Abstract
HspB5, also called αB-crystallin, is a ubiquitous small heat shock protein (sHSP) that is strongly induced by a variety of stresses, but that also functions constitutively in multiple cell types. Extensive research has demonstrated that HspB5 acts as an ATP-independent molecular chaperone by binding unfolding proteins and protecting cells from damage due to irreversible protein aggregation. As a result of its importance in protein homeostasis HspB5 is of significant interest to many areas of cell biology, including the development of cancer. However, the molecular understanding of HspB5’s role in cancer is only beginning to emerge. In this chapter an overview is given of data that provide insight into the oncogenic role of HspB5 in human cancer.
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References
Acunzo J, Katsogiannou M, Rocchi P (2012) Small heat shock proteins HSP27 (HspB1), alphaB-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death. Int J Biochem Cell Biol 44(10):1622–1631. doi:10.1016/j.biocel.2012.04.002
Aoyama A, Steiger RH, Frohli E, Schafer R, von Deimling A, Wiestler OD, Klemenz R (1993) Expression of alpha B-crystallin in human brain tumors. Int J Cancer 55(5):760–764
Arrigo AP (2012) Pathology-dependent effects linked to small heat shock proteins expression: an update. Scientifica 2012:185641. doi:10.6064/2012/185641
Arrigo AP (2013) Human small heat shock proteins: protein interactomes of homo- and hetero-oligomeric complexes: an update. FEBS Lett 587(13):1959–1969. doi:10.1016/j.febslet.2013.05.011
Arrigo AP, Gibert B (2014) HspB1, HspB5 and HspB4 in human cancers: potent oncogenic role of some of their client proteins. Cancers (Basel) 6(1):333–365. doi:10.3390/cancers6010333
Barbash O, Diehl JA (2008) SCF(Fbx4/alphaB-crystallin) E3 ligase: when one is not enough. Cell Cycle 7(19):2983–2986
Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3(6):401–410. doi:10.1038/nrc1093
Boelens WC (2014) Cell biological roles of alphaB-crystallin. Prog Biophys Mol Biol. doi:10.1016/j.pbiomolbio.2014.02.005
Bosman JD, Yehiely F, Evans JR, Cryns VL (2010) Regulation of alphaB-crystallin gene expression by the transcription factor Ets1 in breast cancer. Breast Cancer Res Treat 119(1):63–70. doi:10.1007/s10549-009-0330-4
Bremnes RM, Camps C, Sirera R (2006) Angiogenesis in non-small cell lung cancer: the prognostic impact of neoangiogenesis and the cytokines VEGF and bFGF in tumours and blood. Lung Cancer 51(2):143–158. doi:10.1016/j.lungcan.2005.09.005
Chelouche-Lev D, Kluger HM, Berger AJ, Rimm DL, Price JE (2004) alphaB-crystallin as a marker of lymph node involvement in breast carcinoma. Cancer 100(12):2543–2548. doi:10.1002/cncr.20304
Cherneva R, Petrov D, Georgiev O, Slavova Y, Toncheva D, Stamenova M, Trifonova N (2010) Expression profile of the small heat-shock protein alpha-B-crystallin in operated-on non-small-cell lung cancer patients: clinical implication. Eur J Cardiothorac Surg 37(1):44–50. doi:10.1016/j.ejcts.2009.06.038
de Thonel A, Le Mouel A, Mezger V (2012) Transcriptional regulation of small HSP-HSF1 and beyond. Int J Biochem Cell Biol 44(10):1593–1612. doi:10.1016/j.biocel.2012.06.012
den Engelsman J, Keijsers V, de Jong WW, Boelens WC (2003) The small heat-shock protein alpha B-crystallin promotes FBX4-dependent ubiquitination. J Biol Chem 278(7):4699–4704. doi:10.1074/jbc.M211403200
