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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mammary gland morphogenesis and differentiation are mediated through the combined activities of systemic hormones and locally synthesized growth factors. Activin, a member of the transforming growth factor (TGF)-beta superfamily, is known to regulate the growth and differentiation of several cell types. In the present study, we investigated the role of activin in rat mammary gland on different stages of development. We found that activin A in vitro inhibits the proliferation of isolated acini, and this effect increases with the development of the gland. This factor also produces in vitro an inhibition of the final differentiation of acini obtained from 19th day pregnant rats. We also report the expression of activin receptors IIA and IIB mRNA in whole rat mammary gland and acini, with decreased levels of expression of type IIA (in both compartments) and IIB (in acini) during pregnancy and lactogenesis. In addition, we show that activin betaB-subunit mRNA decreases throughout pregnancy, and that the mRNA levels of follistatin (Fst) (its ligand protein) are high in cycling rats and at the beginning of pregnancy and diminish thereafter, having the acini higher levels of expression. Our data show that activin betaB-subunit, follistatin and ActRIIA and IIB transcripts are expressed in rat mammary gland at appropriate times and locations during development, allowing an interplay that might regulate activin action on growth and differentiation of the gland.
Mol Cell Endocrinol 2004 Jun 30
PMID:Activin and follistatin in rat mammary gland. 1522 28

The participation of a divergent mosquito transforming growth factor-beta (TGF-beta) and mammalian TGF-beta1 in the Anopheles stephensi response to malaria parasite development [Infect. Genet. Evol. 1 (2001) 131-141; Infect. Immun. 71 (2003) 3000-3009] suggests that a network of Anopheles TGF-beta ligands and signaling pathways figure prominently in immune defense of this important vector group. To provide a basis for identifying the roles of these proteins in Anopheles innate immunity, we identified six predicted TGF-beta ligand-encoding genes in the Anopheles gambiae genome, including two expressed, diverged copies of 60A, the first evidence of ligand gene duplication outside of chordates. In addition to five predicted type I and II receptors, we identified three Smad genes in the A. gambiae genome that would be predicted to support both TGF-beta/Activin- and bone morphogenetic protein (BMP)-like signaling. All three Smad genes are expressed in an immunocompetent A. stephensi cell line and in the A. stephensi midgut epithelium, confirming that a conserved signaling architecture is in place to support signaling by divergent exogenous and endogenous TGF-beta superfamily proteins.
Mol Immunol 2004 Aug
PMID:Transforming growth factor-betas and related gene products in mosquito vectors of human malaria parasites: signaling architecture for immunological crosstalk. 1530 59

Both activin and GnRH can independently stimulate expression of the FSHbeta subunit gene. In this study, we used the gonadotrope-derived LbetaT2 cell line to investigate the potential interaction between activin and GnRH in regulating the transcriptional activity of the rat FSHbeta gene promoter. Activin A and GnRH synergistically enhanced rat FSHbeta transcriptional activity. Overexpression of SMAD3 (mediator of decapentaplegic-related protein 3), but not of SMAD2, increased transcriptional activation of the rat (r) FSHbeta gene promoter, which was further enhanced by the combined overexpression of SMAD3 and 4 (3+4). The stimulatory effects of SMAD3 overexpression were localized to -472/-256 of the rFSHbeta gene promoter, and activin- and GnRH-responsive proteins were shown to bind to region -284/-252. Sequence analysis identified a consensus palindromic SMAD-binding site at -266/-259 of the rFSHbeta gene promoter. Mutation of two bases located in the center of this palindrome effectively abrogated SMAD4 binding, markedly reduced SMAD3 and 3+4 stimulation of the rFSHbeta gene promoter, and significantly decreased the synergistic enhancement of promoter activity by both activin A and GnRH, and SMAD3 and GnRH. Blockade of the MAPK-signaling pathway did not significantly affect the response to combined stimulation with activin and GnRH. In contrast, interference with SMAD3 signaling caused a significant reduction in activin and GnRH synergy. The results indicate that SMAD3 plays an important role in the synergistic effects of activin and GnRH and demonstrate that this synergy is mediated by a palindromic cis-element located at -266/-259 of the rFSHbeta gene promoter.
Mol Endocrinol 2005 Jan
PMID:Synergy between activin A and gonadotropin-releasing hormone in transcriptional activation of the rat follicle-stimulating hormone-beta gene. 1537 86

