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Molecular Chaperones As Regulators of Cell Death

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Molecular Chaperones As Regulators of Cell Death Oncogene (2008) 27, 6489–6506 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc REVIEW Molecular chaperones as regulators of cell death A Hishiya and S Takayama Cardiovascular Program, The Boston Biomedical Research Institute, Watertown, MA, USA Molecular chaperones have been reported as multifunc- way of apoptosis, and they will be replaced with newly tional antistress molecules that can regulate diverse proliferated cells. biological processes to maintain cellular homeostasis. Although the protein aggregation and formation of Molecular chaperones have critical roles for maintaining inclusion bodies are commonly observed among these proper protein folding, protein translocation, degradation diseases, recent reports indicated that intracellular of unfolded protein, regulating signal-transduction pro- aggregation does not confer the cellular toxicity teins and so on. Under pathological conditions, inducible (Saudou et al., 1998; Cummings et al., 1999; Chun or constitutively expressed molecular chaperones protect et al., 2002; Watase et al., 2002), rather the protective cells from stress. Non-dividing terminally differentiated effect as they sequester the insoluble aggregation of cells accumulate abnormal proteins due to chronic mutant proteins (Arrasate et al., 2004). Finally, Kayed environmental or physiological stress; thus, proper cha- et al. (2003) showed that the monomeric or oligomeric perone function is critical for maintaining homeostasis of fibrous conformation of mutant proteins termed amy- those cells, such as neuronal and muscular cells. Cancer loid might induceneuronaltoxicity, which is commonly cells also have overexpression of molecular chaperone seen among these diseases. proteins for promoting survival from stress related to It has been reported that apoptotic cell death is growth, cell cycle, hypoxia, metastasis and genetic responsible for the progression of clinical symptom of mutations. Here, we will focus on the function of degenerative disease such as ALS (Ekegren et al., 1999; molecular chaperone proteins for the regulation of cell Martin, 1999), Huntington’s disease (Bova et al., 1999), death in degenerative diseases, ischemic diseases and in Parkinson’s disease (Tatton, 2000; Hartmann et al., cancer. 2001) and Alzheimer’s disease (Rohn et al., 2002; Zhao Oncogene (2008) 27, 6489–6506; doi:10.1038/onc.2008.314 et al., 2003). The intracerebroventricular or intrastriatal administration of caspaseinhibitor (zVAD-fmk) was Keywords: heat-shock proteins; Hsp27; Hsp70; Hsp90; reported as attenuating the symptom of ALS (Li et al., molecular chaperone; co-chaperone 2000) and Huntington’s disease (Ona et al., 1999; Chen et al., 2000; Toulmond et al., 2004). Molecular chaperones in degenerative diseases As misfolded protein is generally believed to be a critical Degenerative disease pathological factor of aggregation diseases, extensive research has been carried out to examine the potential Molecular chaperones regulate protein folding to roles of molecular chaperones in pathogenesis of maintain proper function of proteins. Misfolded or degenerative diseases. Small heat-shock family molecu- aggregated proteins induce cellular toxicity and cause lar chaperones have 10 members in mammalians. Four degenerative diseases such as polyglutamine disease members of small heat-shock proteins (aA-crystallin (Huntington’s disease and so on), Alzheimer’s disease, (HspB4), aB-crystallin (HspB5), Hsp27 (HspB1) and familial amyotrophic lateral sclerosis (ALS) and Hsp22 (HspB8)) have been found as genes responsible Parkinson’s disease. for human degenerative myopathy, neuropathy and Terminally differentiated and non-dividing cells, such congenital cataract (Table 1). Three different mutations as neurons and muscles, are particularly vulnerable to (R120G, Q151X and 464del) of aB-crystallin havebeen the toxicity of misfolded proteins, as accumulation of discovered in human myofibrillar myopathy. R120G misfolded and aggregated protein increases toxicity in mutation causes desmin-related myopathy, which has such organs. Cell division usually dilutes the toxicity, pathological characteristics of myofibrillar degeneration even though the toxicity exceeds the threshold of cell and is categorized as myofibrillar myopathy. Desmin- death. The cells have the choice of ‘active death’ as a related myopathy is sometimes accompanied with cytosolic aggregated protein, including desmin and aB- crystallin (Vicart et al., 1998; Selcen and Engel, 2003). Correspondence: Dr S Takayama, The Boston Biomedical Research Thebiological characterization of aB-crystallin R120G Institute, 64 Grove Street, Watertown, MA 02472, USA. mutation has indicated