FBLN1 (fibulin 1)

2012-05-01   Lorenzo Castagnoli , Elda Tagliabue , Serenella M Pupa 

Fondazione IRCCS Istituto Nazionale Dei Tumori - Molecular Targeting Unit, Dept of Experimental Oncology, Molecular Medicine, Via Amadeo 42, Milan, Italy

Identity

HGNC
LOCATION
22q13.31
IMAGE
Atlas Image
LOCUSID
ALIAS
FBLN,FIBL1
FUSION GENES

DNA/RNA

Atlas Image
Transcription factor.

Description

Sequence length: 97,71 Kb, 20 exons, max. exon length 818, min. exon length: 50. Number of SNPs: 1038. Four splice variants have been identified which differ in the 3 end and encode different isoforms (A, B, C and D) (Pan et al., 1999).
Variant D: This variant is considered the canonic transcript form: 2947 bp;
- Including exons 18, 19 and 20;
- Lacking exons 15 and 16.
Variant B: 2530 bp;
- Including exon 17;
- Lacking exons 16,18, 19 and 20.
Variant A: 2350bp;
- Including exon 15;
- Lackings exons 16 to 20.
Variant C: 2313bp;
- Including exon 16;
- Lacking exons 15 and 17 to 20.

Proteins

Note

Name: Fibulin-1.
Atlas Image

Description

PositionLengthDescription
36-7641Anaphylatoxin-like 1
77-11135Anaphylatoxin-like 2
112-14433Anaphylatoxin-like 3
176-21540EGF-like 1
216-26146EGF-like 2; calcium-binding
262-30746EGF-like 3; calcium-binding
308-35548EGF-like 4; calcium-binding
356-39843EGF-like 5; calcium-binding
399-44042EGF-like 6; calcium-binding
441-48040EGF-like 7; calcium-binding
481-52444EGF-like 8; calcium-binding
525-57854EGF-like 9; calcium-binding

Glycosylation98; 535; 539
Disulfide bond36↔61; 37↔68; 50↔69; 78↔109; 91↔110; 112↔136; 113↔143; 126↔144; 180↔190; 186↔199; 201↔214; 220↔233; 227↔242; 248↔260; 266↔279; 273↔288; 294↔306; 312↔325; 319↔334; 341↔354; 360↔373; 367↔382; 384↔397; 403↔415; 411↔424; 426↔439; 445↔454; 450↔463; 465↔479; 485↔498; 494↔507; 509↔523; 529↔542; 536↔551; 556↔577
Amino acid modifications (UNIPROT)

Fibulin-1 homomultimerizes and interacts with various ECM components such as fibronectin (FN) (Balbona et al., 1992), laminin subunits alpha-1 and alpha-2 (LAMA1 and LAMA2), nidogen (NID), Aggrecan core protein (ACAN), versican core protein (CSPG2) and type IV collagen proteins (Timpl et al., 2003). Fibulin-1 also interacts with amyloid beta A4 (APP) (Ohsawa et al., 2001), insulin-like growth factor-binding protein 9 (NOV) (Perbal et al., 1999), fibrinogen (FGB) (Tran et al., 1995), and human papillomavirus (HPV) type 16, 18, 31 proteins (Du et al., 2002).

Atlas Image

Localisation

Secreted, extracellular space, extracellular matrix.

Function

Fibulin-1 is incorporated into FN-containing matrix fibers. It plays a role in cell adhesion and migration along protein fibers within the ECM and is important for certain developmental processes. Fibulin-1 contributes to the supramolecular organization of ECM architecture, in particular to that of the basement membrane. It is implicated in cellular transformation and tumor invasion, and can behave both as an oncosuppressor and oncogene depending on tissue environment. It also plays a role in hemostasis and thrombosis owing to its ability to bind fibrinogen and incorporate into clots and plays a significant role in modulating the neurotrophic activities of APP, particularly soluble APP (Timpl et al., 2003).

