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Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST-CNRS OPEN ACCESS JOURNAL Gene Section Review FBLN5 (fibulin 5) Miao Wang, Rolf A Brekken Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390-8593, USA (MW, RAB) Published in Atlas Database: May 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/FBLN5ID46779ch14q32.html DOI: 10.4267/2042/51868 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology muscle cells. The expression of Fibulin-5 is downregulated in adult tissue but reactivated upon injury and various disease conditions (Yanagisawa et al., 2009). Fibulin-5 is essential for elastic fiber organization as shown by generation of Fibulin-5 knockout (Fbln5-/-) mice (Nakamura et al., 2002; Yanagisawa et al., 2002) and biochemical analysis (Hirai et al., 2007; Zheng et al., 2007). However, a mouse model with point mutation (D to E) (Fbln5RGE/RGE) in the RGD domain has exhibited intact elastic fibers (Budatha et al., 2011), indicating that Fibulin-5-Integrin interaction is not required for elastic fiber assembly. Fibulin-5 has also been implicated in various pathological conditions including cancer, cutis laxa and age-related macular degeneration. Identity Other names: ADCL2, ARCL1A, ARMD3, DANCE, EVEC, FIBL-5, UP50 HGNC (Hugo): FBLN5 Location: 14q32.12 Note Fibulin-5 is a matricellular glycoprotein, belonging to fibulin family which has 7 members (Yanagisawa et al., 2009). Compared with other fibulins, it has a unique arginine-glycine-aspartic acid (RGD) domain in the Nterminal region that mediates binding to integrins (Nakamura et al., 1999). Fibulin-5 is produced and secreted by endothelial cells, fibroblasts and vascular smooth The protein sequence of human Fibulin-5 (source database: UniProt). Atlas Genet Cytogenet Oncol Haematol. 2013; 17(12) 811 FBLN5 (fibulin 5) Wang M, Brekken RA Schematic drawing of Fibulin-5 protein. It contains an evolutionally conserved RGD sequence in the first CB-EGF-like (Calcium Binding-Epidermal Growth Factor-like) motif and a fibulin module in the C-terminus of the protein. Localisation DNA/RNA Matricellular, secreted, extracellular matrix. Description Function According to Ensembl Genome Browser, human Fbln5 gene locates on Chromosome 14q between region 92335756 and 92414331. This gene has 9 splicing variants transcriptionally. The only one with known protein function has 11 exons and 1347 nucleotides. Fibulin-5 is essential for the assembly of elastic fibers. Biochemical analysis shows that Fibulin-5 preferentially binds to monomeric tropoelastin through N- and C-terminal elastin-binding regions (Zheng et al., 2007). Fbln5-/- mice exhibit severe elastic fibre disorganization throughout the whole body (Nakamura et al., 2002; Yanagisawa et al., 2002). Further studies have shown that Fibulin-5 regulates elastic fiber formation by increasing the efficacy of tropoelastin self-aggregation and cross-linking through direct binding to tropoelastin and lysyl oxidase like Loxl1, Loxl2 and Loxl4 (Yanagisawa et al., 2009). In addition, Fibulin-5 binds cell surface α4β1 and α5β1 integrins, but does not support receptor activation (Lomas et al., 2007). Additionally, Fibulin-5 competes with fibronectin for integrin binding. This competition serves to reduce fibronectin-mediated integrin-induced reactive oxygen species (ROS) generation (Schluterman et al., 2010). Protein Description Fibulin-5 is a secreted protein belonging to the fibulin family. It contains 448 amino acids with an approximate 66-Kda molecular weight. It is mainly produced and secreted by endothelial cells, smooth muscle cells and fibroblasts (Yanagisawa et al., 2009). It has six calcium-binding epidermal growth factor (cb EGF)-like domains, the first one of which contains a RGD motif responsible for cell surface integrin binding. Expression Mutations The expression of Fibulin-5 is most prominent in embryonic vasculature and neural crest cells and downregulated in most adult organs (Nakamura et al., 1999). Fibulin-5 mRNA is detected mainly in heart, ovary and colon of adult human tissue (Nakamura et al., 1999). However, Fibulin-5 expression can be reactivated upon tissue injury. It is reported that the expression of Fibulin-5 is elevated in human umbilical vein endothelial cells (HUVEC) by hypoxia in a HIF1αdependent mechanism (Guadall et al., 2011). Transforming growth factors β (TGF-β) can also increase the expression of Fibulin-5 in human lung fibroblasts (Kuang et al., 2006). Atlas Genet Cytogenet Oncol Haematol. 