1 and the initiation of heat shock gene transcription. We describe three novel auxiliary factors - the proteins I-HSF [HSF inhibitor] and elongation factor- 1 alpha (EF- 1alpha) and a large non-coding RNA (HSR) - that participate in regulation and activation of HSF- I in early stages of heat shock gene transcription. I-HSF inhibits trimerization of HSF- I at normal temperatures. HSR and EF- I a form a complex with HSF- I and facilitate its trimerization and binding to heat shock element (HSE) in the promoters of hsps. It is proposed that structural changes in any one or a combination of these factors in response to heat shock may contribute to the age-associated attenuation in the response to stress. (C) 2004 Elsevier Ireland Ltd. All rights reserved.