Homology

Paralogs: Latent-transforming growth factor beta-binding protein 1 (LTBP1), LTBP2, LTBP3, LTBP4, fibrillin-1 (FBN1), FBN2, FBN3, FBLN5, fibulin-2 (FBLN2), epidermal growth factor-like protein 6 (EGFL6), nephronectin (NPNT), EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2), Von Willebrand factor C (VWCE).

Mutations

Note

- Location: exon 19 (acceptor splice site)
- Substitution: G-A
- Phenotype: Bernard-Soulier syndrome
Atlas Image

Implicated in

Entity name
Epithelial cancers
Entity name
Various cancers
Note
Several studies have reported that fibulin-1 is overexpressed in various human neoplasias and it is implicated in processes such as invasion, motility, and in vivo tumor growth (Du et al., 2002; Greene et al., 2003; Moll et al., 2002; Qing et al., 1997; Twal et al., 2001). Fibulin-1 inhibits in vitro adhesion and motility of various carcinoma cell lines (Twal et al., 2001).
Entity name
Breast cancer
Prognosis
Fibulin-1 was found aberrantly expressed in ~35% of 528 human primary breast cancers. Its expression is associated with improved survival in patients with lymphoid infiltrate at the tumor site (Pupa et al., 2004), suggesting a possible involvement in triggering a protective antitumor immune response. Fibulin-1 induces specific B- and T-cell-mediated responses in breast cancer patients (Forti et al., 2002; Pupa et al., 2004). Its overexpression can serve as a tool for early detection of breast cancer (Pupa et al., 2002) and acts to promote breast cancer cell survival during doxorubicin treatment (Pupa et al., 2007). In a series of 36 primary breast carcinomas, the expression of mature fibulin-1 polypeptide (100 kDa) did not correlate with estrogen receptor-alpha (ERα) or progesterone receptor (PR) levels, whereas a positive correlation was found between fibulin-1 processing (50 kDa fragment) and ERα and PR protein levels (Greene et al., 2003).
Entity name
Ovarian cancer
Disease
The molecular mechanisms involved in ovarian carcinogenesis remain unclear, but growing evidence indicates that estrogens promote progression of ovarian cancer and increase expression levels of some secreted proteins. Differential overexpression of ERα versus -ERβ has been demonstrated during ovarian carcinogenesis (Clinton et al., 1996; Moll et al., 2002), suggesting that estrogen-induced proteins, including fibulin-1, may act as ovarian tumor-promoting agents. In ovarian tissues and cancer cell lines, fibulin-1C and -1D are the predominant forms, whereas fibulin-1A and -1B are weakly expressed. An increased fibulin-1C:-1D mRNA ratio in ovarian cancer cells as compared to that in normal ovaries has been observed, suggesting that the C variant is the main one involved in ovarian carcinogenesis. Fibulin-1C overexpression might provide a clue in understanding the putative role of estrogens in ERα-promoted ovarian tumor progression (Moll et al., 2002). In addition, quantitative proteomic analysis integrated with microarray data reveals that fibulin-1 is one of the ECM-related molecules important for chemotherapy response (Pan et al., 2009).
Entity name
Hypermethylation of fibulin-1 gene in epithelial cancers
Note
It has been previously reported both in gastric and prostate cancer models that Fibulin-1 acts as a tumor suppressor gene and is regulated by promoter hypermethylation (Cheng et al., 2008; Wlazlinski et al., 2007). Very recently, also in hepatocellular carcinoma (HCC) model, a downmodulation of fibulin-1 expression caused by its promoter hypermethylation has been proposed as a marker of HCC progression (Kanda et al., 2011).
Entity name
Mesenchymal cancers
Entity name
Disease
Recently, a distinct gene expression pattern of osteoblastic and non osteoblastic osteosarcoma groups has been proposed. In particular, they found significantly modulated the expression of several genes involved in the formation of extracellular matrix, including fibulin-1, already known to be involved in cell morphology modulation, growth and invasion of sarcoma cells (Qing et al., 1997) and suggest that fibulin-1 could be exploited as potential therapeutic target in the future (Kubista et al., 2011).
Entity name
Hematological cancers
Entity name
Lymphoma
Disease
Using a chemical proteomic approach in Hodgkin Lymphoma (HL), Kischel and coauthors identified several extracellular matrix proteins, including fibulin-1, overexpressed in HL (Kischel et al., 2011). Based on its high expression levels in HL biopsy samples fibulin-1 has been suggested as a potential targets for HL immunotherapy.
