HSP22蛋白变异致腓骨肌萎缩症2L的分子致病机制研究
|
摘要
研究背景：
腓骨肌萎缩症(Charcot-Marie-Tooth Disease, CMT)是一类最常见的遗传性周围神经病,慢性进行性病程,致残率高。临床上依据其病理和电生理特点可分为两型：脱髓鞘型(CMT1型)和轴突型(CMT2型)。CMT2L型被发现是由小分子热休克蛋白22基因(HSP22)的点突变(423G→T)所致。HSP22蛋白变异如何致病目前机制尚不明确,有两种不同的理论推测：1、突变后功能缺失；2、获得的毒性作用。因HSP22蛋白变异所造成的神经肌肉疾病发病年龄均较晚,提示组织功能丧失是一个损伤效应逐渐累积的过程,疾病的发生更可能与突变造成的保护作用下降有关,而非突变直接造成组织损伤。
研究目的：
从腓肠神经筛选出CMT2L患者和正常人的的差异表达蛋白质,探讨CMT2L的可能发病机制,为探索CMT的治疗和预防打下基础。
研究方法：
1、采用2DE-MS技术体系,对人类正常腓肠神经组织和CMT2L患者腓肠神经组织提取蛋白后行双向电泳,PDQUEST7.0软件分析选择差异表达蛋白质,并通过基质辅助激光解吸电离飞行时间质谱(MALDI-TOF-MS)进行蛋白质鉴定结果,筛选差异表达蛋白质。
2、通过免疫荧光染色分析差异表达蛋白质和HSP22是否存在共定位。
结果：
通过2-DE方法及PDQUEST筛选出6个表达明显增高的蛋白,并通过MS成功鉴定出6个差异蛋白：Tubulin alpha-1B.Actin cytoplasmic 2、Tubulin alpha-1A、POTE ankyrin domain family member F、Glutathione S-transferase omega-1及EH domain-containing protein 2。其中Glutathione S-transferase omega-1及EH domain-containing protein 2可能与轴突的退行性病变有一定相关性。这两种蛋白均与HSP22在细胞胞浆内存在共定位。
结论：
Glutathione S-transferase omega-1及EH domain-containing protein 2可能参与了CMT2L的发生和发展,其相关机制尚待进一步阐明。双向电泳一质谱分析技术为CMT发生发展过程中差异表达蛋白的研究提供了有效的技术手段。
Background:
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy presenting with the phenotype of a chronic progressive neuropathy affecting both the motor and sensory nerves and high morbidity. Electrophysiological studies and pathological basis of clinical electrophysiological or anatomical pathology findings distinguish two major types-the demyelinating form and the axonal form. CMT2L was found to be caused by a novel 423G->T (Lys141Asn) missense mutation of HSP22. The mechanism of the HSP22 variation is still unknown, there are two different theoretical speculation:1) the loss of function mutation,2) acquired the toxic effects. The relatively late onset of the disease, which suggests an accumulative tissue damage pattern, indicates a more indirect, perhaps protective role of the wild-type sHSPs rather than an immediate role in proper tissue function.
Objective:
To screen differentially expressed proteins in human sural nerve between CMT2L patients and normal controls for understanding the pathogenesis of CMT.
Results:
Six differential protein spots were identified by PDQUEST analysis. Six proteins were successfully identified by MS, which are Tubulin alpha-1B. Actin cytoplasmic 2、Tubulin alpha-1A、POTE ankyrin domain family member F、Glutathione S-transferase omega-1 and EH domain-containing protein 2. The last two proteins may be of significant implications in axon degeneration, and may have some correction with axon degeneration. They both co-localized with HSP22 in the cell cytoplasm.
Conclusions:
Glutathione S-transferase omega-1 and EH domain-containing protein 2 may be involved in the occurrence and development of CMT2L and the related mechanisms remain to be elucidated. Two-dimensional electrophoresis and mass spectrometry technique provide an effective technique for screening the differentially expressed proteins in the development and progression of CMT.