2013; 17(12) See table below. Implicated in Bladder cancer Note The expression of Fibulin-5 is downregulated in human bladder carcinoma samples (Hu et al., 2011). Increased proliferation and invasiveness were observed in a bladder cancer cell line with overexpression of Fibulin5 (Hu et al., 2011). 812 FBLN5 (fibulin 5) Wang M, Brekken RA Breast cancer Ovarian cancer Note The role of Fibulin-5 in breast cancer is still controversial. Oncomine database shows the reduction of Fibulin-5 mRNA in breast carcinomas, however, induction of Fibulin-5 expression is detected in breast cancer patient tissue by immunostaining (Lee et al., 2008). In addition, overexpression of Fibulin-5 can enhance tumor growth in an orthotopic mouse model of breast cancer (Lee et al., 2008). Meanwhile, overexpression of Fibulin-5 in breast cancer cells can reduce metastasis to liver and lung (Moller et al., 2011). The discrepancy between these studies could be due to cell line and mouse model differences. Fibulin-5 is also reported to participate in epithelial-mesenchymaltransition (EMT) in breast cancer cell lines in a MMPdependent manner (Lee et al., 2008). However, the mechanism of Fibulin-5 regulation of MMP is unclear. For example, Fibulin-5 has been shown to inhibit and activate MMP9 activity, (Budatha et al., 2011; Lee et al., 2008; Moller et al., 2011). Note The expression level of Fibulin-5 correlates inversely with the severity of disease (Wang et al., 2010). Expression of Fibulin-5 is also remarkably decreased in metastatic sites. Pancreatic cancer Note Fibulin-5 is required for aggressive tumor growth and angiogenesis in a mouse model of pancreatic cancer (Schluterman et al., 2010). Tumor weight and blood vessel density in Fbln5-/- or Fbln5RGE/RGE mice are significantly reduced compared with wildtype mice in subcutaneous and orthotopic models. Increased level of ROS, DNA damage and apoptotic endothelial cells were detected in tumors grown in Fibulin-5 deficient mice. In vitro analysis identified that Fibulin-5 reduces ROS production in a fibronectin and integrin β1-dependent manner (Schluterman et al., 2010). Lung cancer Age-related macular degeneration (AMD) Note Fibulin-5 expression is silenced in multiple lung cancer cell lines and human lung cancer samples by hypermethylation of the promoter region (Yue et al., 2009). Overexpression of Fibulin-5 reduces lung cancer invasion and metastasis through suppression of the MMP-7 expression and ERK phosphorylation (Yue et al., 2009). Atlas Genet Cytogenet Oncol Haematol. 2013; 17(12) Note DNA sequencing revealed 10 distinct heterozygous missense mutations in Fbln5 in 1-2% of AMD patients (Auer-Grumbach et al., 2011; Lotery et al., 2006; Stone et al., 2004). The underlying biochemical basis of two missense mutations, I169T and G267S was further studied by 813 FBLN5 (fibulin 5) Wang M, Brekken RA nuclear magnetic resonance (NMR) and chromophoric calcium chelation experiments. The results show that G267S substitution leads to protein misfolding and inhibition of secretion, but not the I169T substitution (Schneider et al., 2010). Disease Age-related macular degeneration (AMD) is an eye disease affecting the macula and is the main reason for irreversible version loss in elderly people (Lotery et al., 2006). for elder women characterized by loss of pelvic floor support leading to protrusion of pelvic organs like uterus, bladder and vagina. Thoracic aortic aneurysmal disease (TAD) Note The expression of aortic Fibulin-5 is significantly decreased in patients with TAD. The low level of Fibulin-5 strongly correlates with disorganization of elastic fibers, which may contribute to aorta abnormality (Wang et al., 2005). Disease Thoracic aortic aneurysmal disease (TAD) is an aortic disorder characterized by loss of elastin in the wall of aorta (Wang et al., 2005). Charcot-Marie-Tooth disease (CMT) Note Missense mutations of Fbln5 were detected in CMT