Dimberg A, Rylova S, Dieterich LC, Olsson AK, Schiller P, Wikner C, Bohman S, Botling J, Lukinius A, Wawrousek EF, Claesson-Welsh L (2008) alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis. Blood 111(4):2015–2023. doi:10.1182/blood-2007-04-087841
Evans JR, Bosman JD, Brown-Endres L, Yehiely F, Cryns VL (2010) Induction of the small heat shock protein alphaB-crystallin by genotoxic stress is mediated by p53 and p73. Breast Cancer Res Treat 122(1):159–168. doi:10.1007/s10549-009-0542-7
Galluzzi L, Morselli E, Kepp O, Vitale I, Pinti M, Kroemer G (2011) Mitochondrial liaisons of p53. Antioxid Redox Signal 15(6):1691–1714. doi:10.1089/ars.2010.3504
Geiger TR, Peeper DS (2009) Metastasis mechanisms. Biochim Biophys Acta 1796(2):293–308. doi:10.1016/j.bbcan.2009.07.006
Ghosh JG, Shenoy AK Jr, Clark JI (2007) Interactions between important regulatory proteins and human alphaB crystallin. Biochemistry 46(21):6308–6317. doi:10.1021/bi700149h
Gopal-Srivastava R, Piatigorsky J (1994) Identification of a lens-specific regulatory region (LSR) of the murine alpha B-crystallin gene. Nucleic Acids Res 22(7):1281–1286
Gopal-Srivastava R, Kays WT, Piatigorsky J (2000) Enhancer-independent promoter activity of the mouse alphaB-crystallin/small heat shock protein gene in the lens and cornea of transgenic mice. Mech Dev 92(2):125–134
Goplen D, Bougnaud S, Rajcevic U, Boe SO, Skaftnesmo KO, Voges J, Enger PO, Wang J, Tysnes BB, Laerum OD, Niclou S, Bjerkvig R (2010) alphaB-crystallin is elevated in highly infiltrative apoptosis-resistant glioblastoma cells. Am J Pathol 177(4):1618–1628. doi:10.2353/ajpath.2010.090063
Guo W, Giancotti FG (2004) Integrin signalling during tumour progression. Nat Rev Mol Cell Biol 5(10):816–826. doi:10.1038/nrm1490
Hamann S, Metrailler S, Schorderet DF, Cottet S (2013) Analysis of the cytoprotective role of alpha-crystallins in cell survival and implication of the alphaA-crystallin C-terminal extension domain in preventing Bax-induced apoptosis. PLoS One 8(2):e55372. doi:10.1371/journal.pone.0055372
Ho PY, Chueh SC, Chiou SH, Wang SM, Lin WC, Lee IL, Yang HY, Peng HC, Lai MK (2013) AlphaB-crystallin in clear cell renal cell carcinoma: tumor progression and prognostic significance. Urol Oncol 31(7):1367–1377. doi:10.1016/j.urolonc.2012.01.015
Hochberg GK, Benesch JL (2014) Dynamical structure of alphaB-crystallin. Prog Biophys Mol Biol. doi:10.1016/j.pbiomolbio.2014.03.003
Hu R, Aplin AE (2010) alphaB-crystallin is mutant B-RAF regulated and contributes to cyclin D1 turnover in melanocytic cells. Pigment Cell Melanoma Res 23(2):201–209. doi:10.1111/j.1755-148X.2010.00668.x
Hu Z, Fan C, Livasy C, He X, Oh DS, Ewend MG, Carey LA, Subramanian S, West R, Ikpatt F, Olopade OI, van de Rijn M, Perou CM (2009) A compact VEGF signature associated with distant metastases and poor outcomes. BMC Med 7:9. doi:10.1186/1741-7015-7-9
Hu X, Wang L, Sun W, Xiao L, Wu Y, Zhuo Y, Nie D, Zhou J, Zhang J (2012) AP-2beta enhances p53-mediated transcription of the alphaB-crystallin gene through stabilizing p53. Mol Biol Rep 39(1):209–214. doi:10.1007/s11033-011-0727-0
Huang Z, Cheng Y, Chiu PM, Cheung FM, Nicholls JM, Kwong DL, Lee AW, Zabarovsky ER, Stanbridge EJ, Lung HL, Lung ML (2012) Tumor suppressor Alpha B-crystallin (CRYAB) associates with the cadherin/catenin adherens junction and impairs NPC progression-associated properties. Oncogene 31(32):3709–3720. doi:10.1038/onc.2011.529