腓骨肌萎缩症(Charcot-Marie-Tooth Disease, CMT)是一类最常见的遗传性周围神经病,慢性进行性病程,致残率高。临床上依据其病理和电生理特点可分为两型：脱髓鞘型(CMT1型)和轴突型(CMT2型)。CMT2L型被发现是由小分子热休克蛋白22基因(HSP22)的点突变(423G→T)所致。HSP22蛋白变异如何致病目前机制尚不明确,有两种不同的理论推测：1、突变后功能缺失；2、获得的毒性作用。因HSP22蛋白变异所造成的神经肌肉疾病发病年龄均较晚,提示组织功能丧失是一个损伤效应逐渐累积的过程,疾病的发生更可能与突变造成的保护作用下降有关,而非突变直接造成组织损伤。
研究目的：
从腓肠神经筛选出CMT2L患者和正常人的的差异表达蛋白质,探讨CMT2L的可能发病机制,为探索CMT的治疗和预防打下基础。
研究方法：
1、采用2DE-MS技术体系,对人类正常腓肠神经组织和CMT2L患者腓肠神经组织提取蛋白后行双向电泳,PDQUEST7.0软件分析选择差异表达蛋白质,并通过基质辅助激光解吸电离飞行时间质谱(MALDI-TOF-MS)进行蛋白质鉴定结果,筛选差异表达蛋白质。
2、通过免疫荧光染色分析差异表达蛋白质和HSP22是否存在共定位。
结果：
通过2-DE方法及PDQUEST筛选出6个表达明显增高的蛋白,并通过MS成功鉴定出6个差异蛋白：Tubulin alpha-1B.Actin cytoplasmic 2、Tubulin alpha-1A、POTE ankyrin domain family member F、Glutathione S-transferase omega-1及EH domain-containing protein 2。其中Glutathione S-transferase omega-1及EH domain-containing protein 2可能与轴突的退行性病变有一定相关性。这两种蛋白均与HSP22在细胞胞浆内存在共定位。
结论：
Glutathione S-transferase omega-1及EH domain-containing protein 2可能参与了CMT2L的发生和发展,其相关机制尚待进一步阐明。双向电泳一质谱分析技术为CMT发生发展过程中差异表达蛋白的研究提供了有效的技术手段。
Background:
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy presenting with the phenotype of a chronic progressive neuropathy affecting both the motor and sensory nerves and high morbidity. Electrophysiological studies and pathological basis of clinical electrophysiological or anatomical pathology findings distinguish two major types-the demyelinating form and the axonal form. CMT2L was found to be caused by a novel 423G->T (Lys141Asn) missense mutation of HSP22. The mechanism of the HSP22 variation is still unknown, there are two different theoretical speculation:1) the loss of function mutation,2) acquired the toxic effects. The relatively late onset of the disease, which suggests an accumulative tissue damage pattern, indicates a more indirect, perhaps protective role of the wild-type sHSPs rather than an immediate role in proper tissue function.
Objective:
To screen differentially expressed proteins in human sural nerve between CMT2L patients and normal controls for understanding the pathogenesis of CMT.
Results:
Six differential protein spots were identified by PDQUEST analysis. Six proteins were successfully identified by MS, which are Tubulin alpha-1B. Actin cytoplasmic 2、Tubulin alpha-1A、POTE ankyrin domain family member F、Glutathione S-transferase omega-1 and EH domain-containing protein 2. The last two proteins may be of significant implications in axon degeneration, and may have some correction with axon degeneration. They both co-localized with HSP22 in the cell cytoplasm.
Conclusions:
Glutathione S-transferase omega-1 and EH domain-containing protein 2 may be involved in the occurrence and development of CMT2L and the related mechanisms remain to be elucidated. Two-dimensional electrophoresis and mass spectrometry technique provide an effective technique for screening the differentially expressed proteins in the development and progression of CMT.
引文
1. Szigeti K, Lupski JR. Charcot-Marie-Tooth disease. Eur J Hum Genet 2009;17:703-10.
2. Tang BS, Zhao GH, Luo W, et al. Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L. Hum Genet 2005;116:222-4.
3. Tang BS, Luo W, Xia K, et al. A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2L) maps to chromosome 12q24. Hum Genet 2004;114:527-33.