that mutant protein lose E-mail: [email protected] chaperone activity, form aggregation alone, perturb Molecular chaperones as regulators of cell death A Hishiya and S Takayama 6490 Table 1 Identified human mutations in molecular chaperones associated with degenerative disease Molecular chaperone Mutation Disease References aA-Crystallin W9X CC Pras et al. (2000) R49C CC Mackay et al. (2003) R116C CC Litt et al. (1998) R116H CC Gu et al. (2008) G98R CC Santhiya et al. (2006) aB-Crystallin R120G DRM Vicart et al. (1998) 450delAa CC Berry et al. (2001) Q151X MM Selcen and Engel (2003) 464delCTXb MM Selcen and Engel (2003) D140N CC Liu et al. (2006b) P20S CC Liu et al. (2006a) Hsp27 S135F CMT2, DHMN Evgrafov et al. (2004) R136W CMT2 R127W DHMN T151I DHMN P182L DHMN Hsp22 K141N CMT2 Tang et al. (2005) K141N DHMN Irobi et al. (2004) K141E DHMN Hsp60 V72I SPG13 Hansen et al. (2002) Hsf4 A20D MC Bu et al. (2002) I78V L115P R120C SIL1 D170EfsX MSS Anttonen et al. (2005) V186-Q215del A152-Q215del R111X H71QfsX Skipping of exons 6 MSS Senderek et al. (2005) Skipping of exons 9 R111X G116fs L316fs M344fs L456fs G346delQ417X Abbreviations: CC, congenital cataract; CMT2, Charcot–Marie–Tooth disease type 2; del, deletion; DHMN, distal hereditary motor neuropathy; DRM, desmin-related myopathy; fs, frameshift; MC, Marner cataract; MM, myofibrillar myopathy; MSS, Marinesco–Sjo¨ gren syndrome; SPG13, hereditary spastic paraplegia; X, stop. a450delA, nucleotide deletion at position 450 that resulted in a frameshift in codon 150 and produced an aberrant protein consisting of 184 residues. b464delCTX, 2 bp nucleotide deletion at position 464 (464delCT) that generates eight missense codons (RAHHSHHP) followed by a stop codon. sarcomere architecture and lose antiapoptotic activity changes with mitochondrial dysfunction and disruption (Bova et al., 1999; Perng et al., 1999; Maloyan et al., of the cytoskeletal network (Sanbe et al., 2004, 2005; 2005; Treweek et al., 2005; Simon et al., 2007). Maloyan et al., 2005). Myofibrillar myopathy is also found in homozygous The ocular lens is transparent and avascular tissue. deletion mouse of bag3, which is a member of the BAG Lens epithelial cells proliferate and differentiate into family co-chaperone and a regulator of Hsp70 molecular lens fiber cells, using similar systems such as apoptosis chaperone. Skeletal muscles of bag3À/À miceexhibitthe to eliminate organelles. Apaf1 knockout micehave foci of myofibrillar disruption and represent an early abnormal lens epithelium differentiation and inhibition pathological alteration with altered Z-discs and apop- of apoptosis in their lenses (Cecconi et al., 1998). DNase totic features in muscular tissues (Homma et al., 2006). II-like acid DNase deficiency in mice produced con- Heart-specific overexpression of R120G mutation of genital cataract formation with undigested DNA during aB-crystallin indicated similar phenotype as human lens differentiation (Nishimoto et al., 2003). Missense desmin-related myopathy and cardiac hypertrophy in mutation of aA-crystallin (HspB4) and aB-crystallin mice(Wang et al., 2001). Thesamegroup has usedthis was found in familiar congenital cataracts (Table 1). In transgenic mouse for analysing the biological effects of ocular lenses, crystallin is the major protein component R120G mutation on apoptosis in vivo. Histological in differentiated lens fiber cells. Using missense examination indicated that amyloidogenic oligomer was mutations of aA- or aB-crystallin found in congenital detected in the heart of R120G transgenic mouse, cataracts, many studies have been carried out analysing suggesting that toxic oligomer was generated by thefunctional significanceof thesemutations in vitro or R120G mutation of aB-crystallin and causes apoptotic in vivo (Kumar et al., 1999; Liu et al., 2006b; Singh et al., Oncogene Molecular chaperones as regulators of cell death A Hishiya and S Takayama 6491 2006; Gu et al., 2008; Li et al., 2008; Xi et al., 2008), proteins, the active form of small heat-shock protein suggesting that mutants of aA- or aB-crystallin lose may not be increased by simple transgenic methods their chaperone activity and antiapoptotic activity. (Zourlidou et al., 2007). Although in vivo models show Recently, double knockout mouse of aA- and some controversial results, relatively consistent aB-crystallin was generated. In this mouse, caspase 3 results have been reported from cellular experiments, activation and increased apoptotic death were observed indicating that many different molecular chaperones can in lens fibers (Morozov and Wawrousek, 2006). Knock- suppress the apoptosis induced by mutant proteins, in mice were created using aA-crystallin R49C, which which make aggregation in degenerative disease indicated increasing apoptosis and congenital cataract (Table3). (Xi et al.,
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