Activin type II receptors (ActRIIs) are the primary receptors that transmit the activin signal to intracellular signaling pathways. Binding of activins to ActRIIs recruits the activin type I receptor and initiates downstream signaling. We have found that PDZ proteins, named activin receptor-interacting proteins (ARIPs), specifically associate with ActRIIs. We have studied the mechanism that ARIPs regulate cell surface expression and cellular localization of ActRIIs. ARIP2 interacts with both ActRIIs and RalBP1 (Ral binding protein 1) through different domains to dramatically change the localization of ActRIIs. Overexpression of ARIP2 enhances endocytosis of ActRIIs. These data indicate that ARIP2 is a novel factor regulating cell surface ActRII expression and activin function. A novel activin binding protein, follistatin-related gene (FLRG) was identified. FLRG protein binds activin and myostatin with a high affinity. The biological activity of FLRG is similar to those of follistatin, however, the regulation and expression patterns of follistatin and FLRG differ. Immunohistochemical analysis shows that FLRG is distributed in spermatogenic cells of the testis, renal tubules, epithelial cells of the lung, and myocardium. Thus, although structurally and functionally similar, follistatin and FLRG likely play distinct roles as activin/GDF binding proteins in vivo.
Mol Cell Endocrinol 2004 Oct 15
PMID:Novel factors in regulation of activin signaling. 1545 61

Activin and follistatin were initially identified in the follicular fluid based on their effects on pituitary FSH secretion in the mid-1980s. It is now evident that activin, follistatin and activin receptors are widely expressed in many tissues where they function as autocrine/paracrine regulators of a variety of physiological processes including reproduction. The major function of follistatin is to bind to activin with high affinity and block activin binding to its receptors. Total activin A and follistatin are also found in the maternal circulation throughout pregnancy. Activin A levels are increased in abnormal pregnancies such as pre-eclampsia, fetal growth restriction and gestational hypertension. The placenta, vascular endothelial cells and activated peripheral mononuclear cells (PBMC) may all contribute to the raised levels of activin A in pre-eclampsia with unaltered follistatin in pre-eclamptic placenta, PBMCs or vascular endothelial cells suggesting the availability of 'free' activin A that could be biologically active in these cells.
Mol Cell Endocrinol 2004 Oct 15
PMID:Activin and follistatin in female reproduction. 1545 67

The role of the inhibins, activins and follistatins in testicular function are being more clearly defined following studies describing the cellular localisation of these proteins to the testis and the availability of specific assay systems enabling measurement of these proteins. Taken together with the results of targetted gene inactivation experiments, several concepts emerge. Inhibin B is predominantly produced by the Sertoli cell in many adult male mammals whereas there is a perinatal peak of inhibin A in the rat. In contrast, activin A has its highest concentrations in the immediate post-natal period during which it is involved in the developmental regulation of both germ cells and Sertoli cells being modulated by follistatin. Activin A levels are considerably lower in the adult testis but Sertoli cell production is stimulated by interleukin-1 and inhibited by FSH. Little is known about the production of activin B due to the absence of a suitable assay but the beta(B) subunit mRNA is expressed in germ cells and Sertoli cells and is stage-dependent. This pattern of expression suggest that it may be involved in autocrine or paracrine actions within the seminiferous epithelium.
Mol Cell Endocrinol 2004 Oct 15
PMID:The role of activin, follistatin and inhibin in testicular physiology. 1545 68

Activins and inhibins are growth factors involved in cell differentiation and proliferation. Human breast tissues such as normal mammary tissue, fibroadenoma, and breast cancer express inhibin and activin mRNA and proteins. Activin A and its binding protein, follistatin, are also present in human milk during the first week of lactation. Using immunohistochemistry, we have observed that the inhibin/activin alpha, betaA, and betaB subunits are present in normal breast tissue regardless of menstrual cycle phase or menopause, as well as in fibrocystic disease, and breast tumors. The mRNAs encoding all three activin/inhibin subunits are expressed in breast carcinoma, fibroadenoma, and normal mammary tissue. The betaA subunit gene expression is higher in either local or metastatic breast carcinoma than in normal tissue. In addition, dimeric activin A is detectable in homogenates of breast cancer tissue at concentrations twice as high as in non-neoplastic adjoining tissue. Recent evidence suggests that some of the activin A produced by breast carcinoma is released into systemic circulation. In women with breast cancer, serum activin A levels are often elevated, and a significant decrease is observed in the first and second days following tumor excision. The role of activin and inhibin as endocrine and/or paracrine factors in the breast is still uncertain. Activin has complex effects on cell growth during branching morphogenesis, but it is generally considered as an inhibitor of cell proliferation as in vitro studies have shown that activin A treatment of breast cancer cells arrests cell growth. Inhibin is generally considered as a tumor suppressor, but its possible role in the breast is less understood.
Mol Cell Endocrinol 2004 Oct 15
PMID:Activin, inhibin and the human breast. 1545 71