4. Irobi J, Van Impe K, Seeman P, et al. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet 2004;36:597-601.
5. Evgrafov OV, Mersiyanova I, Irobi J, et al. Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet 2004;36:602-6.
6. Shemetov AA, Seit-Nebi AS, Gusev NB. Structure, properties, and functions of the human small heat-shock protein HSP22 (HspB8, H11, E2IG1):a critical review. J Neurosci Res 2008;86:264-9.
7. Haslbeck M, Franzmann T, Weinfurtner D, Buchner J. Some like it hot:the structure and function of small heat-shock proteins. Nat Struct Mol Biol 2005;12:842-6.
8. Benndorf R, Welsh MJ. Shocking degeneration. Nat Genet 2004;36:547-8.
9. Kim MV, Kasakov AS, Seit-Nebi AS, Marston SB, Gusev NB. Structure and properties of K141E mutant of small heat shock protein HSP22 (HspB8, H11) that is expressed in human neuromuscular disorders. Arch Biochem Biophys 2006;454:32-41.
10. Carra S, Sivilotti M, Chavez Zobel AT, Lambert H, Landry J. HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells. Hum Mol Genet 2005;14:1659-69.
11. Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol 2009;8:654-67.
12. Petrak J, Ivanek R, Toman O, et al. Deja vu in proteomics. A hit parade of repeatedly identified differentially expressed proteins. Proteomics 2008;8:1744-9.
13. Stock AD, Spallone PA, Dennis TR, et al. Heat shock protein 27 gene: chromosomal and molecular location and relationship to Williams syndrome. Am J Med Genet A 2003; 120A:320-5.
14. Samali A, Robertson JD, Peterson E, et al. Hsp27 protects mitochondria of thermotolerant cells against apoptotic stimuli. Cell Stress Chaperones 2001;6:49-58.
15. Garrido C, Ottavi P, Fromentin A, et al. HSP27 as a mediator of confluence-dependent resistance to cell death induced by anticancer drugs. Cancer Res 1997;57:2661-7.
16. Rudin CM, Yang Z, Schumaker LM, et al. Inhibition of glutathione synthesis reverses Bcl-2-mediated cisplatin resistance. Cancer Res 2003;63:312-8.
17. Mehlen P, Kretz-Remy C, Preville X, Arrigo AP. Human hsp27, Drosophila hsp27 and human alphaB-crystallin expression-mediated increase in glutathione is essential for the protective activity of these proteins against TNFalpha-induced cell death. EMBO J 1996; 15:2695-706.
18. Piaggi S, Raggi C, Corti A, et al. Glutathione transferase omega 1-1 (GSTO1-1) plays an anti-apoptotic role in cell resistance to cisplatin toxicity. Carcinogenesis 2010;PMID:20106899[Epub ahead of print].
19. Guilherme A, Soriano NA, Bose S, et al. EHD2 and the novel EH domain binding protein EHBP1 couple endocytosis to the actin cytoskeleton. J Biol Chem 2004;279:10593-605.
20. Guilherme A, Soriano NA, Furcinitti PS, Czech MP. Role of EHD1 and EHBP1 in perinuclear sorting and insulin-regulated GLUT4 recycling in 3T3-L1 adipocytes. J Biol Chem 2004;279:40062-75.
21. Doherty KR, Demonbreun AR, Wallace GQ, et al. The endocytic recycling protein EHD2 interacts with myoferlin to regulate myoblast fusion. J Biol Chem 2008;283:20252-60.
1. Haslbeck M, Franzmann T, Weinfurtner D, Buchner J. Some like it hot:the structure and function of small heat-shock proteins. Nat Struct Mol Biol 2005; 12:842-6.
2. Irobi J, Van Impe K, Seeman P, et al. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet 2004;36:597-601.
3. Kasakov AS, Bukach OV, Seit-Nebi AS, Marston SB, Gusev NB. Effect of mutations in the beta5-beta7 loop on the structure and properties of human small heat shock protein HSP22 (HspB8, H11). FEBS J 2007;274:5628-42.
4. Zeng L, Hu Z, Lu W, et al. Small Heat Shock Proteins:Recent Advances in Neuropathy. Curr Neurovasc Res 2010. PMID:20334615 [Epub ahead of print].
