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HGNC Approved Gene Symbol: FSTL1
Cytogenetic location: 3q13.33 Genomic coordinates (GRCh38) : 3:120,392,293-120,450,992 (from NCBI)
The FLTS1 transcript can function either as an mRNA that encodes the FLTS1 protein or as a primary microRNA (pri-miRNA) transcript that produces miRNA-198 (MIR198). The FLTS1 protein promotes keratinocyte migration and wound repair, whereas MIR198 downregulates genes required for keratinocyte migration and wound repair (Sundaram et al., 2013).
Using degenerate primers designed against a peptide purified from a rat glioma cell line, Zwijsen et al. (1994) isolated a full-length follistatin-like cDNA (FSTL1), which they called FRP, from a human glioma cDNA library. FSTL1 encodes a deduced 308-amino acid protein with an N-terminal signal peptide of 20 amino acids. FSTL1 contains an FS module, a follistatin-like sequence containing 10 conserved cysteine residues. The number and distribution of the cysteine residues supports the existence of several intramolecular disulfide bridges. Zwijsen et al. (1994) did not detect any membrane-spanning or membrane-associated sequences in the FSTL1 sequence, but they predicted 3 putative N-glycosylation sites and several phosphorylation sites. Under denaturing conditions, Zwijsen et al. (1994) detected several isoforms of FSTL1 with molecular masses of 40 to 48 kD which differs from the 50- to 55-kD products detected by Tanaka et al. (1998). Tanaka et al. (1998) hypothesized that the difference results from the molecular conditions affected by posttranslational modification. FSTL1 shares greater than 92% amino acid identity with the mouse homolog, known as Fstl or TSC-36, identified as a transforming growth factor-beta-inducible protein by Shibanuma et al. (1993). Zwijsen et al. (1994) also noted sequence similarity to follistatin (136470) and agrin (103320), and could not detect any effect of FSTL1 on the cell growth inhibition of TGF-beta (190180). Using Northern blot analysis, Tanaka et al. (1998) detected a broadly expressed 4.4-kb FSTL1 transcript most strongly in the heart, placenta, prostate, ovary, and small intestine. Expression was not detected in peripheral blood leukocytes.
Tanaka et al. (1998) constructed synovium expression cDNA libraries made from rheumatoid arthritis (RA; 180300) patient-derived synovial cell mRNA. By screening the libraries by IgG purified from synovial fluids from RA patients, they identified FSTL1. Using immunoblotting analysis, they detected anti-FSTL1 antibodies as more frequent in the synovial fluids and serum of RA patients than in patients with other systemic rheumatic diseases or in healthy individuals. patients. Immunoprecipitation analysis showed no difference between these groups in the amount of synovial FSTL1 protein, suggesting an elevated turnover in RA.
Using a mouse model of collagen-induced arthritis (CIA) and DNA microarray analysis, Miyamae et al. (2006) observed highly upregulated expression of Fstl1 in mouse paws during early arthritis, particularly at the interface of synovial pannus and eroding bone. Immunohistochemical analysis demonstrated increased expression in Cd90 (THY1; 188230)-positive fibroblasts, particularly early in CIA. Monkey fibroblasts transfected with human FSTL1 spontaneously secreted more IL6 (147620), and human monocytes transfected with FSTL1 and stimulated with mitogens expressed higher IL1B (147720), TNF (191160), and IL6. Mice infected with adenovirus expressing mouse Fstl1 expressed more proinflammatory cytokines and had exacerbated CIA, even in the absence of type II collagen (COL2A1; 120140) administration. Miyamae et al. (2006) suggested that fibroblast-secreted FSTL1 acts on macrophages to increase TNF and IL1B production and IL6 activity.
Wei et al. (2015) found that mouse epicardial cells contain a potent cardiogenic activity that they identified as Fstl1. Epicardial Fstl1 declined following myocardial infarction and was replaced by myocardial expression. Myocardial Fstl1 did not promote regeneration, either basally or upon transgenic overexpression. Application of the human FSTL1 protein via an epicardial patch stimulated cell cycle entry and division of preexisting cardiomyocytes, improving cardiac function and survival in mouse and swine models of myocardial infarction. Wei et al. (2015) concluded that their data suggested that the loss of epicardial FSTL1 is a maladaptive response to injury, and that its restoration would be an effective way to reverse myocardial death and remodeling following myocardial infarction in humans.
