Role of Activin A in cell differentiation and proliferation
Activins are the members of the Transforming growth factor beta (TGF-beta) superfamily which participate in regulation of several biological processes, including cell differentiation and cell proliferation. Among many activins, role of Activin A in this regulation is studied the best.
Like most members of the TGF beta superfamily, Activin A mediates its biological effects through a complex of transmembrane receptor serine/threonine kinases. Activin A initially binds to ActRIIA or ActRIIB and then recruits ALK-4 , .
ALK-4 interacts with and phosphorylates adaptors SMAD2 and SMAD3. SMAD4 is then binds to phosphorylated SMAD2 and SMAD3, followed by translocation of the complex into the nucleus . Once in the nucleus, SMAD2 and SMAD3 may activate transcription of different genes.
It has been shown, that Activin A participates in regulation of stem cell maintenance, via SMAD-dependent activation transcription of marker of Oct-3/4, NANOG, NODAL and NODAL-signaling regulators, Lefty-1 and Lefty-2 , , .
Activin A inhibits cell growth (see negative regulation of cell growth) and proliferation (see negative regulation of cell proliferation) and activates cell differentiation via multiple pathways. In nonmalignant keratinocytes, Activin A stimulates transcription of MAD ,  and inhibits transcription of c-Myc . In addition, Activin A can stimulate transcription of cell cycle inhibitors p15, p21 and p27KIP1 , , . p15 and p21 can be activated by SMAD2 and/or SMAD3 directly (as shown for other members of TGF-beta superfamily) , . Transcription of p27KIP1 can be activated via VDR/ SP1 complex , .
Activin A also stimulates transcription of several hormones. For example, GnRH receptor , .
Moreover, Activin A may stimulate differentiation of granulosa cells from prehierarchal follicles via activation of FSHR and LH receptor. It is believed that initially Activin A activates FSHR-signaling , probably via transcription activation of FSHR . Transcription activation of FSHR may be realized via SF1 , . In addition, Activin A may activate FSHR-signaling via transcription activation of FSH-beta (e.g., via LHX3  or SMAD/ PBX1/PREP1 complex) , ). Then, Activin A and/or FSHR signaling pathways stimulate LH receptor-signaling, possibly, via activation of expression of LH receptor and/or LH-beta , , .
Then, LH receptor stimulates G-protein alpha-s/ Adenylate cyclase/ Cyclic AMP/ PKA-cat (cAMP-dependent)/ CREB1 cascade , which in turn leads to transcription of proteins critical to initiating progesterone production, e.g. STAR and CYP11A1 , .
| ALK-4 || Activin receptor type-1B |
| ActRIIA || Activin receptor type-2A |
| ActRIIB || Activin receptor type-2B |
| Activin A || Activin A Complex |
| Adenylate cyclase || Adenylate cyclase Protein group |
| CREB1 || Cyclic AMP-responsive element-binding protein 1 |
| CYP11A1 || Cholesterol side-chain cleavage enzyme, mitochondrial |
| Cyclic AMP || Chemical IUPAC name (1S,6R,8R,9R)-8-(6-amino-8-bromopurin-9-yl)-3-hydroxy-3-oxo-2,4,7-trioxa-35-phosphabicyclo[4.3.0]nonan-9-ol |
| FSH-beta || Follitropin subunit beta |
| FSHR || Follicle-stimulating hormone receptor |
| G-protein alpha-s || Guanine nucleotide-binding protein G(s) subunit alpha isoforms short |
| GnRH receptor || Gonadotropin-releasing hormone receptor |
| LH receptor || Lutropin-choriogonadotropic hormone receptor |
| LH-beta || Lutropin subunit beta |
| LHX3 || LIM/homeobox protein Lhx3 |
| Lefty-1 || Left-right determination factor 1 |
| Lefty-2 || Left-right determination factor 2 |
| MAD || Max dimerization protein 1 |
| NANOG || Homeobox protein NANOG |
| NODAL || Nodal homolog |
| Oct-3/4 || POU domain, class 5, transcription factor 1 |
| PBX1/PREP1 || PBX1/PREP1 Complex |
| PKA-cat (cAMP-dependent) || Protein kinase, cAMP-dependent, catalytic Protein group |
| SF1 || Steroidogenic factor 1 |
| SMAD2 || Mothers against decapentaplegic homolog 2 |
| SMAD3 || Mothers against decapentaplegic homolog 3 |
| SMAD4 || Mothers against decapentaplegic homolog 4 |
| SP1 || Transcription factor Sp1 |
| STAR || Steroidogenic acute regulatory protein, mitochondrial |
| VDR || Vitamin D3 receptor |
| c-Myc || Myc proto-oncogene protein |
| p15 || Cyclin-dependent kinase 4 inhibitor B |
| p21 || Cyclin-dependent kinase inhibitor 1 |
| p27KIP1 || Cyclin-dependent kinase inhibitor 1B |
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The Journal of biological chemistry 2004 Oct 22;279(43):45076-84
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The Journal of endocrinology 2006 Jul;190(1):141-50
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Activin A suppresses neuroblastoma xenograft tumor growth via antimitotic and antiangiogenic mechanisms.
Cancer research 2005 Mar 1;65(5):1877-86
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Activin A mediates growth inhibition and cell cycle arrest through Smads in human breast cancer cells.
Cancer research 2005 Sep 1;65(17):7968-75
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p27KIP1 and GATA-1 are potential downstream molecules in activin A-induced differentiation and apoptosis pathways in CML cells.
Oncology reports 2006 Nov;16(5):1099-103
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Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer.
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The DNA binding activities of Smad2 and Smad3 are regulated by coactivator-mediated acetylation.
The Journal of biological chemistry 2006 Dec 29;281(52):39870-80
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Sp1 and NF-Y synergistically mediate the effect of vitamin D(3) in the p27(Kip1) gene promoter that lacks vitamin D response elements.
The Journal of biological chemistry 1999 Nov 5;274(45):32309-17
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Journal of cellular biochemistry 2006 Aug 15;98(6):1450-6
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Activin A augments GnRH-mediated transcriptional activation of the mouse GnRH receptor gene.
Endocrinology 2002 Mar;143(3):985-97
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Direct binding of AP-1 (Fos/Jun) proteins to a SMAD binding element facilitates both gonadotropin-releasing hormone (GnRH)- and activin-mediated transcriptional activation of the mouse GnRH receptor gene.
The Journal of biological chemistry 2002 Oct 4;277(40):37469-78
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Endocrinology 2004 Nov;145(11):4866-79
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Activin regulation of the follicle-stimulating hormone beta-subunit gene involves Smads and the TALE homeodomain proteins Pbx1 and Prep1.
Molecular endocrinology (Baltimore, Md.) 2004 May;18(5):1158-70
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Smad3 mediates activin-induced transcription of follicle-stimulating hormone beta-subunit gene.
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Cellular mechanisms and modulation of activin A- and transforming growth factor beta-mediated differentiation in cultured hen granulosa cells.
Biology of reproduction 2004 Dec;71(6):1844-51
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Activin regulates luteinizing hormone beta-subunit gene expression through Smad-binding and homeobox elements.
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