Heat shock factor

Abstract: Our cells and tissues are challenged constantly by exposure to extreme conditions that cause acute and chronic stress. Consequently, survival has necessitated the evolution of stress response networks to detect, monitor, and respond to environmental changes (Morimoto et al. 1990, 1994a; Baeuerle 1995; Baeuerle and Baltimore 1996; Feige et al. 1996; Morimoto and Santoro 1998). Prolonged exposure to stress interferes with efficient operations of the cell, with negative consequences on the biochemical properties of proteins that, under ideal conditions, exist in thermodynamically stable states. In stressed environments, proteins can unfold, misfold, or aggregate. Therefore, the changing demands on the quality control of protein biogenesis, challenges protein homeostasis, for which the heat shock response, through the elevated synthesis of molecular chaperones and proteases, repairs protein damage and assists in the recovery of the cell. The inducible transcription of heat shock genes is the response to a plethora of stress signals (Lis and Wu 1993; Morimoto 1993; Wu 1995) (Fig. 1), including (1) environmental stresses, (2) nonstress conditions, and (3) pathophysiology and disease states. Although changes in heat shock protein (HSP) expression are associated with certain diseases (Morimoto et al. 1990), these observations leave open the question of whether this is an adaptation to the particular pathophysiological state, a reflection of the suboptimal cellular environment associated with the disease, or serves to warn other cells and tissues of imminent danger. The protective role of HSPs is a measure of their capacity to assist in the repair of protein damage. Whether in prokaryotes, plants, or animals, overexpression of one or more HSPs is often sufficient to protect cells and tissues against otherwise lethal exposures to diverse environmental stresses including hydrogen peroxide and other oxidants, toxic chemicals, extreme temperatures, and ethanol-induced toxicity (Parsell and Lindquist 1994). In vertebrate tissue culture cells and animal models, elevating HSPs level, either by modulation of the heat shock response or by constitutive overexpression of specific heat shock proteins, restricts or substantially reduces the level of pathology and cell death (Mizzen and Welch 1988; Huot et al. 1991; Jaattela et al. 1992; Parsell and Lindquist 1994; Mestril et al. 1994; Plumier et al. 1995; Marber et al. 1995; Mehlen et al. 1995; Mosser et al. 1997). This has led to the recognition that HSPs, via their chaperoning effects on proteins, protect cells from many forms of stress-induced cell damage and could influence the course of disease.

Abstract: The Caenorhabditis elegans transcription factor HSF-1, which regulates the heat-shock response, also influences aging. Reducing hsf-1 activity accelerates tissue aging and shortens life-span, and we show that hsf-1 overexpression extends lifespan. We find that HSF-1, like the transcription factor DAF-16, is required for daf-2–insulin/IGF-1 receptor mutations to extend life-span. Our findings suggest this is because HSF-1 and DAF-16 together activate expression of specific genes, including genes encoding small heat-shock proteins, which in turn promote longevity. The small heat-shock proteins also delay the onset of polyglutamine-expansion protein aggregation, suggesting that these proteins couple the normal aging process to this type of age-related disease.