Alternative titles; symbols
HGNC Approved Gene Symbol: SFRP1
Cytogenetic location: 8p11.21 Genomic coordinates (GRCh38): 8:41,261,962-41,309,473 (from NCBI)
Members of the 'frizzled' (FZ) transmembrane protein family (see 600667) are receptors for Wnt family members (see 606359), cysteine-rich glycosylated ligands implicated in a variety of cellular processes, including control of cell polarity, cell fate determination, and malignant transformation. See 164975. Finch et al. (1997) determined the partial sequence of a 36-kD heparin-binding protein that copurified with hepatocyte growth factor (142409) in conditioned medium from a human embryonic lung fibroblast cell line. By screening a human embryonic lung fibroblast cDNA library with degenerate oligonucleotide probes derived from the amino acid sequence, the authors isolated cDNAs encoding a predicted 313-amino acid protein. They designated the protein FRP (frizzled-related protein) because it contains a cysteine-rich domain of approximately 110 residues that is 30 to 40% identical to the putative ligand-binding domain of FZ proteins, but lacks the 7-transmembrane motif that anchors FZ proteins to the plasma membrane. Pulse-chase biosynthetic studies indicated that FRP was secreted but, like Wnts, tended to remain associated with cells. When coexpressed with various Wnt family members in early Xenopus embryos, FRP antagonized Wnt-dependent duplication of the embryonic dorsal axis, behaving like a dominant-negative receptor. Finch et al. (1997) suggested that FRP might function as an inhibitor of Wnt action during development and in the adult. Northern blot analysis revealed that the 4.4-kb FRP mRNA is expressed in several human tissues, with the highest levels in heart.
Independently, Melkonyan et al. (1997) isolated cDNAs encoding FRP, which they called SARP2 (secreted apoptosis-related protein-2), and the related proteins SARP1 (SFRP2; 604157) and SARP3 (SFRP5; 604158). They reported that the predicted SARP2 protein contains 314 amino acids. When expressed in a breast adenocarcinoma cell line, mouse SARP1 and human SARP2 exhibited opposite effects on cell sensitivity to proapoptotic stimuli. Whereas cells with SARP1 had higher resistance, cells expressing SARP2 were sensitized to apoptosis induced by tumor necrosis factor (191160) and ceramide. Expression of SARP1 and SARP2 modified the intracellular levels of beta-catenin (116806), an indicator of Wnt-frizzled protein interaction and signal transduction, suggesting that SARPs interfere with the Wnt-frizzled signaling pathway.
Using RT-PCR, Bodine et al. (2004) showed that Sfrp1 mRNA expression in mice was highest in kidney and ovary, intermediate in heart and spleen, low in gut, lung, bone, brain, and skeletal muscle, and absent in liver. They noted that the tissue distribution of SFRP1 in human is similar, except that expression is highest in heart and intermediate in ovary, testis, and kidney.
By analysis of radiation hybrids and by fluorescence in situ hybridization, Finch et al. (1997) mapped the FRP gene to chromosome 8p12-p11.1.
A frequent epigenetic change in cancer involves aberrantly hypermethylated CpG islands in gene promoters, with loss of transcription of the genes (Baylin and Herman, 2000). Cameron et al. (1999) showed that silencing of hypermethylated genes in cancer is dependent on both methylation of dense CpG islands and histone deacetylase (see 601241) activity. Suzuki et al. (2002) used cDNA microarray analysis to screen for genes that are epigenetically silenced in human colorectal cancer. By screening over 10,000 genes, they showed that they could identify a substantial number of genes with promoter hypermethylation in a given cancer; these are distinct from genes with unmethylated promoters, for which increased expression is produced by histone deacetylase inhibition alone. Many of the hypermethylated genes identified have high potential for roles in tumorigenesis by virtue of their predicted function and chromosome position. They also identified a group of genes that are preferentially hypermethylated in colorectal cancer and gastric cancer. One of these genes, SFRP1, belongs to a gene family; Suzuki et al. (2002) showed that hypermethylation of 4 genes in this family occur frequently in colorectal cancer, providing for (i) a unique potential mechanism for loss of tumor suppressor gene function and (ii) construction of a molecular marker panel that could detect virtually all colorectal cancer.
Fukuhara et al. (2002) investigated the expression and function of SFRP1 in uterine leiomyomas. Northern and Western blot analyses detected increased SFRP1 expression in leiomyomas compared with normal myometrium. Expression was strongest in the late follicular phase (high estrogenic milieu) of the menstrual cycle. Interestingly, expression was negligible in leiomyomas treated with GNRH agonist. They authors concluded that strong SFRP1 expression, which appeared to be independent of cell proliferation, under high estrogenic conditions contributes to the development of uterine leiomyomas through the antiapoptotic effect of SFRP1.
