Molecular Chaperone Accumulation in Cancer and Decrease in Alzheimer's Disease: The Potential Roles of HSF1

Abstract

Molecular chaperones are required to maintain the proteome in a folded and functional state. When challenges to intracellular folding occur, the heat shock response is triggered, leading to increased synthesis of a class of inducible chaperones known as heat shock proteins (HSP). Although HSP synthesis is known to undergo a general decline in most cells with aging, the extent of this process varies quite markedly in some of the diseases associated with advanced age. In Alzheimer's disease (AD), a prevalent protein folding disorder in the brain, the heat shock response of some critical classes of neurons becomes reduced. The resulting decline in HSP expression may be a consequence of the general enfeeblement of many aspects of cell physiology with aging and/or a response to the pathological changes in metabolism observed specifically in AD. Cancer cells, in contrast to normal aging cells, undergo de novo increases in HSP levels. This expansion in HSP expression has been attributed to increases in folding demand in cancer or to the evolution of new mechanisms for induction of the heat shock response in rapidly adapting cancer cells. As the predominant pathway for regulation of HSP synthesis involves transcription factor HSF1, it has been suggested that dysregulation of this factor may play a decisive role in the development of each disease. We will discuss what is known of the mechanisms of HSF1 regulation in regard to the HSP dysregulation seen in in AD and cancer.

Keywords: Alzheimer's disease; cancer; heat shock protein; molecular chaperone; proteotoxic stress.

Figure 1

Regulatory mechanisms governing HSF1 activity. The figure depicts the major functional domains within HSF1 in their linear organization along the protein structure. (note the domains are not drawn to scale). There are, N terminally to C-terminally, a DNA binding domain (DNA), a trimerization domain (leucine zipper 1-3 or LZ1-3), a central regulatory domain (REG), a fourth region of leucine zipper or hydrophobic heptad repeat sequence (LZ4) and the C-terminal double trans-activation domains (TRANS). The primary mechanism for HSF1 regulation appears to the intramolecular coiled coil interaction between LZ4 and LZ 1-3 that prevent trimerization and DNA binding under basal conditions, which is severed during heat shock. A second regulatory mechanism is feedback repression exerted by Hsp70 and Hsp90 that can bind at various positions in the HSF1 molecule to effect inhibition. The regulatory domain contains an array of phosphorylation sites that can govern activity. Most notable among these is serine 303 (pS303) whose phosphorylation mediates inhibition of HSF1, and sumoylated lysine 298 (SuK298). In addition, other PTMs have been found elsewhere in the molecule, with lysine 80 (K80) undergoing repressive acetylation (AcK80) that can be relieved by the deacetylase sirtuin 1.

Figure 2

Role of GSK3 in HSF1 regulation in cancer and AD. We depict GSK3 as a key HSF1 repressor that may govern its activity in cancer and AD. In many types of cancer, GSK3 becomes inhibited when the enzyme Akt is induced by a cascade response involving activated receptor tyrosine kinases (RTK), and phosphatidylinositol-3-kinase (PI-3K). Akt phosphorylates and inactivates GSK3. Thus, HSF1 is relieved of repression and can induce HSPs in tumors. In AD, GSK3 shows increased levels of activity, leading to HSF1 repression. This mechanism may involve activation of GSK3 downstream of aggregated amyloid beta fibrils. Concomitantly Tau is hyperphosphorylated by a mechanism involving active GSK3, leading to Tau aggregation. Phosphorylated residues on HSF1 and Tau are suggested by dark spheres.