Development - Role of Activin A in cell differentiation and proliferation

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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 [1], [2].

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 [1]. 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 [3], [4], [5].

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 [6], [7] and inhibits transcription of c-Myc [8]. In addition, Activin A can stimulate transcription of cell cycle inhibitors p15, p21 and p27KIP1 [9], [10], [11]. p15 and p21 can be activated by SMAD2 and/or SMAD3 directly (as shown for other members of TGF-beta superfamily) [12], [13]. Transcription of p27KIP1 can be activated via VDR/ SP1 complex [14], [15].

Activin A also stimulates transcription of several hormones. For example, GnRH receptor [16], [17].

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 [18], probably via transcription activation of FSHR [18]. Transcription activation of FSHR may be realized via SF1 [19], [20]. In addition, Activin A may activate FSHR-signaling via transcription activation of FSH-beta (e.g., via LHX3 [21] or SMAD/ PBX1/PREP1 complex) [22], [23]). Then, Activin A and/or FSHR signaling pathways stimulate LH receptor-signaling, possibly, via activation of expression of LH receptor and/or LH-beta [18], [24], [25].

Then, LH receptor stimulates G-protein alpha-s/ Adenylate cyclase/ Cyclic AMP/ PKA-cat (cAMP-dependent)/ CREB1 cascade [26], which in turn leads to transcription of proteins critical to initiating progesterone production, e.g. STAR and CYP11A1 [18], [24].



Objects list:

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

References:

  1. Abe Y, Minegishi T, Leung PC
    Activin receptor signaling. Growth factors (Chur, Switzerland) 2004 Jun;22(2):105-10
  2. Larsson J, Karlsson S
    The role of Smad signaling in hematopoiesis. Oncogene 2005 Aug 29;24(37):5676-92
  3. Besser D
    Expression of nodal, lefty-a, and lefty-B in undifferentiated human embryonic stem cells requires activation of Smad2/3. The Journal of biological chemistry 2004 Oct 22;279(43):45076-84
  4. James D, Levine AJ, Besser D, Hemmati-Brivanlou A
    TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development (Cambridge, England) 2005 Mar;132(6):1273-82
  5. Vallier L, Alexander M, Pedersen RA
    Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. Journal of cell science 2005 Oct 1;118(Pt 19):4495-509
  6. Yang L, Yang J, Venkateswarlu S, Ko T, Brattain MG
    Autocrine TGFbeta signaling mediates vitamin D3 analog-induced growth inhibition in breast cells. Journal of cellular physiology 2001 Sep;188(3):383-93
  7. Werner S, Beer HD, Mauch C, Luscher B, Werner S
    The Mad1 transcription factor is a novel target of activin and TGF-beta action in keratinocytes: possible role of Mad1 in wound repair and psoriasis. Oncogene 2001 Nov 8;20(51):7494-504
  8. Matsuo SE, Leoni SG, Colquhoun A, Kimura ET
    Transforming growth factor-beta1 and activin A generate antiproliferative signaling in thyroid cancer cells. The Journal of endocrinology 2006 Jul;190(1):141-50
  9. Panopoulou E, Murphy C, Rasmussen H, Bagli E, Rofstad EK, Fotsis T
    Activin A suppresses neuroblastoma xenograft tumor growth via antimitotic and antiangiogenic mechanisms. Cancer research 2005 Mar 1;65(5):1877-86
  10. Burdette JE, Jeruss JS, Kurley SJ, Lee EJ, Woodruff TK
    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
  11. Fukuchi Y, Yamato K, Kawamura C, Ikeda Y, Kizaki M
    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
  12. Han SU, Kim HT, Seong DH, Kim YS, Park YS, Bang YJ, Yang HK, Kim SJ
    Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer. Oncogene 2004 Feb 19;23(7):1333-41
  13. Simonsson M, Kanduri M, Gronroos E, Heldin CH, Ericsson J
    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
  14. Inoue T, Kamiyama J, Sakai T
    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
  15. Cheng HT, Chen JY, Huang YC, Chang HC, Hung WC
    Functional role of VDR in the activation of p27Kip1 by the VDR/Sp1 complex. Journal of cellular biochemistry 2006 Aug 15;98(6):1450-6
  16. Norwitz ER, Xu S, Jeong KH, Bedecarrats GY, Winebrenner LD, Chin WW, Kaiser UB
    Activin A augments GnRH-mediated transcriptional activation of the mouse GnRH receptor gene. Endocrinology 2002 Mar;143(3):985-97
  17. Norwitz ER, Xu S, Xu J, Spiryda LB, Park JS, Jeong KH, McGee EA, Kaiser UB
    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
  18. Woods DC, Johnson AL
    Regulation of follicle-stimulating hormone-receptor messenger RNA in hen granulosa cells relative to follicle selection. Biology of reproduction 2005 Mar;72(3):643-50
  19. Levallet J, Koskimies P, Rahman N, Huhtaniemi I
    The promoter of murine follicle-stimulating hormone receptor: functional characterization and regulation by transcription factor steroidogenic factor 1. Molecular endocrinology (Baltimore, Md.) 2001 Jan;15(1):80-92
  20. Hermann BP, Heckert LL
    Transcriptional regulation of the FSH receptor: new perspectives. Molecular and cellular endocrinology 2007 Jan 2;260-262:100-8
  21. West BE, Parker GE, Savage JJ, Kiratipranon P, Toomey KS, Beach LR, Colvin SC, Sloop KW, Rhodes SJ
    Regulation of the follicle-stimulating hormone beta gene by the LHX3 LIM-homeodomain transcription factor. Endocrinology 2004 Nov;145(11):4866-79
  22. Bailey JS, Rave-Harel N, McGillivray SM, Coss D, Mellon PL
    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
  23. Suszko MI, Balkin DM, Chen Y, Woodruff TK
    Smad3 mediates activin-induced transcription of follicle-stimulating hormone beta-subunit gene. Molecular endocrinology (Baltimore, Md.) 2005 Jul;19(7):1849-58
  24. Johnson AL, Bridgham JT, Woods DC
    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
  25. Coss D, Thackray VG, Deng CX, Mellon PL
    Activin regulates luteinizing hormone beta-subunit gene expression through Smad-binding and homeobox elements. Molecular endocrinology (Baltimore, Md.) 2005 Oct;19(10):2610-23
  26. Niswender GD
    Molecular control of luteal secretion of progesterone. Reproduction (Cambridge, England) 2002 Mar;123(3):333-9