Aberrant WNT pathway signaling is an early progression event in 90% of colorectal cancers. It occurs through mutations mainly of APC (611731) and less often of CTNNB1 (encoding beta-catenin) or AXIN2 (encoding axin-2, also known as conductin; 604025). These mutations allow ligand-independent WNT signaling that culminates in abnormal accumulation of free beta-catenin in the nucleus. Suzuki et al. (2004) showed that restoration of SFRP function in colorectal cancer cells attenuates WNT signaling even in the presence of downstream mutations. They also showed that the epigenetic loss of SFRP function occurs early in colorectal cancer progression and may thus provide constitutive WNT signaling that is required to complement downstream mutations in the evolution of colorectal cancer. Taketo (2004) noted that approximately 90% of primary colon cancer tissues showed methylation of SFRP1, whereas only approximately 70% had APC mutations. Notably, methylation of SFRP1, SFRP2, and SFRP5 was also found in approximately 90% of early colonic adenomas. Accordingly, silencing SFRP genes may be one of the earliest events in tumorigenesis. Taketo (2004) suggested that it may be possible to suppress WNT signaling in cancer even when APC or CTNNB1 is mutated.
Rodriguez et al. (2005) found that Sfrp1 directly modified and reoriented the growth of chick and frog ganglion cell axons. The activity did not require Wnt inhibition and was modulated by extracellular matrix molecules. Intracellular Sfrp1 activity required G protein-alpha (see GNAS; 139320) activation, protein synthesis, and degradation, and it was modulated by cyclic nucleotide levels.
Using a quantitative proteomics approach with human fibroblasts, Elzi et al. (2012) detected oversecretion of SFRP1 upon etoposide-induced senescence due to enhanced SFRP1 entry into the secretory pathway. Knockdown of p53 (TP53; 191170) abrogated SFRP1 oversecretion, whereas p53 expression increased it, indicating that etoposide-enhanced SFRP1 secretion is p53 dependent. SFRP1 induced senescence by inhibiting Wnt signaling and RB (RB1; 614041) pathway activation upon etoposide treatment. Cancer-associated SFRP1 mutants were defective for antagonizing Wnt signaling and inducing senescence.
Using Western blot analysis, Matsuyama et al. (2014) showed that Sfrp1 protein was increased in kidney after unilateral ureteral obstruction (UUO) in mice. Loss of Sfrp1 exacerbated progression of renal fibrosis after UUO, and Sfrp1 -/- mice displayed enhanced epithelial-to-mesenchymal transition, indicating that Sfrp1 maintained renal tubular epithelial cells during fibrosis. Western blot and immunohistochemical analyses revealed that Sfrp1 regulated the noncanonical Wnt/planar cell polarity (PCP) pathway and modulated maintenance of renal fibrosis after kidney damage.
Gopinathan et al. (2019) found that high expression of SFRP1 in periodontal ligament (PDL) fibroblasts correlated with enrichment of active histone H3 (see 602810) lys4 trimethylation (K4me3) marks at its promoter, indicating epigenetic regulation. Inhibition of SFRP1 by a small molecule inhibitor in differentiating PDL cells increased alkaline phosphatase (see 171760) activity and greatly enhanced mineral deposits in a dose-dependent manner. Expression profile analysis confirmed upregulation of mineralization genes in SFRP1-inhibited cells. SFRP1 knockdown enhanced osteodifferentiation in PDL fibroblasts by increasing H3K4me3 marks on the promoters of the mineralization genes RUNX2 (600211) and SP7 (606633), resulting in increased expression. This SFRP1-mediated regulation of mineral homeostasis was unique to PDL cells, as similar effects of SFRP1 knockdown or inhibition were not observed in alveolar bone progenitors.
Bodine et al. (2004) found that Sfrp1 -/- mice were fertile with no overt phenotype. Deletion of Sfrp1 did not affect most nonskeletal tissues or cortical bones, but it increased trabecular bone parameters and led to increased trabecular bone formation. Deletion of Sfrp1 decreased apoptosis of osteoblast lineage cells, thereby enhancing their proliferation and differentiation in Sfrp1 -/- bone marrow. In addition, an osteoclast differentiation assay showed that deletion of Sfrp1 stimulated osteoclastogenesis.