5. Benndorf R, Sun X, Gilmont RR, et al. HSP22, a new member of the small heat shock protein superfamily, interacts with mimic of phosphorylated HSP27 ((3D)HSP27). J Biol Chem 2001;276:26753-61.
6. Smith CC, Yu YX, Kulka M, Aurelian L. A novel human gene similar to the protein kinase (PK) coding domain of the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10) codes for a serine-threonine PK and is expressed in melanoma cells. J Biol Chem 2000;275:25690-9.
7. Charpentier AH, Bednarek AK, Daniel RL, et al. Effects of estrogen on global gene expression:identification of novel targets of estrogen action. Cancer Res 2000;60:5977-83.
8. Carra S, Sivilotti M, Chavez Zobel AT, Lambert H, Landry J. HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells. Hum Mol Genet 2005;14:1659-69.
9. Shemetov AA, Seit-Nebi AS, Gusev NB. Structure, properties, and functions of the human small heat-shock protein HSP22 (HspB8, H11, E2IG1):a critical review. J Neurosci Res 2008;86:264-9.
10. Kappe G, Verschuure P, Philipsen RL, et al. Characterization of two novel human small heat shock proteins:protein kinase-related HspB8 and testis-specific HspB9. Biochim Biophys Acta 2001; 1520:1-6.
11. Gober MD, Smith CC, Ueda K, Toretsky JA, Aurelian L. Forced expression of the H11 heat shock protein can be regulated by DNA methylation and trigger apoptosis in human cells. J Biol Chem 2003;278:37600-9.
12. Depre C, Hase M, Gaussin V, et al. H11 kinase is a novel mediator of myocardial hypertrophy in vivo. Circ Res 2002;91:1007-14.
13. Langelier Y, Champoux L, Hamel M, et al. The R1 subunit of herpes simplex virus ribonucleotide reductase is a good substrate for host cell protein kinases but is not itself a protein kinase. J Biol Chem 1998;273:1435-43.
14. Kim MV, Seit-Nebi AS, Gusev NB. The problem of protein kinase activity of small heat shock protein Hsp22 (H11 or HspB8). Biochem Biophys Res Commun 2004;325:649-52.
15. Kim MV, Seit-Nebi AS, Marston SB, Gusev NB. Some properties of human small heat shock protein Hsp22 (H11 or HspB8). Biochem Biophys Res Commun
2004;315:796-801.
16. Chavez Zobel AT, Loranger A, Marceau N, Theriault JR, Lambert H, Landry J. Distinct chaperone mechanisms can delay the formation of aggresomes by the myopathy-causing R120G alphaB-crystallin mutant. Hum Mol Genet 2003;12:1609-20.
17. Chowdary TK, Raman B, Ramakrishna T, Rao CM. Mammalian Hsp22 is a heat-inducible small heat-shock protein with chaperone-like activity. Biochem J 2004;381:379-87.
18. Carra S, Seguin SJ, Landry J. HspB8 and Bag3:a new chaperone complex targeting misfolded proteins to macroautophagy. Autophagy 2008;4:237-9.
19. Carra S, Seguin SJ, Lambert H, Landry J. HspB8 chaperone activity toward poly(Q)-containing proteins depends on its association with Bag3, a stimulator of macroautophagy. J Biol Chem 2008;283:1437-44.
20. McCollum AK, Casagrande G, Kohn EC. Caught in the middle:the role of Bag3 in disease. Biochem J 2010;425:e1-3.
21. Sharma BK, Smith CC, Laing JM, Rucker DA, Burnett JW, Aurelian L. Aberrant DNA methylation silences the novel heat shock protein H11 in melanoma but not benign melanocytic lesions. Dermatology 2006;213:192-9.
22. Li B, Smith CC, Laing JM, Gober MD, Liu L, Aurelian L. Overload of the heat-shock protein H11/HspB8 triggers melanoma cell apoptosis through activation of transforming growth factor-beta-activated kinase 1. Oncogene 2007;26:3521-31.
23. Yang C, Trent S, Ionescu-Tiba V, et al. Identification of cyclin D1-and estrogen-regulated genes contributing to breast carcinogenesis and progression. Cancer Res 2006;66:11649-58.
