* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Gene Section FRZB (frizzled related protein) -
Epigenetics of human development wikipedia , lookup
Point mutation wikipedia , lookup
Site-specific recombinase technology wikipedia , lookup
Gene expression programming wikipedia , lookup
Designer baby wikipedia , lookup
Public health genomics wikipedia , lookup
Protein moonlighting wikipedia , lookup
Gene expression profiling wikipedia , lookup
Cancer epigenetics wikipedia , lookup
Wnt signaling pathway wikipedia , lookup
Gene therapy of the human retina wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
Vectors in gene therapy wikipedia , lookup
Therapeutic gene modulation wikipedia , lookup
Genome (book) wikipedia , lookup
Polycomb Group Proteins and Cancer wikipedia , lookup
Oncogenomics wikipedia , lookup
Nutriepigenomics wikipedia , lookup
Mir-92 microRNA precursor family wikipedia , lookup
Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST-CNRS OPEN ACCESS JOURNAL Gene Section Review FRZB (frizzled-related protein) Sarah Thysen, Rik Lories Laboratory for Skeletal Development and Joint Disorders, Department of Development and Regeneration, KU Leuven, Belgium (ST, RL) Published in Atlas Database: June 2012 Online updated version : http://AtlasGeneticsOncology.org/Genes/FRZBID44457ch2q32.html DOI: 10.4267/2042/48464 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 a molecular weight of 36 kDa. FRZB is a member of the secreted frizzled related protein (SFRP) family, of which five members (SFRP1 to SFRP5) are known within the human genome. SFRPs fold into two independent domains, the cysteine-rich domain (CRD) and the Netrin-like domain (NTN). The CRD domain shares sequence homology with the extracellular portion of the WNT receptor Frizzled (Fz). Therefore, the CRD domain is considered the WNT binding domain. The NTN domain contains six cysteine residues that most likely form three disulfide bridges and NTN domains with similar features are found in several unrelated proteins, including Netrin-1, tissue inhibitors of metallo-proteinases (TIMPs), complement proteins and type I procollagen C-proteinase enhancer proteins (PCOLCEs). The overall function of the NTN domain is unknown. However, one study demonstrated that both domains are necessary for optimal WNT inhibition (Jones et al., 2002; Bath et al., 2007). Identity Other names: FRE, FRITZ, FRP-3, FRP, FRZB-1, FRZB-PEN, FRZB1, FZRB, OS1, SFRP3, hFIZ HGNC (Hugo): FRZB Location: 2q32.1 DNA/RNA Description Genomic size: 40762 bp, encoded by 6 exons. Transcription Transcript length: 3162 bp; mRNA: 978 bp. Pseudogene Human FRZB has only 1 known transcript. Protein Description FRZB protein is comprised of 325 amino acids with The FRZB gene (40762 bp) contains a total of 6 exons and the FRZB transcript is 978 bp. Atlas Genet Cytogenet Oncol Haematol. 2013; 17(1) 8 FRZB (frizzled-related protein) Thysen S, Lories R Structure of FRZB. FRZB contains a cysteine-rich domain (CRD) and a Netrin-like (NTN) domain. It is hypothesised that the antagonistic effects of FRZB can be explained by the binding of WNTs to the CRD domain. were found to be associated to knee, hip, generalized and radiographic osteoarthritis (Loughlin et al., 2004; Min et al., 2005; Lories et al., 2005; Lane et al., 2006; Valdes et al., 2007). However, the results from a recent meta-analysis showing no overall effect of FRZB genetic variants on hip or knee OA debated this association (Evangelou et al., 2009). Expression SFRP3 (FRZB) was originally isolated from bovine articular cartilage. During human embryonic and fetal development FRZB is primarily expressed in cartilaginous cores of developing long bones (Hoang et al., 1996). In the early mouse embryo, mFrzb-1 is expressed in the primitive streak, presomitic mesoderm, somites, and brain. Later, mFrzb-1 exhibits sharp boundaries of expression in the limb bud, branchial arches, facial mesenchyme, and in cartilaginous elements of the appendicular skeleton (Hoang et al., 1998). Implicated in Osteoarthritis Note Osteoarthritis is a chronic degenerative joint disease without underlying autoimmune or autoinflammatory