neuropathy patients (Auer-Grumbach et al., 2011). Disease Charcot-Marie-Tooth disease (CMT) is an autosomal dominantly inherited disorder of peripheral nervous system (Auer-Grumbach et al., 2011). It is characterized by lifelong disabilities because of muscle weakness and loss of touch sensation (Auer-Grumbach et al., 2011). References Nakamura T, Ruiz-Lozano P, Lindner V, Yabe D, Taniwaki M, Furukawa Y, Kobuke K, Tashiro K, Lu Z, Andon NL, Schaub R, Matsumori A, Sasayama S, Chien KR, Honjo T. DANCE, a novel secreted RGD protein expressed in developing, atherosclerotic, and balloon-injured arteries. J Biol Chem. 1999 Aug 6;274(32):22476-83 Cutis laxa Note Mutations in Fbln5 have been identified in hereditary and acquired forms of cutis laxa. Three homozygous mutations (C217R, S227P and R284X) in Fbln5 have been reported in autosomal recessive cutis laxa patients (Claus et al., 2008; Elahi et al., 2006; Loeys et al., 2002). In addition, a heterozygous in-frame tandem duplication of Fbln5 exon 5-8 has been discovered in a sporadic cutis laxa patient (Markova et al., 2003). Mutational analysis also shows that a cutis laxa patient has a heterozygous missense mutation (G202R) in Fbln5 and compound heterozygous mutation in elastin alleles (A55V and G773D) (Hu et al., 2006b). These findings further support that Fibulin-5 is essential for the formation and maturation of the tropoelastin self-aggregation process, which is required for elastic fiber assembly (Hu et al., 2006a). Disease Cutis laxa is a connective tissue disorder characterized by loose and redundant skin and multiple internal organ abnormalities due to fragmentation and paucity of elastic fibers. Loeys B, Van Maldergem L, Mortier G, Coucke P, Gerniers S, Naeyaert JM, De Paepe A. Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum Mol Genet. 2002 Sep 1;11(18):2113-8 Nakamura T, Lozano PR, Ikeda Y, Iwanaga Y, Hinek A, Minamisawa S, Cheng CF, Kobuke K, Dalton N, Takada Y, Tashiro K, Ross Jr J, Honjo T, Chien KR. Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature. 2002 Jan 10;415(6868):171-5 Yanagisawa H, Davis EC, Starcher BC, Ouchi T, Yanagisawa M, Richardson JA, Olson EN. Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature. 2002 Jan 10;415(6868):168-71 Markova D, Zou Y, Ringpfeil F, Sasaki T, Kostka G, Timpl R, Uitto J, Chu ML. Genetic heterogeneity of cutis laxa: a heterozygous tandem duplication within the fibulin-5 (FBLN5) gene. Am J Hum Genet. 2003 Apr;72(4):998-1004 Stone EM, Braun TA, Russell SR, Kuehn MH, Lotery AJ, Moore PA, Eastman CG, Casavant TL, Sheffield VC. Missense variations in the fibulin 5 gene and age-related macular degeneration. N Engl J Med. 2004 Jul 22;351(4):346-53 Wang X, LeMaire SA, Chen L, Carter SA, Shen YH, Gan Y, Bartsch H, Wilks JA, Utama B, Ou H, Thompson RW, Coselli JS, Wang XL. Decreased expression of fibulin-5 correlates with reduced elastin in thoracic aortic dissection. Surgery. 2005 Aug;138(2):352-9 Pelvic organ prolapse (POP) Note Lower level expression of Fibulin-5 was identified in patients with POP (Soderberg et al., 2009; Takacs et al., 2009). It is reported that Fibulin-5 can prevent the development of POP by regulating elastic fiber homeostasis and inactivating MMP-9 in the vaginal wall (Budatha et al., 2011). Disease Pelvic organ prolapse (POP) is a common disease Atlas Genet Cytogenet Oncol Haematol. 2013; 17(12) Elahi E, Kalhor R, Banihosseini SS, Torabi N, Pour-Jafari H, Houshmand M, Amini SS, Ramezani A, Loeys B. Homozygous missense mutation in fibulin-5 in an Iranian autosomal recessive cutis laxa pedigree and associated haplotype. J Invest Dermatol. 2006 Jul;126(7):1506-9 Hu Q, Loeys BL, Coucke PJ, De Paepe A, Mecham RP, Choi J, Davis EC, Urban Z. Fibulin-5 mutations: mechanisms of impaired elastic fiber formation in recessive cutis laxa. Hum Mol Genet. 2006a Dec 1;15(23):3379-86 Hu Q, Reymond JL, Pinel N, Zabot MT, Urban Z. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated 814 FBLN5 (fibulin 5) Wang M, Brekken RA with missense alleles in the elastin and fibulin-5 genes. J Invest Dermatol. 