24. Badri KR, Modem S, Gerard HC, et al. Regulation of Sam68 activity by small heat shock protein 22. J Cell Biochem 2006;99:1353-62.
25. Hase M, Depre C, Vatner SF, Sadoshima J. Hll has dose-dependent and dual hypertrophic and proapoptotic functions in cardiac myocytes. Biochem J 2005;388:475-83.
26. Wilhelmus MM, Boelens WC, Otte-Holler I, et al. Small heat shock protein HspB8:its distribution in Alzheimer's disease brains and its inhibition of amyloid-beta protein aggregation and cerebrovascular amyloid-beta toxicity. Acta Neuropathol 2006;111:139-49.
27. Wilhelmus MM, Boelens WC, Kox M, et al. Small heat shock proteins associated with cerebral amyloid angiopathy of hereditary cerebral hemorrhage with amyloidosis (Dutch type) induce interleukin-6 secretion. Neurobiol Aging 2009;30:229-40.
28. Tang BS, Zhao GH, Luo W, et al. Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L. Hum Genet 2005;116:222-4.
29. Benndorf R, Welsh MJ. Shocking degeneration. Nat Genet 2004;36:547-8.
30. Kim MV, Kasakov AS, Seit-Nebi AS, Marston SB, Gusev NB. Structure and properties of K141E mutant of small heat shock protein HSP22 (HspB8, Hll) that is expressed in human neuromuscular disorders. Arch Biochem Biophys 2006;454:32-41.
31. Fuchs M, Poirier DJ, Seguin SJ, et al. Identification of the key structural motifs involved in HspB8/HspB6-Bag3 interaction. Biochem J 2010;425:245-55.
32. Read DE, Gorman AM. Heat shock protein 27 in neuronal survival and neurite outgrowth. Biochem Biophys Res Commun 2009;382:6-8.
2. Tang BS, Zhao GH, Luo W, et al. Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L. Hum Genet 2005;116:222-4.
3. Tang BS, Luo W, Xia K, et al. A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2L) maps to chromosome 12q24. Hum Genet 2004;114:527-33.
4. Irobi J, Van Impe K, Seeman P, et al. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet 2004;36:597-601.
5. Evgrafov OV, Mersiyanova I, Irobi J, et al. Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet 2004;36:602-6.
6. Shemetov AA, Seit-Nebi AS, Gusev NB. Structure, properties, and functions of the human small heat-shock protein HSP22 (HspB8, H11, E2IG1):a critical review. J Neurosci Res 2008;86:264-9.
7. Haslbeck M, Franzmann T, Weinfurtner D, Buchner J. Some like it hot:the structure and function of small heat-shock proteins. Nat Struct Mol Biol 2005;12:842-6.
8. Benndorf R, Welsh MJ. Shocking degeneration. Nat Genet 2004;36:547-8.
9. Kim MV, Kasakov AS, Seit-Nebi AS, Marston SB, Gusev NB. Structure and properties of K141E mutant of small heat shock protein HSP22 (HspB8, H11) that is expressed in human neuromuscular disorders. Arch Biochem Biophys 2006;454:32-41.
10. Carra S, Sivilotti M, Chavez Zobel AT, Lambert H, Landry J. HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells. Hum Mol Genet 2005;14:1659-69.
11. Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol 2009;8:654-67.
12. Petrak J, Ivanek R, Toman O, et al. Deja vu in proteomics. A hit parade of repeatedly identified differentially expressed proteins. Proteomics 2008;8:1744-9.
13. Stock AD, Spallone PA, Dennis TR, et al. Heat shock protein 27 gene: chromosomal and molecular location and relationship to Williams syndrome. Am J Med Genet A 2003; 120A:320-5.
14. Samali A, Robertson JD, Peterson E, et al. Hsp27 protects mitochondria of thermotolerant cells against apoptotic stimuli. Cell Stress Chaperones 2001;6:49-58.
15. Garrido C, Ottavi P, Fromentin A, et al. HSP27 as a mediator of confluence-dependent resistance to cell death induced by anticancer drugs. Cancer Res 1997;57:2661-7.