Entity name
Synpolydactyly
Disease
Synpolydactyly is a rare genetic disorder characterized by malformations in the hands and feet, with abnormalities including increased finger and toe numbers and fusion of digits into a single digit. Molecular analysis of the reciprocal chromosomal translocation t(12;22)(p11.2;q13.3) cosegregating with a complex type of synpolydactyly indicated involvement of an alternatively spliced exon of the fibulin-1 gene (FBLN1 located in 22q13.3). Investigation of the possible functional involvement of the fibulin-1 protein in the observed phenotype showed that fibulin-1 is expressed in the ECM in association with the digits in the developing limb (Debeer et al., 2002). Thus, t(12;22) might result in haplo-insufficiency of the fibulin-1D variant, leading to the observed limb malformations.
Entity name
Bernard-Soulier syndrome
Disease
Bernard-Soulier syndrome is an autosomic-dominant disease that causes alterations of the megakaryocyte/platelet lineage and is characterized by bleeding tendency, giant blood platelets and low platelet counts. An unexpected mutation in the splice acceptor site of fibulin-1 exon 19 was found in affected individuals of the Israeli Fechtner family. In all affected individuals from eight families, expression of fibulin-1 variant D was inhibited by putative antisense RNA (Lanza, 2006), raising the possibility that these autosomal-dominant giant platelet syndromes are associated with aberrant antisense gene regulation of fibulin-1.
Entity name
Placenta dysplasia
Disease
Placental dysplasia is a rare human placental disorder in which the placenta is enlarged and contains cystic villi and dilated vasculature. A significant correlation was observed between fibulin-1 gene overexpression and murine placental overgrowth (Singh et al., 2006), suggesting that the gene and its product have a functional role in placenta development.
Entity name
Morphogenesis of neural crest-derived structures
Disease
A significant negative correlation between fibulin-1 gene expression and some morphogenic anomalies of neural crest-derived structures in mice has been reported (Cooley et al., 2008). Such fibulin-1-deficient mice exhibit cardiac ventricular wall thinning and ventricular septal defects, with double outlet right ventricle or overriding aorta, as well as aortic arch arteries anomalies, hypoplasia of the thymus and thyroid, underdeveloped skull bones, malformations of cranial nerves and hemorrhagic blood vessels in the head and neck. The spectrum of malformations is consistent with a role for fibulin-1 in neural crest cell-dependent development of these tissues.
Entity name
Acute aortic dissection
Disease
Acute aortic dissection (AAD) is a tear in the wall of the aorta that causes blood to flow between the layers of the wall of the aorta and force the layers apart. AAD is a life-threatening condition with high mortality and a mostly unclear pathophysiological mechanism. Downregulation of fibulin-1 noted in AAD compared to control samples might determine a weakening of ECM in the aorta and/or interfere with the transmission of cellular signals causing AAD (Mohamed et al., 2009).
Entity name
Atherosclerotic lesions
Disease
Fibulin-1 deposits were found in association with fibrinogen in atherosclerotic lesions and in regions containing fresh thrombi. By contrast, fibulin-1 was not detected in sclerotic regions and low levels were associated with smooth muscle cells within and outside lesions (Argraves et al., 2009). Further, an accumulation of fibulin-1 deposits were found in the arterial wall and in plasma of patients with type 2 diabetes and appears to be a factor associated with arterial extracellular matrix alterations (Cangemi et al., 2011).
Entity name
Thrombosis
Disease
Thrombosis, the formation of a blood clot (thrombus) inside a blood vessel, obstructs blood flow through the circulatory system. Analyses of blood plasma revealed an interaction between fibulin-1 and fibrinogen (Tran et al., 1995), pointing to potential new roles for fibulin-1 in hemostasis as well as thrombosis.
Entity name
Infection disease
Note
Streptococcus Pyogenes, which belongs to the group A of streptococcus, has been found to interact with the host fibulin 1 through its major serum opacity factor (SOF) receptor that is a major fibronectin binding protein involved in adhesion to host cells. The SOF-fibulin-1 interaction can lead to initial bacterial adhesion (Courtney et al., 2009).

