Abstract
Lysyl oxidase (LOX) is an amine oxidase involved in protein cross-linking of the extracellular matrix. Less well characterized is the role that LOX plays among nuclear proteins, and molecular mechanisms of its transport to the nucleus are currently unknown. Here, we have employed yeast two-hybrid library screening and found that the LOX catalytic domain interacts with the transcription repressor p66β. This interaction has been confirmed in vitro and has been found to be accomplished through the CR2-containing domain of p66β. Moreover, co-expression of p66β and LOX in living tumor cells leads to the nuclear accumulation of LOX. Thus, p66β might be important for the regulation of LOX in the nucleus.
Abbreviations
- ECM:
-
Extracellular matrix
- EMT:
-
Epithelial to mesenchymal transition
- LOX:
-
Lysyl oxidase
- ppLOX:
-
Preprolysyl oxidase
- PBS:
-
Phosphate-buffered saline
- TBST:
-
TRIS-buffered saline with 0.1 % Tween-20
References
Allen HF, Wade PA, Kutateladze TG (2013) The NuRD architecture. Cell Mol Life Sci 70:3513–3524
Atsawasuwan P, Mochida Y, Katafuchi M, Kaku M, Fong KS, Csiszar K, Yamauchi M (2008) Lysyl oxidase binds transforming growth factor-β and regulates its signaling via amine oxidase activity. J Biol Chem 283:34229–34240
Brackertz M, Gong Z, Leers J, Renkawitz R (2006) p66α and p66β of the Mi-2/NuRD complex mediate MBD2 and histone interaction. Nucleic Acids Res 34:397–406
Cain SA, McGovern A, Small E, Ward LJ, Baldock C, Shuttleworth A, Kielty CM (2009) Defining elastic fiber interactions by molecular fishing: an affinity purification and mass spectrometry approach. Mol Cell Proteomics 8:2715–2732
Chen H, Wu X, Pan ZK, Huang S (2010) Integrity of SOS1/EPS8/ABI1 tri-complex determines ovarian cancer metastasis. Cancer Res 70:9979–9990
Choudhury R, McGovern A, Ridley C, Cain SA, Baldwin A, Wang MC, Guo C, Mironov A Jr, Drymoussi Z, Trump D, Shuttleworth A, Baldock C, Kielty CM (2009) Differential regulation of elastic fiber formation by fibulin-4 and −5. J Biol Chem 284:24553–24567
Contente S, Yeh TJ, Friedman RM (2009) Tumor suppressive effect of lysyl oxidase proenzyme. Biochim Biophys Acta 1793:1272–1278
Cox TR, Bird D, Baker AM, Barker HE, Ho MW, Lang G, Erler JT (2013) LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res 73:1721–1732
El-Haibi CP, Bell GW, Zhang J, Collmann AY, Wood D, Scherber CM, Csizmadia E, Mariani O, Zhu C, Campagne A, Toner M, Bhatia SN, Irimia D, Vincent-Salomon A, Karnoub AE (2012) Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy. Proc Natl Acad Sci U S A 109:17460–17465
Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, Chi JT, Jeffrey SS, Giaccia AJ (2006) Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440:1222–1226
Feng Q, Cao R, Xia L, Erdjument-Bromage H, Tempst P, Zhang Y (2002) Identification and functional characterization of the p66/p68 components of the MeCP1 complex. Mol Cell Biol 22:536–546
Fogelgren B, Polgar N, Szauter KM, Ujfaludi Z, Laczko R, Fong KS, Csiszar K (2005) Cellular fibronectin binds to lysyl oxidase with high affinity and is critical for its proteolytic activation. J Biol Chem 280:24690–24697
Friedman RM, Yeh A, Gutman P, Contente S, Kenyon K (1997) Reversion by deletion of transforming oncogene following interferon-β and retinoic acid treatment. J Interferon Cytokine Res 17:647–651
Fu J, Qin L, He T, Qin J, Hong J, Wong J, Liao L, Xu J (2011) The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis. Cell Res 21:275–289
Giampuzzi M, Botti G, Di Duca M, Arata L, Ghiggeri G, Gusmano R, Ravazzolo R, Di Donato A (2000) Lysyl oxidase activates the transcription activity of human collagene III promoter. Possible involvement of Ku antigen. J Biol Chem 275:36341–36349
Giampuzzi M, Oleggini R, Di Donato A (2003) Demonstration of in vitro interaction between tumor suppressor lysyl oxidase and histones H1 and H2: definition of the regions involved. Biochim Biophys Acta 1647:245–251
Giampuzzi M, Oleggini R, Albanese C, Pestell R, Di Donato A (2005) β-Catenin signaling and regulation of cyclin D1 promoter in NRK-49 F cells transformed by down-regulation of the tumor suppressor lysyl oxidase. Biochim Biophys Acta 1745:370–381
Hannafon BN, Sebastiani P, de las Morenas A, Lu J, Rosenberg CL (2011) Expression of microRNA and their gene targets are dysregulated in preinvasive breast cancer. Breast Cancer Res 13:R24
Herranz N, Dave N, Millanes-Romero A, Morey L, Díaz VM, Lórenz-Fonfría V, Gutierrez-Gallego R, Jerónimo C, Di Croce L, García de Herreros A, Peiró S (2012) Lysyl oxidase-like 2 deaminates lysine 4 in histone H3. Mol Cell 46:369–376
Hirai M, Ohbayashi T, Horiguchi M, Okawa K, Hagiwara A, Chien KR, Kita T, Nakamura T (2007) Fibulin-5/DANCE has an elastogenic organizer activity that is abrogated by proteolytic cleavage in vivo. J Cell Biol 176:1061–1071