16. Rudin CM, Yang Z, Schumaker LM, et al. Inhibition of glutathione synthesis reverses Bcl-2-mediated cisplatin resistance. Cancer Res 2003;63:312-8.
17. Mehlen P, Kretz-Remy C, Preville X, Arrigo AP. Human hsp27, Drosophila hsp27 and human alphaB-crystallin expression-mediated increase in glutathione is essential for the protective activity of these proteins against TNFalpha-induced cell death. EMBO J 1996; 15:2695-706.
18. Piaggi S, Raggi C, Corti A, et al. Glutathione transferase omega 1-1 (GSTO1-1) plays an anti-apoptotic role in cell resistance to cisplatin toxicity. Carcinogenesis 2010;PMID:20106899[Epub ahead of print].
19. Guilherme A, Soriano NA, Bose S, et al. EHD2 and the novel EH domain binding protein EHBP1 couple endocytosis to the actin cytoskeleton. J Biol Chem 2004;279:10593-605.
20. Guilherme A, Soriano NA, Furcinitti PS, Czech MP. Role of EHD1 and EHBP1 in perinuclear sorting and insulin-regulated GLUT4 recycling in 3T3-L1 adipocytes. J Biol Chem 2004;279:40062-75.
21. Doherty KR, Demonbreun AR, Wallace GQ, et al. The endocytic recycling protein EHD2 interacts with myoferlin to regulate myoblast fusion. J Biol Chem 2008;283:20252-60.
1. Haslbeck M, Franzmann T, Weinfurtner D, Buchner J. Some like it hot:the structure and function of small heat-shock proteins. Nat Struct Mol Biol 2005; 12:842-6.
2. Irobi J, Van Impe K, Seeman P, et al. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet 2004;36:597-601.
3. Kasakov AS, Bukach OV, Seit-Nebi AS, Marston SB, Gusev NB. Effect of mutations in the beta5-beta7 loop on the structure and properties of human small heat shock protein HSP22 (HspB8, H11). FEBS J 2007;274:5628-42.
4. Zeng L, Hu Z, Lu W, et al. Small Heat Shock Proteins:Recent Advances in Neuropathy. Curr Neurovasc Res 2010. PMID:20334615 [Epub ahead of print].
5. Benndorf R, Sun X, Gilmont RR, et al. HSP22, a new member of the small heat shock protein superfamily, interacts with mimic of phosphorylated HSP27 ((3D)HSP27). J Biol Chem 2001;276:26753-61.
6. Smith CC, Yu YX, Kulka M, Aurelian L. A novel human gene similar to the protein kinase (PK) coding domain of the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10) codes for a serine-threonine PK and is expressed in melanoma cells. J Biol Chem 2000;275:25690-9.
7. Charpentier AH, Bednarek AK, Daniel RL, et al. Effects of estrogen on global gene expression:identification of novel targets of estrogen action. Cancer Res 2000;60:5977-83.
8. Carra S, Sivilotti M, Chavez Zobel AT, Lambert H, Landry J. HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells. Hum Mol Genet 2005;14:1659-69.
9. Shemetov AA, Seit-Nebi AS, Gusev NB. Structure, properties, and functions of the human small heat-shock protein HSP22 (HspB8, H11, E2IG1):a critical review. J Neurosci Res 2008;86:264-9.
10. Kappe G, Verschuure P, Philipsen RL, et al. Characterization of two novel human small heat shock proteins:protein kinase-related HspB8 and testis-specific HspB9. Biochim Biophys Acta 2001; 1520:1-6.
11. Gober MD, Smith CC, Ueda K, Toretsky JA, Aurelian L. Forced expression of the H11 heat shock protein can be regulated by DNA methylation and trigger apoptosis in human cells. J Biol Chem 2003;278:37600-9.
12. Depre C, Hase M, Gaussin V, et al. H11 kinase is a novel mediator of myocardial hypertrophy in vivo. Circ Res 2002;91:1007-14.
13. Langelier Y, Champoux L, Hamel M, et al. The R1 subunit of herpes simplex virus ribonucleotide reductase is a good substrate for host cell protein kinases but is not itself a protein kinase. J Biol Chem 1998;273:1435-43.