Breakpoints

Note

Phenotype: Synpolydactyly
Analysis of a Belgian family with a complex type of synpolydactyly (SPD2) and a t(12;22)(p11.2;q13.3) translocation identified the breakpoints located in the intron between the last 2 exons of the fibulin-1D splice variant isoform (exons 19, 20) and the 5 UTR of the C12ORF2 gene. Fibroblasts derived from the patients displayed decreased levels of ECM-related fibulin-1D secreted into the culture medium, whereas levels of the fibulin-1C variant were normal. The findings are consistent with the notion that the t(12;22)(p11.2;q13.3) translocation results in haplo-insufficiency of the fibulin-1D variant, leading to the observed limb malformations. The authors noted that the entire fibulin-1 gene is deleted in the chromosome 22q13.3 deletion syndrome (Debeer et al 2002).

Bibliography

Pubmed IDLast YearTitleAuthors
196935312009Fibulin-1 and fibrinogen in human atherosclerotic lesions.Argraves WS et al
219261802011Fibulin-1 is a marker for arterial extracellular matrix alterations in type 2 diabetes.Cangemi C et al
189850392008Fibulin 1 is downregulated through promoter hypermethylation in gastric cancer.Cheng YY et al
85526291996Estrogens increase the expression of fibulin-1, an extracellular matrix protein secreted by human ovarian cancer cells.Clinton GM et al
185387582008Fibulin-1 is required for morphogenesis of neural crest-derived structures.Cooley MA et al
192760782009Serum opacity factor is a streptococcal receptor for the extracellular matrix protein fibulin-1.Courtney HS et al
118363572002The fibulin-1 gene (FBLN1) is disrupted in a t(12;22) associated with a complex type of synpolydactyly.Debeer P et al
122001422002Interaction of oncogenic papillomavirus E6 proteins with fibulin-1.Du M et al
121603302002Identification of breast cancer-restricted antigens by antibody screening of SKBR3 cDNA library using a preselected patient's serum.Forti S et al
126448242003Elevated expression and altered processing of fibulin-1 protein in human breast cancer.Greene LM et al
212681322011Promoter hypermethylation of fibulin 1 gene is associated with tumor progression in hepatocellular carcinoma.Kanda M et al
219752232011Identification of stromal proteins overexpressed in nodular sclerosis Hodgkin lymphoma.Kischel P et al
203400162011Microarray analysis identifies distinct gene expression profiles associated with histological subtype in human osteosarcoma.Kubista B et al
171097442006Bernard-Soulier syndrome (hemorrhagiparous thrombocytic dystrophy).Lanza F et al
196527642009Pathway analysis of differentially expressed genes in patients with acute aortic dissection.Mohamed SA et al
118508272002Estrogen induction and overexpression of fibulin-1C mRNA in ovarian cancer cells.Moll F et al
112387262001Fibulin-1 binds the amino-terminal head of beta-amyloid precursor protein and modulates its physiological function.Ohsawa I et al
194223012009Quantitative proteomics analysis integrated with microarray data reveals that extracellular matrix proteins, catenins, and p53 binding protein 1 are important for chemotherapy response in ovarian cancers.Pan S et al
100371441999Complete exon-intron organization of the mouse fibulin-1 gene and its comparison with the human fibulin-1 gene.Pan TC et al
99276601999The C-terminal domain of the regulatory protein NOVH is sufficient to promote interaction with fibulin 1C: a clue for a role of NOVH in cell-adhesion signaling.Perbal B et al
146914542004Immunological and pathobiological roles of fibulin-1 in breast cancer.Pupa SM et al
119964832002Humoral immune response for early diagnosis of breast carcinoma.Pupa SM et al
174833392007Regulation of breast cancer response to chemotherapy by fibulin-1.Pupa SM et al
93939741997Suppression of anchorage-independent growth and matrigel invasion and delayed tumor formation by elevated expression of fibulin-1D in human fibrosarcoma-derived cell lines.Qing J et al
163380032006Expression and functional analysis of fibulin-1 (Fbln1) during normal and abnormal placental development of the mouse.Singh U et al
127781272003Fibulins: a versatile family of extracellular matrix proteins.Timpl R et al
76426291995The interaction of fibulin-1 with fibrinogen. A potential role in hemostasis and thrombosis.Tran H et al
117928232001Fibulin-1 suppression of fibronectin-regulated cell adhesion and motility.Twal WO et al
179292692007Downregulation of several fibulin genes in prostate cancer.Wlazlinski A et al
191890512009Fibulins: multiple roles in matrix structures and tissue functions.de Vega S et al

