Function

In 1962, F. Ritossa observed large "puffs" of activity at specific cytological locations after elevating the temperature of Drosophila polytene chromosome preparations. This was the first demonstration that elevated temperature could result in increased gene expression. Later it was discovered that a specific Heat Shock Factor (HSF) mediates the bulk of the an organism's response to heat and other stresses. Upon cloning the gene that encodes the HSF it was determined to be a member of the Helix-Turn Helix transcriptoin factor family.

In normal non-stressed cells the HSF is maintained as a non-active monomer in the cytoplasm but after the cell is challenged by a stress of some sort, the HSF monomers translocate to the nucleus and take on an active trimeric form which is capable of binding Heat Shock Elements (HSE's) within the promoter of the heat shock genes. HSE's consist of 5'-nGAAn-3' penta-nucleotide repeats which usually occur in a string of four or more. After HSF has bound the HSE's it recruits the transcription machinery through its transactivation domain, leading to increased transcription of the heat shock genes.

During stress the proteins within a cell begin to denature and become non-functional, leading to cell death if the proteins are not repaired in time. The heat shock genes encode a huge protein complex that facilitates the refolding of unfolded or mis-folded proteins. It is still unclear how the heat shock protein complexes recover the native state of proteins but it is known that energy derived from the hydrolysis of ATP is a necessary component of the reaction. Even though it is well documented that purified HSF can acquire DNA binding activity and increase the expression of the heat shock genes upon in vitro heat shock it is still unclear how HSF responds to other stresses and whether there are other factors that negatively regulate HSF activity.

Recently, it has been shown that the heat shock proteins, HSP70 and HDJ1, play a role in the attenuation of the heat shock response by directly interacting with HSF. In accordance with this observation, overexpression of the heat shock proteins in un-stressed cells inhibits the activation of heat shock genes after subsequent heat shock. Whether the interaction between HSP70/HDJ1 complexes and HSF disrupts the DNA binding capacity of HSF or works through some other mechanism has yet to be determined and is actively being persued. A second putative regulator of HSF activity has been found in the worm C. elegans that interacts preferentially with the trimerization domain of HSF. This protein, mamed heat shock factor binding protein 1 (HSBP 1) appears to inactivate HSF and repress expression of the heat shock proteins. Whether HSBP1 is expressed subsequent to heat shock and what the affects of HSBP1's interaction with HSF are remain to be answered but it is clear that several, possibly redundant, mechanisms are in place to ensure the precise and rpaid response to stressful situations.