Huang XY, Ke AW, Shi GM, Zhang X, Zhang C, Shi YH, Wang XY, Ding ZB, Xiao YS, Yan J, Qiu SJ, Fan J, Zhou J (2013) alphaB-crystallin complexes with 14-3-3zeta to induce epithelial-mesenchymal transition and resistance to sorafenib in hepatocellular carcinoma. Hepatology 57(6):2235–2247. doi:10.1002/hep.26255
Ito H, Okamoto K, Nakayama H, Isobe T, Kato K (1997) Phosphorylation of alphaB-crystallin in response to various types of stress. J Biol Chem 272(47):29934–29941
Ivanov O, Chen F, Wiley EL, Keswani A, Diaz LK, Memmel HC, Rademaker A, Gradishar WJ, Morrow M, Khan SA, Cryns VL (2008) alphaB-crystallin is a novel predictor of resistance to neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat 111(3):411–417. doi:10.1007/s10549-007-9796-0
Jin X, Moskophidis D, Hu Y, Phillips A, Mivechi NF (2009) Heat shock factor 1 deficiency via its downstream target gene alphaB-crystallin (Hspb5) impairs p53 degradation. J Cell Biochem 107(3):504–515. doi:10.1002/jcb.22151
Kamradt MC, Chen F, Cryns VL (2001) The small heat shock protein alpha B-crystallin negatively regulates cytochrome c- and caspase-8-dependent activation of caspase-3 by inhibiting its autoproteolytic maturation. J Biol Chem 276(19):16059–16063. doi:10.1074/jbc.C100107200
Kappe G, Boelens WC, de Jong WW (2010) Why proteins without an alpha-crystallin domain should not be included in the human small heat shock protein family HSPB. Cell Stress Chaperones 15(4):457–461. doi:10.1007/s12192-009-0155-4
Kase S, He S, Sonoda S, Kitamura M, Spee C, Wawrousek E, Ryan SJ, Kannan R, Hinton DR (2010) alphaB-crystallin regulation of angiogenesis by modulation of VEGF. Blood 115(16):3398–3406. doi:10.1182/blood-2009-01-197095
Kato K, Ito H, Kamei K, Inaguma Y, Iwamoto I, Saga S (1998) Phosphorylation of alphaB-crystallin in mitotic cells and identification of enzymatic activities responsible for phosphorylation. J Biol Chem 273(43):28346–28354
Kim HS, Lee Y, Lim YA, Kang HJ, Kim LS (2011) alphaB-Crystallin is a novel oncoprotein associated with poor prognosis in breast cancer. J Breast Cancer 14(1):14–19. doi:10.4048/jbc.2011.14.1.14
Koritzinsky M, Wouters BG (2013) The roles of reactive oxygen species and autophagy in mediating the tolerance of tumor cells to cycling hypoxia. Semin Radiat Oncol 23(4):252–261. doi:10.1016/j.semradonc.2013.05.006
Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 15(3):178–196. doi:10.1038/nrm3758
Lanneau D, Wettstein G, Bonniaud P, Garrido C (2010) Heat shock proteins: cell protection through protein triage. Sci World J 10:1543–1552. doi:10.1100/tsw.2010.152
Launay N, Tarze A, Vicart P, Lilienbaum A (2010) Serine 59 phosphorylation of {alpha}B-crystallin down-regulates its anti-apoptotic function by binding and sequestering Bcl-2 in breast cancer cells. J Biol Chem 285(48):37324–37332. doi:10.1074/jbc.M110.124388
Li R, Reiser G (2011) Phosphorylation of Ser45 and Ser59 of alphaB-crystallin and p38/extracellular regulated kinase activity determine alphaB-crystallin-mediated protection of rat brain astrocytes from C2-ceramide- and staurosporine-induced cell death. J Neurochem 118(3):354–364. doi:10.1111/j.1471-4159.2011.07317.x
Lin DI, Barbash O, Kumar KG, Weber JD, Harper JW, Klein-Szanto AJ, Rustgi A, Fuchs SY, Diehl JA (2006) Phosphorylation-dependent ubiquitination of cyclin D1 by the SCF(FBX4-alphaB crystallin) complex. Mol Cell 24(3):355–366. doi:10.1016/j.molcel.2006.09.007
Liu S, Li J, Tao Y, Xiao X (2007) Small heat shock protein alphaB-crystallin binds to p53 to sequester its translocation to mitochondria during hydrogen peroxide-induced apoptosis. Biochem Biophys Res Commun 354(1):109–114. doi:10.1016/j.bbrc.2006.12.152