Kagan HM, Williams MA, Calaman SD, Berkowitz EM (1983) Histone H1 is a substrate for lysyl oxidase and contains endogenous sodium borotritide-reducible residues. Biochem Biophys Res Commun 115:186–192
Kalinina T, Gungor C, Thieltges S, Moller-Krull M, Penas EM, Wicklein D, Streichert T, Schumacher U, Kalinin V, Simon R, Otto B, Dierlamm J, Schwarzenbach H, Effenberger KE, Bockhorn M, Izbicki JR, Yekebas EF (2010) Establishment and characterization of a new human pancreatic adenocarcinoma cell line with high metastatic potential to the lung. BMC Cancer 10:295
Kenyon K, Contente S, Trackman PC, Tang J, Kagan HM, Friedman RM (1991) Lysyl oxidase and rrg messenger RNA. Science 253:802
Kim CK, Nguyen TL, Joo KM, Nam DH, Park J, Lee KH, Cho SW, Ahn JY (2010) Negative regulation of p53 by the long isoform of ErbB3 binding protein Ebp1 in brain tumors. Cancer Res 70:9730–9741
Liu Z, Oh SM, Okada M, Liu X, Cheng D, Peng J, Brat DJ, Sun SY, Zhou W, Gu W, Ye K (2009) Human BRE1 is an E3 ubiquitin ligase for Ebp1 tumor suppressor. Mol Biol Cell 20:757–768
Maki JM, Kivirikko KI (2001) Cloning and characterization of a fourth human lysyl oxidase isoenzyme. Biochem J 355:381–387
Mello ML, Contente S, Vidal BC, Planding W, Schenck U (1995) Modulation of ras transformation affecting chromatin supraorganization as assessed by image analysis. Exp Cell Res 220:374–382
Mello ML, Alvarenga EM, Vidal BC, Di Donato A (2011) Chromatin supraorganization, mitotic abnormalities and proliferation in cells with increased or down-regulated LOX expression: indirect evidence of a LOX-histone H1 interaction in vivo. Micron 42:8–16
Oleggini R, Di Donato A (2011) Lysyl oxidase regulates MMTV promoter: indirect evidence of histone H1 involvement. Biochem Cell Biol 89:522–532
Oleggini R, Gastaldo N, Di Donato A (2007) Regulation of elastin promoter by lysyl oxidase and growth factors: cross control of lysyl oxidase on TGF-β1 effects. Matrix Biol 26:494–505
Payne SL, Hendrix MJ, Kirschmann DA (2007) Paradoxical roles for lysyl oxidases in cancer—a prospect. J Cell Biochem 101:1338–1354
Peinado H, Del Carmen Iglesias-de la Cruz M, Olmeda D, Csiszar K, Fong KS, Vega S, Nieto MA, Cano A, Portillo F (2005) A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. EMBO J 24:3446–3458
Pestov NB, Korneenko TV, Radkov R, Zhao H, Shakhparonov MI, Modyanov NN (2004) Identification of the β-subunit for nongastric H-K-ATPase in rat anterior prostate. Am J Physiol Cell Physiol 286:1229–1237
Pestov NB, Okkelman IA, Shmanai VV, Hurski AL, Giaccia AJ, Shchepinov MS (2011) Control of lysyl oxidase activity through site-specific deuteration of lysine. Bioorg Med Chem Lett 21:255–258
Polgar N, Fogelgren B, Shipley JM, Csiszar K (2007) Lysyl oxidase interacts with hormone placental lactogen and synergistically promotes breast epithelial cell proliferation and migration. J Biol Chem 282:3262–3272
Ramirez J, Hagman J (2009) The Mi-2/NuRD complex: a critical epigenetic regulator of hematopoietic development, differentiation and cancer. Epigenetics 4:532–536
Schietke R, Warnecke C, Wacker I, Schodel J, Mole DR, Campean V, Amann K, Goppelt-Struebe M, Behrens J, Eckardt KU, Wiesener MS (2010) The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF-1. J Biol Chem 285:6658–6669
Semenza GL (2012) Molecular mechanisms mediating metastasis of hypoxic breast cancer cells. Trends Mol Med 18:534–543
Yang Z, Bu Y, Wang C, Liu G, Song F (2010) Growth inhibition, morphology change, and cell cycle alterations in NFBD1-depleted human esophageal cancer cells. Mol Cell Biochem 342:1–6
Yang X, Li S, Li W, Chen J, Xiao X, Wang Y, Yan G, Chen L (2013) Inactivation of lysyl oxidase by β-aminopropionitrile inhibits hypoxia-induced invasion and migration of cervical cancer cells. Oncol Rep 29:541–548
Yuan C, Bu Y, Wang C, Yi F, Yang Z, Huang X, Cheng L, Liu G, Wang Y, Song F (2012) NFBD1/MDC1 is a protein of oncogenic potential in human cervical cancer. Mol Cell Biochem 359:333–346
Acknowledgments
We are grateful to A. Giaccia for anti-LOX antibodies, to H. Nishina, R. Dmitriev, and C. Cardoso for marker plasmids, and to V. Baklaushev for help with confocal microsopy.
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These studies were supported by MCB RAS and the Russian Foundation for Basic Research (grants 13-04-01413 and 12-04-31374).
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Okkelman, I.A., Sukaeva, A.Z., Kirukhina, E.V. et al. Nuclear translocation of lysyl oxidase is promoted by interaction with transcription repressor p66β. Cell Tissue Res 358, 481–489 (2014). https://doi.org/10.1007/s00441-014-1972-z
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DOI: https://doi.org/10.1007/s00441-014-1972-z