MicroRNA 198
Using expression profiling, Sundaram et al. (2013) found that MIR198 was dowregulated concomitant with FSTL1 upregulation following scratch wounding in human skin ex vivo organ cultures. In situ hybridization and immunohistochemical analysis confirmed that MIR198 was highly expressed in normal human epidermis and that FSTL1 mRNA and protein were highly expressed at the leading edge of epidermal keratinocytes following injury. Sundaram et al. (2013) found that the splicing regulator KSRP (KHSRP; 603445) was required for MIR198 processing from the FSTL1 transcript. Upon injury, TGF-beta-1 directly suppressed MIR198 generation via MIR181A (612742)-dependent KSRP downregulation, resulting in stabilization of the FSTL1 transcript and other MIR198 target transcripts that encode proteins essential for cell migration and wound repair, including PLAU (191840), DIAPH1 (602121), and LAMC2 (150292). Chronic nonhealing ulcer wounds of patients with diabetes mellitus (see 222100) exhibited downregulated expression of PLAU, DIAPH, LAMC2, and FSTL1 and persistent high levels of MIR198. Sundaram et al. (2013) proposed that low levels of TGF-beta-1 and absence of TGF-beta-1 receptors (190181) in chronic wounds may directly contribute to constitutive expression of MIR198, thereby inhibiting wound repair.
Ye et al. (2013) found that MIR198 directly downregulated livin (BIRC7; 605737) expression in human prostate cancer cell lines by binding to the 3-prime end of the livin transcript.
Sundaram et al. (2013) determined that FSTL1 gene contains 11 exons. The first exon is noncoding, and exon 11 contains the MIR198 stem-loop structure within the 3-prime UTR for the FSTL1 mRNA.
Hartz (2009) mapped the FSTL1 gene to chromosome 3q13.33 based on an alignment of the FSTL1 sequence (GenBank U06863) with the genomic sequence (GRCh37).
Hartz, P. A. Personal Communication. Baltimore, Md. 10/2/2009.
Miyamae, T., Marinov, A. D., Sowders, D., Wilson, D. C., Devlin, J., Boudreau, R., Robbins, P., Hirsch, R. Follistatin-like protein-1 is a novel proinflammatory molecule. J. Immun. 177: 4758-4762, 2006. [PubMed: 16982916] [Full Text: https://doi.org/10.4049/jimmunol.177.7.4758]
Shibanuma, M., Mashimo, J., Mita, A., Kuroki, T., Nose, K. Cloning from a mouse osteoblastic cell line of a set of transforming-growth- factor-beta-1-regulated genes, one of which seems to encode a follistatin-related polypeptide. Europ. J. Biochem. 217: 13-19, 1993. [PubMed: 7901004] [Full Text: https://doi.org/10.1111/j.1432-1033.1993.tb18212.x]
Sundaram, G. M., Common, J. E. A., Gopal, F. E., Srikanta, S., Lakshman, K., Lunny, D. P., Lim, T. C., Tanavde, V., Lane, E. B., Sampath, P. 'See-saw' expression of microRNA-198 and FSTL1 from a single transcript in wound healing. Nature 495: 103-106, 2013. [PubMed: 23395958] [Full Text: https://doi.org/10.1038/nature11890]
Tanaka, M., Ozaki, S., Osakada, F., Mori, K., Okubo, M., Nakao, K. Cloning of follistatin-related protein as a novel autoantigen in systemic rheumatic diseases. Int. Immun. 10: 1305-1314, 1998. [PubMed: 9786430] [Full Text: https://doi.org/10.1093/intimm/10.9.1305]
Wei, K., Serpooshan, V., Hurtado, C., Diez-Cunado, M., Zhao, M., Maruyama, S., Zhu, W., Fajardo, G., Noseda, M., Nakamura, K., Tian, X., Liu, Q., and 15 others. Epicardial FSTL1 reconstitution regenerates the adult mammalian heart. Nature 525: 479-485, 2015. [PubMed: 26375005] [Full Text: https://doi.org/10.1038/nature15372]
Ye, L., Li, S., Ye, D., Yang, D., Yue, F., Guo, Y., Chen, X., Chen, F., Zhang, J., Song, X. Livin expression may be regulated by miR-198 in human prostate cancer cell lines. Europ. J. Cancer 49: 734-740, 2013. [PubMed: 23069480] [Full Text: https://doi.org/10.1016/j.ejca.2012.08.029]
Zwijsen, A., Blockx, H., van Arnhem, W., Willems, J., Fransen, L., Devos, K., Raymackers, J., van de Voorde, A., Slegers, H. Characterization of a rat C6 glioma-secreted follistatin-related protein (FRP): cloning and sequence of the human homologue. Europ. J. Biochem. 225: 937-946, 1994. [PubMed: 7957230] [Full Text: https://doi.org/10.1111/j.1432-1033.1994.0937b.x]