Disease relevance of FSTL3

• Besides the t(11;19)-carrying leukemia described in this work, structural rearrangements of the FLRG locus have been found in a non-Hodgkin lymphoma, suggesting that it may play a role in leukemogenesis [1].
• We found that homozygous FSTL3 knockout adults developed a distinct group of metabolic phenotypes, including increased pancreatic islet number and size, beta cell hyperplasia, decreased visceral fat mass, improved glucose tolerance, and enhanced insulin sensitivity, changes that might benefit obese, insulin-resistant patients [2].
• OBJECTIVE: The human gene FLRG, identified from a B-cell chronic lymphocytic leukemia bearing a t(11;19) translocation, encodes a secreted glycoprotein highly homologous with follistatin [3].
• Our results suggest that IGFBP1 and Follistatin-like 3 are highly up-regulated in IUGR in the placenta [4].
• FLRG was weakly immunostained in endometrial adenocarcinoma [5].

High impact information on FSTL3

• This combination of phenotypes appears to arise from increased activin and myostatin bioactivity in specific tissues resulting from the absence of the FSTL3 antagonist [2].
• FSTL3 deletion reveals roles for TGF-beta family ligands in glucose and fat homeostasis in adults [2].
• Functional studies show that FLRG inhibits myostatin activity in a reporter gene assay [6].
• Northern blotting revealed that mRNAs for FLRG were abundantly expressed in heart, lung, kidney, and testis in mouse [7].
• The mouse cDNA encodes a 256-residue precursor and most likely a mouse homologue of human FLRG, which was found at the breakpoint of the chromosomal rearrangement in a B-cell line [7].

Biological context of FSTL3

• These results suggest that FSTL3 is likely to be a local regulator of activin action in gonadal development and gametogenesis and, further, that activin appears to have important actions in gonadal development and function that are critical for normal reproduction [8].
• Three FST isoforms have been described that differ in tissue distribution and cell-surface binding activity, suggesting that the FST isoforms and FSTL3 may have some nonoverlapping biological actions [9].
• Activin-binding affinities and kinetics were comparable between the isoforms and FSTL3, whereas cell-surface binding differed markedly (FST288 > FST303 > FST315 > FSTL3) [9].
• We therefore investigated the expression and effects of FLRG during human hematopoiesis with particular focus on the effect of this soluble glycoprotein in the regulation of erythropoiesis [10].
• Deletion analysis of the promoter regions indicates that a proximal 550 base pairs are enough for basal FLRG promoter activity in the cell lines [11].

Anatomical context of FSTL3

• To investigate the role of local FSTL3 as a potential regulator of activin action in gonad development and function, we examined FSTL3 expression in the mouse testis [8].
• FSTL3 protein was localized to Leydig cells, spermatagonia, and mature spermatids in normal male mice [8].
• Moreover, when FSTL3, which does not associate with cell membranes, was expressed as a membrane-anchored protein, its endogenous activin inhibitory activity was dramatically increased [9].
• Our results indicate that despite their high structural homology, follistatin and FLRG do not regulate the same signaling targets, therefore highlighting distinct functions and mechanisms for these two proteins in the human hematopoietic system [10].
• In this study we showed that FLRG mRNA was expressed in human endometrium across the menstrual cycle and in decidua of early pregnancy [12].

Associations of FSTL3 with chemical compounds

• However, insertion of the HBS into FSTL3 did not restore heparin binding or pituitary-cell bioactivity [13].
• Glutathione S-transferase fusion proteins encoding various regions of FLRG were produced and studied [7].
• These results suggest that FLRG expression in endometrial stromal cells is regulated by the concerted action of ovarian steroid hormones via decidualization, and FLRG protein may participate in the regulation of stromal cell decidualization as a binding protein for members of TGF beta superfamily [12].
• Using in vitro decidualization model, we demonstrated that 17 beta-estradiol plus progesterone, but not 17 beta-estradiol or progesterone alone, induced FLRG expression significantly [12].
• Regulation of follistatin-related gene (FLRG) expression by protein kinase C and prostaglandin E(2) in cultured granulosa-luteal cells [14].
• We showed that FLRG silencing effects resulted from restoration of endogenous activin functions as shown by increased levels of phosphorylated smad2 and up-regulation of activin target gene transcripts [15].

Physical interactions of FSTL3

• We have now tested the ability of FS288 and FSTL-3 to bind and neutralize activin B relative to activin A [16].
• By deletion and point-mutation analysis of the FLRG promoter, we identified a Smad-binding element involved in the TGFbeta-inducible expression of the FLRG gene [17].

Regulatory relationships of FSTL3

• We demonstrate here that FLRG mRNA expression is rapidly induced by TGFbeta or by transfection with Smad protein expression vectors in human HepG2 cells [17].
• FLRG protein inhibits activin-induced and bone morphogenetic protein-2-induced transcriptional responses in a dose-dependent manner, and its mRNA is abundantly expressed in human placenta, heart, aorta, testis, and adrenal gland [12].

Other interactions of FSTL3

• We produced recombinant FST isoforms and FSTL3 and compared their biochemical and biological properties [9].
• Interestingly, this FSTL3 retained activin-antagonizing activity [18].
• Moreover, transactivation of the FLRG promoter by TGFbeta was compromised by dominant-negative mutants of Smad3 and Smad4 proteins [17].
• Taken together, our data imply that Smad proteins participate in the regulation of expression of FLRG, a new target of TGFbeta transcription activation [17].
• Consistent with our data in discordant chorionic twin placentas, three of four IUGR placentas showed up-regulation of the IGFBP1 and all four IUGR placentas showed upregulation of Follistatin-like 3 genes when compared to the AGA placentas [4].

Analytical, diagnostic and therapeutic context of FSTL3

• METHODS: Expression levels of follistatin, follistatin-like 3, and activin subunits beta(A) as well as beta(E) were investigated in chemically induced rat and human liver tumours by real-time PCR and immunohistochemistry [19].
• MATERIALS AND METHODS: The binding of FLRG with activin A was investigated by immunoprecipitation and Far-Western blot analysis [3].
• FLRG mRNA was detected by RT-PCR in fresh and cultured granulosa-luteal cells, as well as in normal ovarian stroma, theca and granulosa cells [14].

References