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Activin beta-A, Activin-A; Homo sapiensActivin-A/EDF, a TGF-beta family member, is the homeodimer of the INHBA gene product inhibin/activin beta-A chain. The human gene INHBA (map locus 7p15-P13; Ensembl 7p14.1) gene product is a 426 AA long (47.4 kDa) precursor protein that contains a 20 AA single sequence (1-20), a 290 AA propeptide sequence (21 to 310) and a 116 AA inhibin/activin subunit (311 to 426). The subunit contains four potential disulfide intra-chain bridges (314-322; 321-391; 350-423; 354-425) and a potential interchain disulfide bridge at Cys390. Activin A and TGF-beta 1 are structurally related disulfide-linked homodimers synthesized as large precursors. The pro-regions are required for proper folding, disulfide bonding and export of the homodimers, Gray AM and Mason AJ. (1990). Activin-A participates in a diverse array of functions that include; hypothalamic/pituitary/gonadal hormone secretion, insulin secretion; cell growth, differentiation and survival (apoptosis); embryonic patterning and development; wound healing; and inflammation/immune response. It was initially identified as a follicle stimulating hormone/FSH-releasing protein (gonadal hormone), Ling N, et al. (1986) and erythroid differentiation factor (EDF), Schwall R, et al. (1989). The FSH activity is linked to an increase in the population of pituitary gonadotrophs by Katayama T, et al. (1990). In addition to gonadotrophs, activin-A also modifies somatotrophs and lactotrophs, Kitaoka, et al. (1988). Activin-A stimulates glycogenolysis in isolated rat hepatocytes, Mine T ET. al. (1989) and elevates insulin release from rat pancreatic islets, Verspohl EJ et al. (1993). Activin-A stimulates insulin secretion in rat pancreatic islets, Totsuka Y, et al. (1988). Follistatin, an activin-binding protein, is a principle regulator of activin activity, de Winter JP, et al. (1996); however during embryogenesis, Cripto is an important noncompetitive activin antagonist that facilitates Nodal signaling, Kelber JA, et al. (2008). A role for activin-A as a regulator of cell proliferation was recognized by Gonzalez-Manchon C and Vale W. (1989); wherein Act-A inhibited the growth of and induced morphological changes in CHO-KI cells in culture, in a way similar to but less potent than TGF-beta. Activin A is involved with the entire process of embryo development from germ cells thru embryonic development to adult tissues. It stimulates spermatogonial proliferation in germ-Sertoli cell cocultures, Mather JP, et al. (1990) and is a maturation factor for oocytes, Itoh M, et al. (1990). Activin A promotes proliferation of human luteinized preovulation granulose cells (ovarian granulose cells), Rabinovici J, et al. (1990). In the preimplantation embryo, Activin-A stimulates the rate of morula formation and the velocity of embryo cleavage, Orimo, T, et al. (1996). Recombinant activin A stimulates development of one-cell embryos to morula and blastocyst stages in vitro, Yoshioka K, and Kamonae H. (1996). Activin-A and -B are both potent vegetizing factors. Activin-A was suspected as a blastula level mesoderm-inducing factor (MIF) when it was identified as a homologue of Xenopus XTF-MIF, Smith JC, et al. (1990); van den Eijnden-Van Raaij AJ, et al. (1990); Albano RM, et al. (1990). Thomsen G, et al. (1990) reported that Activin-B transcripts appear earlier than Activin-A transcripts in Xenopus development. Beta-B was first detected in the blastula, whereas beta-A did not appear until late gastrula stage. They suggested that early MIF and axial patterning was due to Activin-B not A. Asashima M, et al. (1991) reported that activin is present in unfertilized Xenopus eggs and blastulae, but this may be of maternal origin. They agree with Thomsen that newly synthesized A appears in late gastrula stage. Activin-A mRNA was not detected in early post-implantation embryo, but was found in nearby maternal decidual cells, Manova K, et al. (1992) and placental cells, Rabinovici J, et al. (1992). Restricted expression of activin-A appears in the gastrula-stage of embryonic development, but the pre-implantation and post-implantation embryos may be exposed to maternally-derived activin A. Activin-A is expressed in both the oviducts, Ganfolfi F, et al. (1995) and decidual cells in the endometrium, Jones RL, et al. (2002). Activin-A is a critical factor in germ layer and cell lineage specification during gastrulation. Gastrulation is the time when cells of the epiblast (primitive ectoderm) differentiate from totipotent to specific lineage precursor cells. Activin-A plays an important role in this transition. Embryonic stem cells (ES) derived from the inner cell mass represent a model for epiblast and germ layer differentiation. Activin is involved in the regulation of both self-renewal and differentiation depending upon cell context. Activin-A induces and/or activates many genes involved with embryonic development including Notch, Delta-1, Delta-2 (mesodermal inducing), Abe T, et al. (2004); Nodal, lefty-A and lefty B (via Smad2/3 activation induced genes), Besser D. (2004); and Oct4, Nanog, Wnt3, bFGF and FGF8, Xiao L, et al. (2006). Activin/Nodal signaling supports the