Lung HL, Lo CC, Wong CC, Cheung AK, Cheong KF, Wong N, Kwong FM, Chan KC, Law EW, Tsao SW, Chua D, Sham JS, Cheng Y, Stanbridge EJ, Robertson GP, Lung ML (2008) Identification of tumor suppressive activity by irradiation microcell-mediated chromosome transfer and involvement of alpha B-crystallin in nasopharyngeal carcinoma. Int J Cancer 122(6):1288–1296. doi:10.1002/ijc.23259
Maddala R, Rao VP (2005) alpha-Crystallin localizes to the leading edges of migrating lens epithelial cells. Exp Cell Res 306(1):203–215. doi:10.1016/j.yexcr.2005.01.026
Malin D, Strekalova E, Petrovic V, Deal AM, Al Ahmad A, Adamo B, Miller CR, Ugolkov A, Livasy C, Fritchie K, Hamilton E, Blackwell K, Geradts J, Ewend M, Carey L, Shusta EV, Anders CK, Cryns VL (2014) alphaB-crystallin: a novel regulator of breast cancer metastasis to the brain. Clin Cancer Res 20(1):56–67. doi:10.1158/1078-0432.CCR-13-1255
Mao YW, Xiang H, Wang J, Korsmeyer S, Reddan J, Li DW (2001) Human bcl-2 gene attenuates the ability of rabbit lens epithelial cells against H2O2-induced apoptosis through down-regulation of the alpha B-crystallin gene. J Biol Chem 276(46):43435–43445. doi:10.1074/jbc.M102195200
Mao YW, Liu JP, Xiang H, Li DW (2004) Human alphaA- and alphaB-crystallins bind to Bax and Bcl-X(S) to sequester their translocation during staurosporine-induced apoptosis. Cell Death Differ 11(5):512–526. doi:10.1038/sj.cdd.4401384
Morrison LE, Hoover HE, Thuerauf DJ, Glembotski CC (2003) Mimicking phosphorylation of alphaB-crystallin on serine-59 is necessary and sufficient to provide maximal protection of cardiac myocytes from apoptosis. Circ Res 92(2):203–211
Moyano JV, Evans JR, Chen F, Lu M, Werner ME, Yehiely F, Diaz LK, Turbin D, Karaca G, Wiley E, Nielsen TO, Perou CM, Cryns VL (2006) AlphaB-crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer. J Clin Invest 116(1):261–270. doi:10.1172/JCI25888
Peschek J, Braun N, Rohrberg J, Back KC, Kriehuber T, Kastenmuller A, Weinkauf S, Buchner J (2013) Regulated structural transitions unleash the chaperone activity of alphaB-crystallin. Proc Natl Acad Sci U S A 110(40):E3780–E3789. doi:10.1073/pnas.1308898110
Pestell RG (2013) New roles of cyclin D1. Am J Pathol 183(1):3–9. doi:10.1016/j.ajpath.2013.03.001
Petrovic V, Malin D, Cryns VL (2013) alphaB-crystallin promotes oncogenic transformation and inhibits caspase activation in cells primed for apoptosis by Rb inactivation. Breast Cancer Res Treat 138(2):415–425. doi:10.1007/s10549-013-2465-6
Roskoski R Jr (2007) Vascular endothelial growth factor (VEGF) signaling in tumor progression. Crit Rev Oncol Hematol 62(3):179–213. doi:10.1016/j.critrevonc.2007.01.006
Ruan Q, Han S, Jiang WG, Boulton ME, Chen ZJ, Law BK, Cai J (2011) alphaB-crystallin, an effector of unfolded protein response, confers anti-VEGF resistance to breast cancer via maintenance of intracrine VEGF in endothelial cells. Mol Cancer Res 9(12):1632–1643. doi:10.1158/1541-7786.MCR-11-0327
Shin JH, Piao CS, Lim CM, Lee JK (2008) LEDGF binding to stress response element increases alphaB-crystallin expression in astrocytes with oxidative stress. Neurosci Lett 435(2):131–136. doi:10.1016/j.neulet.2008.02.029
Singh BN, Rao KS, Ramakrishna T, Rangaraj N, Rao Ch M (2007) Association of alphaB-crystallin, a small heat shock protein, with actin: role in modulating actin filament dynamics in vivo. J Mol Biol 366(3):756–767. doi:10.1016/j.jmb.2006.12.012
