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.
[Show abstract][Hide abstract] 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
"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). "
[Show abstract][Hide abstract] 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.
"These observations help validate the experimental approach and this ovary list. IGFBP2 is involved in growth inhibition in fetal development, and is abundant in Leydig cells (Wang et al. 1994, Schneyer et al. 2004, Terrien et al. 2005, Yao 2005). AMH receptor 2 (AMHR2) is known to bind AMH to promote Mü llerian duct regression in the developing male, and to negatively regulate postnatal Leydig cell differentiation (Jamin et al. 2002, Mendis-Handagama et al. 2006). "
[Show abstract][Hide abstract] ABSTRACT: Gene expression profiles during sex determination and gonadal differentiation were investigated to identify new potential regulatory factors. Embryonic day 13 (E13), E14, and E16 rat testes and ovaries were used for microarray analysis, as well as E13 testis organ cultures that undergo testis morphogenesis and develop seminiferous cords in vitro. A list of 109 genes resulted from a selective analysis for genes present in male gonadal development and with a 1.5-fold change in expression between E13 and E16. Characterization of these 109 genes potentially important for testis development revealed that cytoskeletal-associated proteins, extracellular matrix factors, and signaling factors were highly represented. Throughout the developmental period (E13-E16), sex-enriched transcripts were more prevalent in the male with 34 of the 109 genes having testis-enriched expression during sex determination. In ovaries, the total number of transcripts with a 1.5-fold change in expression between E13 and E16 was similar to the testis, but none of those genes were both ovary enriched and regulated during the developmental period. Genes conserved in sex determination were identified by comparing changing transcripts in the rat analysis herein, to transcripts altered in previously published mouse studies of gonadal sex determination. A comparison of changing mouse and rat transcripts identified 43 genes with species conservation in sex determination and testis development. Profiles of gene expression during E13-E16 rat testis and ovary development are presented and candidate genes for involvement in sex determination and testis differentiation are identified. Analysis of cellular pathways did not reveal any specific pathways involving multiple candidate genes. However, the genes and gene network identified influence numerous cellular processes with cellular differentiation, proliferation, focal contact, RNA localization, and development being predominant.
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