Other Information

Locus ID:

NCBI: 2192
MIM: 135820
HGNC: 3600
Ensembl: ENSG00000077942

Variants:

dbSNP: 2192
ClinVar: 2192
TCGA: ENSG00000077942
COSMIC: FBLN1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000077942ENST00000262722P23142
ENSG00000077942ENST00000327858P23142
ENSG00000077942ENST00000340923P23142
ENSG00000077942ENST00000402984B1AHL2
ENSG00000077942ENST00000411478B1AHM9
ENSG00000077942ENST00000437711H7C1M6
ENSG00000077942ENST00000439835B1AHM5
ENSG00000077942ENST00000442170P23142
ENSG00000077942ENST00000445110B1AHM6
ENSG00000077942ENST00000451475B1AHM8
ENSG00000077942ENST00000454279B1AHM7
ENSG00000077942ENST00000455233B1AHN3
ENSG00000077942ENST00000460300A0A0U1RRA4

Expression (GTEx)

0
100
200
300
400
500
600
700
800
900

Pathways

PathwaySourceExternal ID
Extracellular matrix organizationREACTOMER-HSA-1474244
Elastic fibre formationREACTOMER-HSA-1566948
Molecules associated with elastic fibresREACTOMER-HSA-2129379

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
160614712005Fibulin-1 acts as a cofactor for the matrix metalloprotease ADAMTS-1.42
117928232001Fibulin-1 suppression of fibronectin-regulated cell adhesion and motility.40
212681322011Promoter hypermethylation of fibulin 1 gene is associated with tumor progression in hepatocellular carcinoma.33
118363572002The fibulin-1 gene (FBLN1) is disrupted in a t(12;22) associated with a complex type of synpolydactyly.27
189850392008Fibulin 1 is downregulated through promoter hypermethylation in gastric cancer.26
170626662006GROalpha is highly expressed in adenocarcinoma of the colon and down-regulates fibulin-1.25
182229702008Basement membrane derived fibulin-1 and fibulin-5 function as angiogenesis inhibitors and suppress tumor growth.25
126448242003Elevated expression and altered processing of fibulin-1 protein in human breast cancer.21
200986152010Application of gene network analysis techniques identifies AXIN1/PDIA2 and endoglin haplotypes associated with bicuspid aortic valve.20

Citation

Lorenzo Castagnoli ; Elda Tagliabue ; Serenella M Pupa

FBLN1 (fibulin 1)

Atlas Genet Cytogenet Oncol Haematol. 2012-05-01

Online version: http://atlasgeneticsoncology.org/gene/44462/fbln1

Historical Card

2010-09-01 FBLN1 (fibulin 1) by  Lorenzo Castagnoli,Elda Tagliabue,Serenella M Pupa 

Fondazione IRCCS Istituto Nazionale Dei Tumori - Molecular Targeting Unit, Dept of Experimental Oncology, Molecular Medicine, Via Amadeo 42, Milan, Italy