Several years ago, we cloned and characterized from a B cell leukemia a new secreted protein which, on the basis of its high degree of structural homology with follistatin, was defined as a member of the follistatin family and accordingly named follistatin-related gene (FLRG). However, follistatin and FLRG revealed non-overlapping patterns of expression in various tissues thereby indicating the existence of non-redundant functional roles for these proteins throughout the organism. As known for a long time, follistatin is a biological regulator of activin and bone morphogenetic protein (BMP) function in various cellular systems: in particular, it inhibits the effects of activin on hematopoiesis. 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. For this purpose, we have for the first time, compared the role of Activin A, BMP2 and BMP4 during erythropoiesis, in primary human cells. Our results indicate that, BMP2 acts on early erythroid cells while Activin A acts on a more differentiated population. We report the induction by Activin A and BMP2 of cell commitment towards erythropoiesis in the absence of EPO. This induction involves two key events: increase of EPO-R and the decrease of GATA2 expression. 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. We thus propose a working model for the regulation of activin or BMP-induced human erythropoiesis by follistatin/FLRG.
Mol Cell Endocrinol 2004 Oct 15
PMID:FLRG, member of the follistatin family, a new player in hematopoiesis. 1545 75

The TGF-beta family of receptor serine/threonine kinases (RSTKs) is responsible for a diverse array of functions in metazoans. Here, we describe the isolation of SmRK2, a type II RSTK expressed in schistosomula and adult stages of Schistosoma mansoni. Based on amino acid sequence homology, SmRK2 is most closely related to the Activin type II receptor subset of RSTKs. SmRK2 appears to be expressed as three different transcripts: one encoding a full-length receptor with 5'- and 3'-untranslated regions (UTRs) (SmRK2), a second encoding a longer form containing no 3'-UTR and no stop codon (SmRK2a), and a third truncated variant (SmRK2b), which contains sequence encoding the first 53 amino acids of the N-terminal extracellular domain followed by an inserted 10 residue hydrophobic domain. Using an anti-peptide antibody raised against a partial extracellular domain sequence common to all three isoforms, SmRK2 was localized predominantly to the tegumental surface of the parasites. We hypothesize that SmRK2 is the receptor partner for the previously reported type I RSTK SmRK1 (or SmTbetaR1) and that together these proteins constitute a receptor system for receiving signals from the mammalian host.
Mol Biochem Parasitol 2004 Aug
PMID:Tegumental expression of a novel type II receptor serine/threonine kinase (SmRK2) in Schistosoma mansoni. 1547 94

The promoters of mouse and rat GnRH receptor (GnRHR) genes differ markedly in regard to activin regulation. Activin stimulates the mouse GnRHR promoter, although it has no impact on that of the rat. To test whether this difference was due to a single nucleotide change in the rat GnRHR activating sequence (GRAS) homolog, we tested a mouse promoter with the rat GRAS homolog and a rat promoter with intact mouse GRAS. The single change in GRAS eliminated activin responsiveness of the mouse GnRHR promoter; however, intact mouse GRAS did not confer activin responsiveness to the rat promoter. Thus, although necessary, GRAS is not sufficient for activin responsiveness of the murine GnRHR promoter. Use of chimeric rat and mouse promoters led to the identification of a 36-bp region residing immediately downstream of GRAS that is necessary for activin responsiveness of the mouse GnRHR gene promoter. Scanning mutagenesis of the 36-bp region localized the functional boundaries of the key regulatory element to adjacent TAAT motifs. The presence of tandem TAAT motifs, the core binding site for multiple members of the homeodomain family of binding proteins, raised the possibility that this region represented a binding site for a homeodomain protein. This region displayed specific binding to a recombinant homeodomain of LHX2. We suggest that GRAS and the downstream activin regulatory element together define a unique and complex activin/TGFbeta-responsive "enhanceosome" whose functional attributes depend on the binding of multiple classes of transcription factors at spatially distinct sites in the promoter of the murine GnRHR gene.
Mol Endocrinol 2005 Apr
PMID:Activin responsiveness of the murine gonadotropin-releasing hormone receptor gene is mediated by a composite enhancer containing spatially distinct regulatory elements. 1563 49


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