Sitterding SM, Wiseman WR, Schiller CL, Luan C, Chen F, Moyano JV, Watkin WG, Wiley EL, Cryns VL, Diaz LK (2008) AlphaB-crystallin: a novel marker of invasive basal-like and metaplastic breast carcinomas. Ann Diagn Pathol 12(1):33–40. doi:10.1016/j.anndiagpath.2007.02.004
Solares CA, Boyle GM, Brown I, Parsons PG, Panizza B (2010) Reduced alphaB-crystallin staining in perineural invasion of head and neck cutaneous squamous cell carcinoma. Otolaryngol Head Neck Surg 142(3 Suppl 1):S15–S19. doi:10.1016/j.otohns.2009.12.001
Stegh AH, Kesari S, Mahoney JE, Jenq HT, Forloney KL, Protopopov A, Louis DN, Chin L, DePinho RA (2008) Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma. Proc Natl Acad Sci U S A 105(31):10703–10708. doi:10.1073/pnas.0712034105
Tan K, Goldstein D, Crowe P, Yang JL (2013) Uncovering a key to the process of metastasis in human cancers: a review of critical regulators of anoikis. J Cancer Res Clin Oncol 139(11):1795–1805. doi:10.1007/s00432-013-1482-5
Tang Q, Liu YF, Zhu XJ, Li YH, Zhu J, Zhang JP, Feng ZQ, Guan XH (2009) Expression and prognostic significance of the alpha B-crystallin gene in human hepatocellular carcinoma. Hum Pathol 40(3):300–305. doi:10.1016/j.humpath.2008.09.002
Tsang JY, Lai MW, Wong KH, Chan SK, Lam CC, Tsang AK, Yu AM, Tan PH, Tse GM (2012) alphaB-crystallin is a useful marker for triple negative and basal breast cancers. Histopathology 61(3):378–386. doi:10.1111/j.1365-2559.2012.04234.x
van de Schootbrugge C, Bussink J, Span PN, Sweep FC, Grenman R, Stegeman H, Pruijn GJ, Kaanders JH, Boelens WC (2013) alphaB-crystallin stimulates VEGF secretion and tumor cell migration and correlates with enhanced distant metastasis in head and neck squamous cell carcinoma. BMC Cancer 13:128. doi:10.1186/1471-2407-13-128
van de Schootbrugge C, Schults EM, Bussink J, Span PN, Grenman R, Pruijn GJ, Kaanders JH, Boelens WC (2014) Effect of hypoxia on the expression of alphaB-crystallin in head and neck squamous cell carcinoma. BMC Cancer 14:252. doi:10.1186/1471-2407-14-252
Volkmann J, Reuning U, Rudelius M, Hafner N, Schuster T, Becker VRA, Weimer J, Hilpert F, Kiechle M, Durst M, Arnold N, Schmalfeldt B, Meindl A, Ramser J (2013) High expression of crystallin alphaB represents an independent molecular marker for unfavourable ovarian cancer patient outcome and impairs TRAIL- and cisplatin-induced apoptosis in human ovarian cancer cells. Int J Cancer J Int Cancer 132(12):2820–2832. doi:10.1002/ijc.27975
Wang F, Chen X, Li C, Sun Q, Chen Y, Wang Y, Peng H, Liu Z, Chen R, Liu K, Yan H, Ye BH, Kwiatkowski DJ, Zhang H (2013) Pivotal role of augmented alphaB-crystallin in tumor development induced by deficient TSC1/2 complex. Oncogene. doi:10.1038/onc.2013.401
Watanabe G, Kato S, Nakata H, Ishida T, Ohuchi N, Ishioka C (2009) alphaB-crystallin: a novel p53-target gene required for p53-dependent apoptosis. Cancer Sci 100(12):2368–2375. doi:10.1111/j.1349-7006.2009.01316.x
Xi JH, Bai F, McGaha R, Andley UP (2006) Alpha-crystallin expression affects microtubule assembly and prevents their aggregation. FASEB J 20(7):846–857. doi:10.1096/fj.05-5532com
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Boelens, W.C. (2015). Role of Small Heat Shock Protein HspB5 in Cancer. In: Tanguay, R., Hightower, L. (eds) The Big Book on Small Heat Shock Proteins. Heat Shock Proteins, vol 8. Springer, Cham. https://doi.org/10.1007/978-3-319-16077-1_12
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