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REVIEW Heat Shock Proteins – Modulators of Apoptosis in Tumour Leukemia (2000) 14, 1161–1173 2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu REVIEW Heat shock proteins – modulators of apoptosis in tumour cells EM Creagh, D Sheehan and TG Cotter Tumour Biology Laboratory, Department of Biochemistry, University College Cork, Lee Maltings, Prospect Row, Cork, Ireland Apoptosis is a genetically programmed, physiological method ditions, when the stress level eliminates the capacity for regu- of cell destruction. A variety of genes are now recognised as lated activation of the apoptotic cascade, the cells undergo positive or negative regulators of this process. Expression of inducible heat shock proteins (hsp) is known to correlate with necrosis. At lower levels, injured cells activate their own increased resistance to apoptosis induced by a range of apoptotic programme. However, if the level of stress is low diverse cytotoxic agents and has been implicated in chemo- enough, cells attempt to survive and activate a stress response therapeutic resistance of tumours and carcinogenesis. Inten- system (Figure 1). This response involves a shut-down of all sive research on apoptosis over the past number of years has cellular protein synthesis apart from a rapid induction of heat provided significant insights into the mechanisms and molecu- shock proteins, which results in a transient state of thermotol- lar events that occur during this process. The modulatory 8 effects of hsps on apoptosis are well documented, however, erance. Once the stress element is removed, these cells func- the mechanisms of hsp-mediated protection against apoptosis tion normally and the levels of hsps drop back to basal levels remain to be fully defined, although several hypotheses have with time. During the intervening period, while hsp levels are been proposed. Elucidation of these mechanisms should elevated, cells are refractory to the toxicity of various agents.9 reveal novel targets for manipulating the sensitivity of leu- Many tumour cells, however, appear to have constitutively kaemic cells to therapy. This review aims to explain the cur- elevated levels of hsps which may serve to protect them from rently understood process of apoptosis and the effects of hsps on this process. Several proposed mechanisms for hsp protec- otherwise harmful conditions/agents. This abnormal hsp tion against apoptosis and the therapeutic implications of hsps expression has recently been implicated in chemotherapeutic in leukaemia are also discussed. Leukemia (2000) 14, 1161– resistance and carcinogenesis;10–12 and increased activity of 1173. hsps appears to result in aggressively growing and therapy Keywords: apoptosis; hsp70; hsp27; leukaemia resistant tumours.13–15 This is a simplified view of the stress response and the cellu- lar protective effects of hsps. In reality, diverse apoptotic sig- Introduction nalling pathways are triggered within the cell by different treatment modalities, and these pathways converge at a com- Normal development of cells and maintenance of tissue mon point in the apoptotic pathway. Each member of the hsp homeostasis require tight regulation of proliferation, differen- family appears to have a distinct set of functions within the tiation and death processes. Deregulation of any of these pro- cell.9 The mechanisms by which various hsps protect against cesses can have severe consequences, resulting in diseases different apoptotic stimuli remain to be fully defined. In fact, such as leukaemia, autoimmunity, viral infections, allergic evidence now exists to suggest that certain hsps can enhance and neurodegenerative disorders.1–3 Abnormal heat shock apoptosis in some systems.16–18 A better understanding of the protein (hsp) expression has recently been identified as one of molecular mechanisms of hsp protection against apoptosis is the deregulating factors in cellular development and this area is rapidly emerging as an exciting field of research. Eukaryotic cell death can follow two fundamentally distinct pathways, necrosis or apoptosis. Necrosis is the result of acute cellular dysfunction due to extreme trauma or injury to the cell. It is a passive and disruptive process in which the cell rapidly loses control of ion flux. This leads to the uptake of water, giving rise to cell and organelle swelling, resulting in cytolysis. The release of cell contents into surrounding tissue perpetuates a local inflammatory response.4 In contrast, apoptosis is a genetically regulated process which, unlike necrosis, occurs through the activation of a cell-intrinsic death cascade. This cascade can be modulated by many exogenous signals. The dying cell undergoes a relatively ordered form of cell death characterised morphologically by cell shrinkage, membrane blebbing, chromatin