14. Kim MV, Seit-Nebi AS, Gusev NB. The problem of protein kinase activity of small heat shock protein Hsp22 (H11 or HspB8). Biochem Biophys Res Commun 2004;325:649-52.
15. Kim MV, Seit-Nebi AS, Marston SB, Gusev NB. Some properties of human small heat shock protein Hsp22 (H11 or HspB8). Biochem Biophys Res Commun
2004;315:796-801.
16. Chavez Zobel AT, Loranger A, Marceau N, Theriault JR, Lambert H, Landry J. Distinct chaperone mechanisms can delay the formation of aggresomes by the myopathy-causing R120G alphaB-crystallin mutant. Hum Mol Genet 2003;12:1609-20.
17. Chowdary TK, Raman B, Ramakrishna T, Rao CM. Mammalian Hsp22 is a heat-inducible small heat-shock protein with chaperone-like activity. Biochem J 2004;381:379-87.
18. Carra S, Seguin SJ, Landry J. HspB8 and Bag3:a new chaperone complex targeting misfolded proteins to macroautophagy. Autophagy 2008;4:237-9.
19. Carra S, Seguin SJ, Lambert H, Landry J. HspB8 chaperone activity toward poly(Q)-containing proteins depends on its association with Bag3, a stimulator of macroautophagy. J Biol Chem 2008;283:1437-44.
20. McCollum AK, Casagrande G, Kohn EC. Caught in the middle:the role of Bag3 in disease. Biochem J 2010;425:e1-3.
21. Sharma BK, Smith CC, Laing JM, Rucker DA, Burnett JW, Aurelian L. Aberrant DNA methylation silences the novel heat shock protein H11 in melanoma but not benign melanocytic lesions. Dermatology 2006;213:192-9.
22. Li B, Smith CC, Laing JM, Gober MD, Liu L, Aurelian L. Overload of the heat-shock protein H11/HspB8 triggers melanoma cell apoptosis through activation of transforming growth factor-beta-activated kinase 1. Oncogene 2007;26:3521-31.
23. Yang C, Trent S, Ionescu-Tiba V, et al. Identification of cyclin D1-and estrogen-regulated genes contributing to breast carcinogenesis and progression. Cancer Res 2006;66:11649-58.
24. Badri KR, Modem S, Gerard HC, et al. Regulation of Sam68 activity by small heat shock protein 22. J Cell Biochem 2006;99:1353-62.
25. Hase M, Depre C, Vatner SF, Sadoshima J. Hll has dose-dependent and dual hypertrophic and proapoptotic functions in cardiac myocytes. Biochem J 2005;388:475-83.
26. Wilhelmus MM, Boelens WC, Otte-Holler I, et al. Small heat shock protein HspB8:its distribution in Alzheimer's disease brains and its inhibition of amyloid-beta protein aggregation and cerebrovascular amyloid-beta toxicity. Acta Neuropathol 2006;111:139-49.
27. Wilhelmus MM, Boelens WC, Kox M, et al. Small heat shock proteins associated with cerebral amyloid angiopathy of hereditary cerebral hemorrhage with amyloidosis (Dutch type) induce interleukin-6 secretion. Neurobiol Aging 2009;30:229-40.
28. Tang BS, Zhao GH, Luo W, et al. Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L. Hum Genet 2005;116:222-4.
29. Benndorf R, Welsh MJ. Shocking degeneration. Nat Genet 2004;36:547-8.
30. Kim MV, Kasakov AS, Seit-Nebi AS, Marston SB, Gusev NB. Structure and properties of K141E mutant of small heat shock protein HSP22 (HspB8, Hll) that is expressed in human neuromuscular disorders. Arch Biochem Biophys 2006;454:32-41.
31. Fuchs M, Poirier DJ, Seguin SJ, et al. Identification of the key structural motifs involved in HspB8/HspB6-Bag3 interaction. Biochem J 2010;425:245-55.
32. Read DE, Gorman AM. Heat shock protein 27 in neuronal survival and neurite outgrowth. Biochem Biophys Res Commun 2009;382:6-8.