Apoptosis 2003; 8: 61–70 C  2003 Kluwer Academic Publishers On the role of Hsp27 in regulating apoptosis C. G. Concannon, A. M. Gorman and A. Samali Department of Biochemistry and National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland Heat shock proteins (Hsps) comprise several different families of proteins that are induced in response to a wide variety of physiological and environmental insults. One such protein which is highly induced during the stress response is a 27-kDa protein, termed Hsp27 whose ex- pression is seen to correlate with increased survival in re- sponse to cytotoxic stimuli. It has been shown to prevent cell death by a wide variety of agents that cause apop- tosis. Hsp27 is a molecular chaperone with an ability to interact with a large number of proteins. Recent evidence has shown that Hsp27 regulates apoptosis through an ability to interact with key components of the apoptotic signalling pathway, in particular, those involved in cas- pase activation and apoptosis. This article will review re- cent advances in the field and will address some of the potential mechanisms by which Hsp27 functions as an anti-apoptotic molecule. Keywords: apoptosis; caspase; Hsp27; stress. During the course of evolution, cells have developed complex dynamic mechanisms to respond to the many physiological and environmental insults they encounter. Analysis of these responses has led to the discovery of highly conserved proteins, termed heat shock proteins (Hsps), whose synthesis is transiently induced in response to low levels of stress, in a process referred to as the stress response. 1 Hsps encompass several groups of proteins and may be divided into five major families on the basis of their size, structure and function: 2 the Hsp110, Hsp90, Hsp70, Hsp60 and small Hsp families. Hsps were origi- nally named because of their rapid induction in response to elevated temperatures, 3 however, it has since been shown that a wide variety of different physical, chemical and bi- ological stimuli are also capable of inducing Hsps includ- ing oxidative stress, heavy metals, amino acid analogues, osmotic stress, and metabolic poisons. 2 Some Hsps are constitutively expressed and increase in response to stress while the expression of others is only Correspondence to: A. Samali, Department of Biochemistry and National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland. Tel: +353-91-750393; Fax: +353-91-512504; e-mail: afshin.samali@nuigalway.ie induced following exposure of cells to environmental and physiological stresses. In unstressed cells, constitutively expressed Hsps are essential for maintaining cell home- ostasis, functioning as molecular chaperones to facilitate the transport, folding and assembly of polypeptides. Dur- ing the stress response the intracellular levels of many Hsps rapidly increase due to the increased concentration of unfolded proteins that occurs. The induced expression of these Hsps is seen to be cytoprotective, protecting cells from toxic insult and preventing their demise. 4 Such in- ducible Hsps bind to damaged and misfolded polypep- tides and mediate their refolding or degradation, thus protecting cells from potential deleterious effects and pro- moting cell recovery. 5 This review will focus on Hsp27, which is one of the main inducible Hsps and has recently been reported to be a molecular inhibitor of apoptosis, a property which contributes to its cytoprotective effects. Hsp27 and the small Hsp family Hsp27 belongs to a family of abundant and ubiquitous stress proteins, the small heat shock proteins (sHsps), which are detectable in virtually all organisms from prokaryotes to mammals. 6 sHsps vary in size from 15 to 30 kDa and to date nine different members of this family have been identified: Hsp27, p20, HspB3, MKBP/HspB2, HspB8, HspB9, cvHsp, α-A crystallin and α-B crystallin. 7–14 Although members of this family share low amino acid homology, they are grouped together based on similar structural and functional properties, with all sHsps having a conserved core region that was first identi- fied within the crystallin proteins of the vertebrate eye. 15 This domain, termed the crystallin box, comprises 80– 100 amino acids in the C-terminus of the protein and has an IgG-like fold, which is followed by a short more freely flexing C-terminal extension. In contrast, the N- terminus of sHsps is much more variable both in sequence and length 16 and contains the WDPF motif, which is in- volved in oligomerization of the protein. 17 Within unstressed cells Hsp27 levels are generally low and it exists predominantly as a large oligomeric unit of up to 800 kDa, usually comprised of six tetrameric complexes Apoptosis · Vol 8 · No 1 · 2003 61