2006b Feb;126(2):283-90 inhibiting matrix metalloproteinase-7 expression. Cancer Res. 2009 Aug 1;69(15):6339-46 Kuang PP, Joyce-Brady M, Zhang XH, Jean JC, Goldstein RH. Fibulin-5 gene expression in human lung fibroblasts is regulated by TGF-beta and phosphatidylinositol 3-kinase activity. Am J Physiol Cell Physiol. 2006 Dec;291(6):C1412-21 Schluterman MK, Chapman SL, Korpanty G, Ozumi K, Fukai T, Yanagisawa H, Brekken RA. Loss of fibulin-5 binding to beta1 integrins inhibits tumor growth by increasing the level of ROS. Dis Model Mech. 2010 May-Jun;3(5-6):333-42 Lotery AJ, Baas D, Ridley C, Jones RP, Klaver CC, Stone E, Nakamura T, Luff A, Griffiths H, Wang T, Bergen AA, Trump D. Reduced secretion of fibulin 5 in age-related macular degeneration and cutis laxa. Hum Mutat. 2006 Jun;27(6):56874 Schneider R, Jensen SA, Whiteman P, McCullagh JS, Redfield C, Handford PA. Biophysical characterisation of fibulin-5 proteins associated with disease. J Mol Biol. 2010 Aug 27;401(4):605-17 Wang Q, Li XG, Zhang Y, Cao LQ, Deng ZH, Chen Y. [Expression of EVEC in ovarian carcinoma and its biological significance]. Zhonghua Zhong Liu Za Zhi. 2010 Sep;32(9):676-80 Hirai M, Ohbayashi T, Horiguchi M, Okawa K, Hagiwara A, Chien KR, Kita T, Nakamura T. Fibulin-5/DANCE has an elastogenic organizer activity that is abrogated by proteolytic cleavage in vivo. J Cell Biol. 2007 Mar 26;176(7):1061-71 Auer-Grumbach M, Weger M, Fink-Puches R, Papić L, Fröhlich E, Auer-Grumbach P, El Shabrawi-Caelen L, Schabhüttl M, Windpassinger C, Senderek J, Budka H, Trajanoski S, Janecke AR, Haas A, Metze D, Pieber TR, Guelly C. Fibulin-5 mutations link inherited neuropathies, age-related macular degeneration and hyperelastic skin. Brain. 2011 Jun;134(Pt 6):1839-52 Lomas AC, Mellody KT, Freeman LJ, Bax DV, Shuttleworth CA, Kielty CM. Fibulin-5 binds human smooth-muscle cells through alpha5beta1 and alpha4beta1 integrins, but does not support receptor activation. Biochem J. 2007 Aug 1;405(3):417-28 Zheng Q, Davis EC, Richardson JA, Starcher BC, Li T, Gerard RD, Yanagisawa H. Molecular analysis of fibulin-5 function during de novo synthesis of elastic fibers. Mol Cell Biol. 2007 Feb;27(3):1083-95 Budatha M, Roshanravan S, Zheng Q, Weislander C, Chapman SL, Davis EC, Starcher B, Word RA, Yanagisawa H. Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans. J Clin Invest. 2011 May;121(5):2048-59 Claus S, Fischer J, Mégarbané H, Mégarbané A, Jobard F, Debret R, Peyrol S, Saker S, Devillers M, Sommer P, Damour O. A p.C217R mutation in fibulin-5 from cutis laxa patients is associated with incomplete extracellular matrix formation in a skin equivalent model. J Invest Dermatol. 2008 Jun;128(6):1442-50 Guadall A, Orriols M, Rodríguez-Calvo R, Calvayrac O, Crespo J, Aledo R, Martínez-González J, Rodríguez C. Fibulin-5 is upregulated by hypoxia in endothelial cells through a hypoxiainducible factor-1 (HIF-1α)-dependent mechanism. J Biol Chem. 2011 Mar 4;286(9):7093-103 Lee YH, Albig AR, Regner M, Schiemann BJ, Schiemann WP. Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF-beta in mammary epithelial cells via a MMP-dependent mechanism. Carcinogenesis. 2008 Dec;29(12):2243-51 Hu Z, Ai Q, Xu H, Ma X, Li HZ, Shi TP, Wang C, Gong DJ, Zhang X. Fibulin-5 is down-regulated in urothelial carcinoma of bladder and inhibits growth and invasion of human bladder cancer cell line 5637. Urol Oncol. 2011 Jul-Aug;29(4):430-5 Söderberg MW, Byström B, Kalamajski S, Malmström A, Ekman-Ordeberg G. Gene expressions of small leucine-rich repeat proteoglycans and fibulin-5 are decreased in pelvic organ prolapse. Mol Hum Reprod. 2009 Apr;15(4):251-7 Møller HD, Ralfkjær U, Cremers N, Frankel M, Pedersen RT, Klingelhöfer J, Yanagisawa H, Grigorian M, Guldberg P, Sleeman J, Lukanidin E, Ambartsumian N. Role of fibulin-5 in metastatic organ colonization. Mol Cancer Res. 2011 May;9(5):553-63 Takacs P, Nassiri M, Viciana A, Candiotti K, Fornoni A, Medina CA. Fibulin-5 expression is decreased in women with anterior vaginal wall prolapse. Int Urogynecol J Pelvic Floor Dysfunct. 2009 Feb;20(2):207-11 This article should be referenced as such: Wang M, Brekken RA. FBLN5 (fibulin 5). Atlas Genet Cytogenet Oncol Haematol. 2013; 17(12):811-815. Yue W, Sun Q, Landreneau R, Wu C, Siegfried JM, Yu J, Zhang L. Fibulin-5 suppresses lung cancer invasion by Atlas Genet Cytogenet Oncol Haematol. 2013; 17(12) 815