Baylin, S. B., Herman, J. G. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet. 16: 168-174, 2000. [PubMed: 10729832] [Full Text: https://doi.org/10.1016/s0168-9525(99)01971-x]
Bodine, P. V. N., Zhao, W., Kharode, Y. P., Bex, F. J., Lambert, A.-J., Goad, M. B., Gaur, T., Stein, G. S., Lian, J. B., Komm, B. S. The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Molec. Endocr. 18: 1222-1237, 2004. [PubMed: 14976225] [Full Text: https://doi.org/10.1210/me.2003-0498]
Cameron, E. E., Bachman, K. E., Myohanen, S., Herman, J. G., Baylin, S. B. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nature Genet. 21: 103-107, 1999. [PubMed: 9916800] [Full Text: https://doi.org/10.1038/5047]
Elzi, D. J., Song, M., Hakala, K., Weintraub, S. T., Shiio, Y. Wnt antagonist SFRP1 functions as a secreted mediator of senescence. Molec. Cell. Biol. 32: 4388-4399, 2012. [PubMed: 22927647] [Full Text: https://doi.org/10.1128/MCB.06023-11]
Finch, P. W., He, X., Kelley, M. J., Uren, A., Schaudies, R. P., Popescu, N. C., Rudikoff, S., Aaronson, S. A., Varmus, H. E., Rubin, J. S. Purification and molecular cloning of a secreted, frizzled-related antagonist of Wnt action. Proc. Nat. Acad. Sci. 94: 6770-6775, 1997. [PubMed: 9192640] [Full Text: https://doi.org/10.1073/pnas.94.13.6770]
Fukuhara, K., Kariya, M., Kita, M., Shime, H., Kanamori, T., Kosaka, C., Orii, A., Fujita, J., Fujii, S. Secreted frizzled related protein 1 is overexpressed in uterine leiomyomas, associated with a high estrogenic environment and unrelated to proliferative activity. J. Clin. Endocr. Metab. 87: 1729-1736, 2002. [PubMed: 11932307] [Full Text: https://doi.org/10.1210/jcem.87.4.8375]
Gopinathan, G., Foyle, D., Luan, X., Diekwisch, T. G. H. The Wnt antagonist SFRP1: a key regulator of periodontal mineral homeostasis. Stem Cells Dev. 28: 1004-1014, 2019. [PubMed: 31215318] [Full Text: https://doi.org/10.1089/scd.2019.0124]
Matsuyama, M., Nomori, A., Nakakuni, K., Shimono, A., Fukushima, M. Secreted frizzled-related protein 1 (Sfrp1) regulates the progression of renal fibrosis in a mouse model of obstructive nephropathy. J. Biol. Chem. 289: 31526-31533, 2014. [PubMed: 25253698] [Full Text: https://doi.org/10.1074/jbc.M114.584565]
Melkonyan, H. S., Chang, W. C., Shapiro, J. P., Mahadevappa, M., Fitzpatrick, P. A., Kiefer, M. C., Tomei, L. D., Umansky, S. R. SARPs: a family of secreted apoptosis-related proteins. Proc. Nat. Acad. Sci. 94: 13636-13641, 1997. [PubMed: 9391078] [Full Text: https://doi.org/10.1073/pnas.94.25.13636]
Rodriguez, J., Esteve, P., Weinl, C., Ruiz, J. M., Fermin, Y., Trousse, F., Dwivedy, A., Holt, C., Bovolenta, P. SFRP1 regulates the growth of retinal ganglion cell axons through the Fz2 receptor. Nature Neurosci. 8: 1301-1309, 2005. [PubMed: 16172602] [Full Text: https://doi.org/10.1038/nn1547]
Suzuki, H., Gabrielson, E., Chen, W., Anbazhagan, R., van Engeland, M., Weijenberg, M. P., Herman, J. G., Baylin, S. B. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nature Genet. 31: 141-149, 2002. [PubMed: 11992124] [Full Text: https://doi.org/10.1038/ng892]
Suzuki, H., Watkins, D. N., Jair, K.-W., Schuebel, K. E., Markowitz, S. D., Chen, W. D., Pretlow, T. P., Yang, B., Akiyama, Y., van Engeland, M., Toyota, M., Tokino, T., Hinoda, Y., Imai, K., Herman, J. G., Baylin, S. B. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nature Genet. 36: 417-422, 2004. [PubMed: 15034581] [Full Text: https://doi.org/10.1038/ng1330]
Taketo, M. M. Shutting down Wnt signal-activated cancer. Nature Genet. 36: 320-322, 2004. [PubMed: 15054482] [Full Text: https://doi.org/10.1038/ng0404-320]