condensation, internucleoso- mal DNA fragmentation and the formation of apoptotic bodies.1,5–7 Injured/stressed cells may undergo necrosis or apoptosis, depending on the level of the stress. Under extreme con- Figure 1 The stress response; mild stress triggers the rapid induc- tion of hsps, resulting in thermotolerance. Increasing levels of stress Correspondence: TG Cotter; Fax: 353-21-904259 result in the apoptotic response and under extreme conditions Received 21 January 2000; accepted 27 March 2000 necrosis occurs. Review EM Creagh et al 1162 required before directed therapeutical interventions can be stress inducible member, hsp70 (hsp72) is present at basal lev- made. This review summarises the regulation of heat shock els in unstressed cells, but following stress becomes strongly proteins and the apoptotic process as currently understood. induced and is present in the cytosol and nucleus.8 As hsp70 Effects of hsps on the apoptotic process and several proposed is the major anti-apoptotic hsp, most of the studies investigat- mechanisms of hsp protection against apoptosis are also ing mechanisms of hsp protection are carried out using hsp70 discussed. overexpression. The apoptotic events that have been proposed to be involved in hsp protection against apoptosis and the theories on mechanisms for this protection are detailed later Heat shock proteins in the text. The stress inducible expression of hsp27, a member of the The response of cells or organisms to environmental stresses small hsp family, also has a significant role in protection such as heat shock or chemicals is related to the induction or against apoptosis.23,24 The intracellular localisation, level of enhancement of a number of heat shock proteins (hsps). Hsps oligomerisation and phosphorylation status of hsp27 appear gained their name following experiments by Ritossa in 1962, to be involved in the regulation of its biological reactivity.25 who exposed Drosphilia salivary glands to heat, dinitrophenol For example, monomeric, non-phosphorylated hsp27 has or salycilate.19 Ritossa observed a new chromosomal puffing been shown to be the only form that inhibits in vitro actin pattern following these stresses. Further work by Tissieres in polymerisation, a potential biochemical function of hsp27.26 1974 on protein synthesis following heat shock on Drosphilia However, the active form of hsp27 for other described func- salivary gland revealed that heat shock activated the synthesis tions, such as cell protection, has not yet been conclusively of only a few polypeptides and strongly inhibited the synthesis determined. of most others.20 It is now clear that the hsps comprise a large superfamily of proteins that are found in all plant, yeast, bacterial and mammalian cells.21 Hsps as molecular chaperones Most of the members of the hsp family are universally con- served proteins represented by a spectrum of functional hom- Molecular chaperones are currently defined as proteins that ologues in all cellular compartments and organelles. Hsps are bind to and stabilise an otherwise unstable conformer of not only induced during stress, some family members are another protein, and by controlled binding and release of the constitutively expressed, indicating a cellular function under substrate protein, facilitates its correct fate in vivo: be it fold- normal conditions. This superfamily of proteins are also ing, oligomeric assembly, transport to a particular subcellular referred to as ‘molecular chaperones’, due to their ability to compartment or controlled switching between active/inactive stabilise proteins and polypeptides, thereby minimising pro- conformations. The major classes of hsps that have chaperone tein misfolding and aggregation within the cell. The major functions are hsp70, hsp60 and hsp90 (reviewed in Ref. 27). families of hsps, and their respective functions, are summar- Hsp70 and hsp60 are not substrate specific, ie they bind to ised in Table 1. a wide range of unfolded proteins with approximately the The hsp70 family of proteins function mainly as chap- same affinity. Both hsp70 and hsp60 chaperones function in erones, interacting transiently with many proteins in an ATP- conjunction with other proteins, termed co-chaperones, dependent manner (reviewed in Ref. 22). Constitutively syn- which are specific for their chaperone but can distinguish thesised members are localised in distinct intracellular com- between ATP-bound and ADP-bound structural variants. Both partments including: the constitutive hsp73/hsc70 (cognate) classes of chaperones are ATPases and ATP hydrolysis present within the cytosol/nucleus; the constitutive glucose provides energy for their function. regulated 78 kDa (Grp78 or BiP) protein present within the An obvious mechanism for hsp protection
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