mechanisms. The disease leads to pain and disability and affects millions of people worldwide. Although once considered as a disease of the articular cartilage, the current concept holds that the whole joint is involved, including the subchondral bone, menisci, ligaments, periarticular muscle, capsule and synovium. Osteoarthritis is a complex disorder to which both genetic and acquired factors contribute (Hunter et al., 2006). Polymorphisms in FRZB (Arg200Trp and Arg324Gly) have been associated with osteoarthritis (Loughlin et al., 2004; Min et al., 2005; Lories et al., 2005; Lane et al., 2006; Valdes et al., 2007). However, the results from a recent meta-analysis showing no overall effect of FRZB genetic variants on hip or knee OA debated this association (Evangelou et al., 2009). Recently, a transcriptomics analysis in Frzb-/- mice provided evidence for a tight regulation of WNT signalling and highlighted the complex role for FRZB in joint homeostasis (Lodewyckx et al., 2012). Moreover, Frzb-/- mice show increased cartilage damage when challenged by different models of acute and short-term joint, suggesting a role for FRZB in osteoarthritis. The observed cartilage damage was associated with increased WNT signalling and matrix metalloproteinase 3 (MMP-3) expression and activity. Localisation Extracellular space, bound to plasma membrane. Function FRZB is involved in the WNT/beta-catenin signalling pathway by acting as an inhibitor by binding to WNT ligands. However, recent studies indicate that SFRPs can modulate WNT signalling and are able to interact with molecules that are unrelated to the WNT signalling cascades and among which there is no apparent relationship (Bovolenta et al., 2008). Homology FRZB is a member of the secreted frizzled related protein (SFRP) family (SFRP1-5). Based on their amino acid sequence homology, they are divided into a subgroup consisting of SFRP1, SFRP2 and SFRP5 and a subgroup comprising SFRP3 (FRZB) and SFRP4. SFRPs contain a CRD domain that shares sequence homology with the extracellular portion of the WNT receptor Frizzled (Fz) (Jones et al., 2005). Mutations Germinal The only clinically associated variants of FRZB are Arg200Trp (exon 4) and Arg324Gly (exon 6). Both of them are substitutions for a conserved arginine residue. One or two FRZB SNPs or a haplotype containing both Atlas Genet Cytogenet Oncol Haematol. 2013; 17(1) 9 FRZB (frizzled-related protein) Thysen S, Lories R Additionally, Frzb-/- mice have increased cortical bone thickness and density without changes in the trabecular bone (Lories et al., 2007). Cytogenetics The haplotype coding for substitutions of two highly conserved arginine residues (Arg200Trp and Arg324Gly) in FRZB are associated with hip osteoarthritis in females. Moreover, transfection studies indicated that substitutions of these positively charged residues reduced the ability of FRZB to inhibit WNT signalling (Loughlin et al., 2004). Additionally, an association analysis confirmed that the R324G variant of the FRZB gene is involved in osteoarthritis and indicates a role of this variant in several generalized OA phenotypes (Min et al., 2005). Next, evidence was found for a differential association of the FRZB Arg200Trp polymorphism with hip osteoarthritis and osteoporosis (Lories et al., 2005). Lane et al. confirmed the earlier finding that a rare haplotype with both Arg200Trp and Arg324Gly FRZB variants contributes to hip osteoarthritis in women. Further, an association of genetic polymorphisms of FRZB and knee osteoarthritis was found (Valdes et al., 2007). In contrast, Rodriguez-Lopez et al. could not find an association of FRZB polymorphisms with either generalised osteoarthritis or hip OA. But, their results suggest that the Arg324Gly SNP may have an effect in the development of osteoarthritis in multiple joints. Furthermore, a large-scale meta-analysis of individuallevel data does not support the association of SNPs of FRZB with osteoarthritis (Evangelou et al., 2009). Osteogenic sarcoma Note Micro-array analysis shows that FRZB has virtually no mRNA expression in osteogenic sarcoma-derived specimens compared to control (Mandal et al., 2007). Breast cancer Note Expression of FRZB is turned off in breast carcinomas (versus normal breasts). These results suggest that FRZB is a candidate gene for malignancies (Ugolini et al., 1999). Renal cancer Note A kidney tissue microarray and analysis of FRZB overexpression in a renal cancer cell line shows that sFRP3 expression promotes cell growth, invasion, and inhibition of apoptosis in renal cancer cells (Hirata et al., 2010). Bladder cancer Note Methylation of HOXB2, KRT13 and FRZB are associated with aggressive invasive bladder cancer (Marsit et al., 2010). Malignant pleural mesothelioma Note The transcription of the SFRP family is frequently down-regulated in human malignant pleural mesothelioma (Lee et al., 2004). Colorectal cancer Soft tissue sarcomas Note The functional genetic variant Arg324Gly of FRZB was shown to be associated with colorectal cancer risk (Shanmugam et al., 2007). However, Berndt et al. observed no association for either polymorphisms (Arg324Gly and Arg200Trp) or any haplotypes with colorectal adenoma or colorectal cancer. Note FRZB overexpression in fibrosarcoma and liposarcoma cell lines reduces cell motility, invasiveness and tumorigenesis. These results implicate an important tumor suppressive function for FRZB in sarcomas (Guo et al., 2008). Melanoma Gastric cancer Note FRZB expression is reduced in malignant melanoma tissues and cell lines compared to normal cells and this down-regulation is related to methylation of the FRZB gene. Additionally, recombinant FRZB decreases migration and invasion of melanoma cells (Ekström et al., 2011). Note Overexpression of FRZB in gastric cancer cell suppresses proliferation and modulates the balance between proliferation and differentiation in gastric cancer (Qu et al., 2008c). Additionally, FRZB exhibits anti-tumor ability in gastric cancer cell line SGC-7901 in vitro and in vivo, and decreases the expression of MMP-2, MMP-7 and MMP-9 leading to a reduced invasion ability of the tumor cells (Qu et al., 2008b). References Ugolini F, Adélaïde J, Charafe-Jauffret E, Nguyen C, Jacquemier J, Jordan B, Birnbaum D, Pébusque MJ. Differential expression assay of chromosome arm 8p genes identifies Frizzled-related (FRP1/FRZB) and Fibroblast Growth Factor Receptor 1 (FGFR1) as candidate breast cancer genes. Oncogene. 1999 Mar 11;18(10):1903-10 Prostate cancer Note Ectopic expression of FRZB in an androgenindependent prostate cancer cellular model results in the suppression of tumor growth and cellular invasiveness. This provides evidence that FRZB can act as a tumor suppressor gene (Zi et al., 2005). Atlas Genet Cytogenet Oncol Haematol. 2013; 17(1) Jones SE, Jomary C. Secreted Frizzled-related proteins: searching for relationships and patterns. Bioessays. 2002 Sep;24(9):811-20 10 FRZB (frizzled-related protein) Thysen S, Lories R Lee AY, He B, You L, Dadfarmay S, Xu Z, Mazieres J, Mikami I, McCormick F, Jablons DM. Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma. Oncogene. 2004 Aug 26;23(39):6672-6 Bovolenta P, Esteve P, Ruiz JM, Cisneros E, Lopez-Rios J. Beyond Wnt inhibition: new functions of secreted Frizzledrelated proteins in development and disease. J Cell Sci. 2008 Mar 15;121(Pt 6):737-46 Loughlin J, Dowling B, Chapman K, Marcelline L, Mustafa Z, Southam L, Ferreira A, Ciesielski C, Carson DA, Corr M. Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9757-62 Guo Y, Xie J, Rubin E, Tang YX, Lin F, Zi X, Hoang BH. Frzb, a secreted Wnt antagonist, decreases growth and invasiveness of fibrosarcoma cells associated with inhibition of Met signaling. Cancer Res. 2008 May 1;68(9):3350-60 Qu Y, Cai Q, Li JF, Wang YW, Liu BY, Zhu ZG. [Expression and intracellular localization of FRZB gene in gastric cancer and its significance]. Zhonghua Wei Chang Wai Ke Za Zhi. 2008a Mar;11(2):154-8 Min JL, Meulenbelt I, Riyazi N, Kloppenburg M, HouwingDuistermaat JJ, Seymour AB, Pols HA, van Duijn CM, Slagboom PE. Association of the Frizzled-related protein gene with symptomatic osteoarthritis at multiple sites. Arthritis Rheum. 2005 Apr;52(4):1077-80 Qu Y, Li JF, Cai Q, Liu BY, Zhu ZG. [Effects of FRZB on growth and metastasis of gastric cancer cell line SGC-7901]. Ai Zheng. 