Differential actions of follistatin and follistatin-like 3

Reproductive Endocrine Unit, BHX-5, Massachusetts General Hospital, Boston, MA 02114, USA.
Molecular and Cellular Endocrinology (Impact Factor: 4.41). 11/2004; 225(1-2):25-8. DOI: 10.1016/j.mce.2004.02.009
Source: PubMed


Follistatin (FS) is an important physiological regulator of activin and other TGFbeta superfamily members. The recently discovered follistatin-like 3 (FSTL3; a.k.a. FLRG; FSRP) shares significant structural and functional homology with FS, but also has some interesting differences, including a prominent nuclear localization. The existence of these two related proteins allows detailed molecular and biochemical comparisons of the biologic roles of their individual structural elements. Current studies indicate that the heparin binding sequence is essential for the ability of FS to inhibit autocrine activin but is not sufficient to confer this activity on FSTL3. Preliminary analysis of FSTL3 transgenic mice suggests that FSTL3 regulates gonadal development and function through inhibition of the paracrine activity of activin and/or other related factors. These studies have identified important structural elements necessary for biological activity of FS and FSTL3 and potential roles for FSTL3 in vivo.

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    • "They can bind to all activins and inhibit their biological functions [10]. The mRNA expression levels of FST and FSTL3 in mesothelioma cells were analyzed next. "
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    ABSTRACT: Activin-A and activin-B, members of the TGF-β superfamily, are regulators of reproductive functions, inflammation and wound healing. These dimeric molecules regulate various cellular activities such as proliferation, migration and suvival. Malignant mesothelioma is an asbestos exposure related tumor affecting mainly pleura and it usually has a dismal prognosis. Here, we demonstrate that both activin-A and -B are abundantly expressed in mesothelioma tumor tissue as well as in cultured primary and established mesothelioma cells. Migratory and invasive mesothelioma cells were also found to have attenuated activation of the Smad2/3 pathway in response to activins. Migration and invasive growth of the cells in three-dimentional matrix was prevented by inhibition of activin activity using a soluble activin receptor 2B (sActR2B-Fc). This was associated with decreased ERK activity. Furthermore, migration and invasive growth was significantly inhibited by blocking ERK phosphorylation. Mesothelioma tumors are locally invasive and our results clearly suggest that acivins have a tumor-promoting function in mesothelioma through increasing expression and switching from canonical Smad3 pathway to non-canonical ERK pathway signaling. Blocking activin activity offers a new therapeutic approach for inhibition of mesothelioma invasive growth.
    Experimental Cell Research 12/2014; 182(1). DOI:10.1016/j.yexcr.2014.12.010 · 3.25 Impact Factor
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    • "The follistatin assay uses a pair of monoclonal antibodies raised against recombinant human FS300 and detects both FS288 and FS315 with 95% recovery. However, when applied to serum samples, it reflects essentially FS315 because this isoform accounts for .90% of the follistatin in circulation (Schneyer et al., 2004). The assay measures total (free + conjugated ) serum follistatin and has a detection limit of 29 pg/ml, with a linear detection range from 250 to 16 000 pg/ml. "
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    ABSTRACT: Activin A is a growth factor, produced by the endometrium, whose actions are modulated by the binding protein follistatin. Both proteins are detectable in the peripheral serum and their concentrations may be increased in women with endometriosis. The present study was designed to evaluate whether serum levels of activin A and follistatin are altered, and therefore have a potential diagnostic value, in women with peritoneal, ovarian and deep infiltrating endometriosis. We performed a multicenter controlled study evaluating simultaneously serum activin A and follistatin concentrations in women with and without endometriosis. Women with endometriosis (n = 139) were subdivided into three groups: peritoneal endometriosis (n = 28); ovarian endometrioma (n = 61) and deep infiltrating endometriosis (n = 50). The control group (n = 75) consisted of healthy women with regular menstrual cycles. Blood samples were collected from a peripheral vein and assayed for activin A and follistatin using commercially available enzyme immunoassay kits. The ovarian endometrioma group had serum activin A levels significantly higher than healthy controls (0.22 ± 0.01 ng/ml versus 0.17 ± 0.01 ng/ml, P < 0.01). None of the endometriosis groups had serum follistatin levels which were significantly altered compared with healthy controls; however, levels found in the endometrioma group (2.34 ± 0.32 ng/ml) were higher than that in the deep endometriosis group (1.50 ± 0.17 ng/ml, P < 0.05). The area under the receiver operating characteristic curve of activin A was 0.700 (95% confidence interval: 0.605-0.794), while that of follistatin was 0.620 (95% confidence interval: 0.510-0.730) for the diagnosis of ovarian endometrioma. The combination of both markers into a duo marker index did not improve significantly their diagnostic accuracy. The present study demonstrated that serum activin A and follistatin are not significantly altered in peritoneal or deep infiltrating endometriosis and have limited diagnostic accuracy in the diagnosis of ovarian endometrioma.
    Human Reproduction 03/2012; 27(5):1445-50. DOI:10.1093/humrep/des055 · 4.57 Impact Factor
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    • "FLGR was first identified as playing a role in leukemogenesis with wide-range effects on cell differentiation , proliferation and organization, suggesting a participation in cell transformation and growth regulation (Hayette et al., 1998). Although FLRG shares significant structural and functional homology with follistatin (FS), further characterization confirmed some major differences between the two proteins, suggesting that FLRG is differentially regulated both spatially and temporally and performs distinct functions (Schneyer et al., 2004). FLRG mRNA expression is exceptionally high in the placenta (Tortoriello et al., 2001). "
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    ABSTRACT: To determine maternal plasma levels of follistatin-related gene protein (FLRG) in the first trimester of pregnancy and assess its potential role as a marker for prenatal screening of Down syndrome. Maternal plasma levels of FLRG were determined in 100 pregnant women with normal fetuses in their first trimester of pregnancy (i.e. 11th to 15th weeks). These results were compared with 20 cases with Down syndrome fetuses, taking into consideration clinical and demographic variables, such as maternal age, maternal weight, gestational age, smoking status and ethnicity. Maternal plasma median of FLRG in the normal population was 1.41 ng/mL with 95% confidence interval (CI) of 1.37-1.70 and interquartile range (IQR) of 0.88, during the 11th to 15th weeks of pregnancy. Maternal age and weight were the only variables significantly related to FLRG levels (p = 0.030 and 0.020, respectively). Only maternal and gestational ages were related to Down syndrome (p = 0.039 and 0.006, respectively). Maternal plasma levels of FLRG were not significantly different in the presence of Down syndrome fetuses compared to normal population (p = 0.63). FLRG can be successfully detected in maternal plasma in the first trimester of pregnancy. However, its levels are not significantly altered in the presence of Down syndrome fetuses.
    Prenatal Diagnosis 03/2010; 30(3):224-8. DOI:10.1002/pd.2441 · 3.27 Impact Factor
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