proliferation (mitosis) of embryonic stem cells in culture; wherein these factors are derived via endogenously active autocrine loops, Ogawa K et al. (2007). In culture, endogenously activated autocrine loops of Activin/Nodal signaling supports propagation of mESC, Ogawa K et al. (2007). Activin-A is necessary and sufficient for the maintenance of self-renewal and pluripotency, Xiao L. et al. (2006). Activin-A maintains pluripotency (stemness) of human embryonic stem cells in culture, Beattie GM, et al. (2005); Valdimarsdottir G and Mummery C. (2005); however, under appropriate conditions it promotes germ layer and tissue differentiation. ES transition from pluripotent to germ layer depends upon at least two conditions: Activin/Nodal signaling and release from IGF/insulin inhibition generated thru PI3K signaling, McLean AB, et al. (2007). In undifferentiated hESC, TGFbeta/activin/nodal/smad2/3 signaling pathway activity is necessary for maintenance of pluripotency, James D, et al. (2005) and the FGF, Wnt and Hedgehog (Hh) signaling pathways are active, Xiao L et al. (2006). The suppression of induction of differentiation of hESC into mesendoderm and endoderm by Activin-A and Nodal depends upon the activation of the phosphatidylinositol 3-kinase pathway (PI3K) by factors such as IGF or insulin; when this pathway is inactive differentiation proceeds, McLean AB, et al. (2007). BMP and Notch promote differentiation. The mesendoderm, endoderm and tissue specification activities of Activin-A can be demonstrated in vitro using embryonic stem cells (ESC) and cell lineage precursor cells. Tada S, et al. (2005) demonstrated that activin A could induce a phenotypically defined (Gsc-GFP+E-cadherin(ECD)+PDFGRalpha(alphaR)+ population) mesendoderm from ESC in culture. Activin-A can induce embryonic stem cells within embryoid bodies (EB) to form definitive endoderm (DE) (markers Sox17, CXCR4, Goosecoid and FoxA2) in serum-free culture, Kubo A. et al. (2004); D’Amour KA, et al. (2005). Mouse embryonic stem cells can be induced to form dorsoanterior-like mesoderm by Activin A in chemically defined medium, Johansson BM and Wiles MV. (1995). Activin or Nodal direct nascent mesoderm towards axial mesoderm and mesendoderm; FGF signaling supports the epithelial-to-mesenchymal transition of new mesoderm (increased expression of axial mesoderm markers). The mesoderm inducing activity of Activin-A requires FGF-2 (basic FGF), Cornell RA and Kimelman D. (1994). FGF-dependent Activin/Nodal signaling also supports anterior visceral endoderm (aVE) formation, Willems E and Leyns L. (2008). Doral mesoderm induction by activin-A is modified by the Wnt family factor Xwnt8, Sokol SY, et al. (1992). Activin-A is an important regulator of early embryonic organogenesis. Activin-A directs differentiation of definitive endoderm (DE) derivatives towards neuronal- and glial-like cell-types, McKiernan E, et al. (2007). Activin-A inhibits chondrogenic differentiation during chick limb bud formation, Chen P, et al. (1993), but it induces Shh-dependent differentiation of intestinal tissue from embryonic pancreas, van Eyll JM, et al. (2004). Activin-A is an essential early mesenchymal signal in tooth development, Ferguson CA, et al. (1998) and metanephric mesenchyme during kidney development, Maeshima A, et al. (3003). Activin-A, along with FGF-2, BMP4 and VEGF (VegfA) supports differentiation of hematopoeitic progenitor cells from ES cells. BMP4 promotes formation of mesoderm. Basic FGF and activin-A induce differentiation of these mesoderm precursors to hemangioblast fate (Runx1, Scl (Tal1) and Hhex expression is upregulated within 3 hours of stimulation; whereas upregulation of Lmo2 and Fli1 is observed later and VEGF stimulates commitment to hematopoeitic progenitors, Pearson S, et al. (2008). Activin-A is a regulator of cell differentiation in adult tissues. It is involved with the regulation of differentiation of multiple cell types including: cardiac myogenesis, Sugi Y and Lough J, (1995); cytotrophoblasts, Caniggia I et al. (1997); keratinocytes, Seishima M, et al. (1999); osteoclasts, Fuller K, et al. (2000) and Sakai R, et al. (1993); astrocytes, Satoh M, et al. (2000); and erythroid cells, Boxmeyer HE, et al. (1988). Its ability to induce fibroblasts to differentiate into myofibroblasts Ohga E, et al. (1996) suggests a role in tissue repair processes and potential fibrotic diseases, Hubner G, et al. (1999); Munz B, et al. (2001); Bamberger C, et al. (2005). Activin-A can induce apoptosis in specific cell lines including B-cells, Nishihara T, et al. (1993, 1995), and murine hepatocytes, Hully JR, et al. (1994). Activin-A induces apoptosis in BAX expressing cell lines. Activin-A apoptosis is suppressed by Bcl-2 and BcL-XL upregulation, Koseki T, et al. (1995, 1998). Smad7, but not Smad6 is an activin A-inducible antagonist of activin A-induced growth arrest and apoptosis in HS-72 cells, Ishisaki A, et al. (1999). Sigma offers antibodies, shRNAs and other products useful for the study of the Activin beta-A gene. References: Abe T, et al. (2004) Activin-like signaling activates Notch signaling during mesodermal induction. Int J Dev Biol. 48: 327-332. |
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