2008b Aug;27(8):795-802 Zi X, Guo Y, Simoneau AR, Hope C, Xie J, Holcombe RF, Hoang BH. Expression of Frzb/secreted Frizzled-related protein 3, a secreted Wnt antagonist, in human androgenindependent prostate cancer PC-3 cells suppresses tumor growth and cellular invasiveness. Cancer Res. 2005 Nov 1;65(21):9762-70 Qu Y, Li JF, Cai Q, Wang YW, Gu QL, Zhu ZG, Liu BY. Overexpression of FRZB in gastric cancer cell suppresses proliferation and induces differentiation. J Cancer Res Clin Oncol. 2008c Mar;134(3):353-64 Berndt SI, Huang WY, Yeager M, Weissfeld JL, Chanock SJ, Hayes RB. Genetic variants in frizzled-related protein (FRZB) and the risk of colorectal neoplasia. Cancer Causes Control. 2009 May;20(4):487-90 Hunter DJ, Felson DT. Osteoarthritis. BMJ. 2006 Mar 18;332(7542):639-42 Lane NE, Lian K, Nevitt MC, Zmuda JM, Lui L, Li J, Wang J, Fontecha M, Umblas N, Rosenbach M, de Leon P, Corr M. Frizzled-related protein variants are risk factors for hip osteoarthritis. Arthritis Rheum. 2006 Apr;54(4):1246-54 Evangelou E, Chapman K, Meulenbelt I, Karassa FB, Loughlin J, Carr A, Doherty M, Doherty S, Gómez-Reino JJ, Gonzalez A, Halldorsson BV, Hauksson VB, Hofman A, Hart DJ, Ikegawa S, Ingvarsson T, Jiang Q, Jonsdottir I, Jonsson H, Kerkhof HJ, Kloppenburg M, Lane NE, Li J, Lories RJ, van Meurs JB, Näkki A, Nevitt MC, Rodriguez-Lopez J, Shi D, Slagboom PE, Stefansson K, Tsezou A, Wallis GA, Watson CM, Spector TD, Uitterlinden AG, Valdes AM, Ioannidis JP. Large-scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand. Arthritis Rheum. 2009 Jun;60(6):1710-21 Lories RJ, Boonen S, Peeters J, de Vlam K, Luyten FP. Evidence for a differential association of the Arg200Trp singlenucleotide polymorphism in FRZB with hip osteoarthritis and osteoporosis. Rheumatology (Oxford). 2006 Jan;45(1):113-4 Bhat RA, Stauffer B, Komm BS, Bodine PV. Structure-function analysis of secreted frizzled-related protein-1 for its Wnt antagonist function. J Cell Biochem. 2007 Dec 15;102(6):151928 Hirata H, Hinoda Y, Ueno K, Majid S, Saini S, Dahiya R. Role of secreted frizzled-related protein 3 in human renal cell carcinoma. Cancer Res. 2010 Mar 1;70(5):1896-905 Lories RJ, Peeters J, Bakker A, Tylzanowski P, Derese I, Schrooten J, Thomas JT, Luyten FP. Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. Arthritis Rheum. 2007 Dec;56(12):4095-103 Marsit CJ, Houseman EA, Christensen BC, Gagne L, Wrensch MR, Nelson HH, Wiemels J, Zheng S, Wiencke JK, Andrew AS, Schned AR, Karagas MR, Kelsey KT. Identification of methylated genes associated with aggressive bladder cancer. PLoS One. 2010 Aug 23;5(8):e12334 Mandal D, Srivastava A, Mahlum E, Desai D, Maran A, Yaszemski M, Jalal SM, Gitelis S, Bertoni F, Damron T, Irwin R, O'connor M, Schwartz H, Bolander ME, Sarkar G. Severe suppression of Frzb/sFRP3 transcription in osteogenic sarcoma. Gene. 2007 Jan 15;386(1-2):131-8 Ekström EJ, Sherwood V, Andersson T. Methylation and loss of Secreted Frizzled-Related Protein 3 enhances melanoma cell migration and invasion. PLoS One. 2011 Apr 8;6(4):e18674 Rodriguez-Lopez J, Pombo-Suarez M, Liz M, Gomez-Reino JJ, Gonzalez A. Further evidence of the role of frizzled-related protein gene polymorphisms in osteoarthritis. Ann Rheum Dis. 2007 Aug;66(8):1052-5 Lodewyckx L, Cailotto F, Thysen S, Luyten FP, Lories RJ. Tight regulation of wingless-type signaling in the articular cartilage subchondral bone biomechanical unit: transcriptomics in Frzb-knockout mice. Arthritis Res Ther. 2012 Jan 20;14(1):R16 Shanmugam KS, Brenner H, Hoffmeister M, Chang-Claude J, Burwinkel B. The functional genetic variant Arg324Gly of frizzled-related protein is associated with colorectal cancer risk. Carcinogenesis. 2007 Sep;28(9):1914-7 This article should be referenced as such: Valdes AM, Loughlin J, Oene MV, Chapman K, Surdulescu GL, Doherty M, Spector TD. Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee. Arthritis Rheum. 2007 Jan;56(1):137-46 Atlas Genet Cytogenet Oncol Haematol. 2013; 17(1) Thysen S, Lories R. FRZB (frizzled-related protein). Atlas Genet Cytogenet Oncol Haematol. 2013; 17(1):8-11. 11