  1. Abe Y, Minegishi T, Leung PC
    Activin receptor signaling. Growth factors (Chur, Switzerland) 2004 Jun;22(2):105-10
  2. Larsson J, Karlsson S
    The role of Smad signaling in hematopoiesis. Oncogene 2005 Aug 29;24(37):5676-92
  3. Besser D
    Expression of nodal, lefty-a, and lefty-B in undifferentiated human embryonic stem cells requires activation of Smad2/3. The Journal of biological chemistry 2004 Oct 22;279(43):45076-84
  4. James D, Levine AJ, Besser D, Hemmati-Brivanlou A
    TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development (Cambridge, England) 2005 Mar;132(6):1273-82
  5. Vallier L, Alexander M, Pedersen RA
    Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. Journal of cell science 2005 Oct 1;118(Pt 19):4495-509
  6. Yang L, Yang J, Venkateswarlu S, Ko T, Brattain MG
    Autocrine TGFbeta signaling mediates vitamin D3 analog-induced growth inhibition in breast cells. Journal of cellular physiology 2001 Sep;188(3):383-93
  7. Werner S, Beer HD, Mauch C, Luscher B, Werner S
    The Mad1 transcription factor is a novel target of activin and TGF-beta action in keratinocytes: possible role of Mad1 in wound repair and psoriasis. Oncogene 2001 Nov 8;20(51):7494-504
  8. Matsuo SE, Leoni SG, Colquhoun A, Kimura ET
    Transforming growth factor-beta1 and activin A generate antiproliferative signaling in thyroid cancer cells. The Journal of endocrinology 2006 Jul;190(1):141-50
  9. Panopoulou E, Murphy C, Rasmussen H, Bagli E, Rofstad EK, Fotsis T
    Activin A suppresses neuroblastoma xenograft tumor growth via antimitotic and antiangiogenic mechanisms. Cancer research 2005 Mar 1;65(5):1877-86
  10. Burdette JE, Jeruss JS, Kurley SJ, Lee EJ, Woodruff TK
    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
  11. Fukuchi Y, Yamato K, Kawamura C, Ikeda Y, Kizaki M
    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
  12. Han SU, Kim HT, Seong DH, Kim YS, Park YS, Bang YJ, Yang HK, Kim SJ
    Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer. Oncogene 2004 Feb 19;23(7):1333-41
  13. Simonsson M, Kanduri M, Gronroos E, Heldin CH, Ericsson J
    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
  14. Inoue T, Kamiyama J, Sakai T
    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
  15. Cheng HT, Chen JY, Huang YC, Chang HC, Hung WC
    Functional role of VDR in the activation of p27Kip1 by the VDR/Sp1 complex. Journal of cellular biochemistry 2006 Aug 15;98(6):1450-6
  16. Norwitz ER, Xu S, Jeong KH, Bedecarrats GY, Winebrenner LD, Chin WW, Kaiser UB
    Activin A augments GnRH-mediated transcriptional activation of the mouse GnRH receptor gene. Endocrinology 2002 Mar;143(3):985-97
  17. Norwitz ER, Xu S, Xu J, Spiryda LB, Park JS, Jeong KH, McGee EA, Kaiser UB
    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
  18. Woods DC, Johnson AL
    Regulation of follicle-stimulating hormone-receptor messenger RNA in hen granulosa cells relative to follicle selection. Biology of reproduction 2005 Mar;72(3):643-50
  19. Levallet J, Koskimies P, Rahman N, Huhtaniemi I
    The promoter of murine follicle-stimulating hormone receptor: functional characterization and regulation by transcription factor steroidogenic factor 1. Molecular endocrinology (Baltimore, Md.) 2001 Jan;15(1):80-92
  20. Hermann BP, Heckert LL
    Transcriptional regulation of the FSH receptor: new perspectives. Molecular and cellular endocrinology 2007 Jan 2;260-262:100-8
  21. West BE, Parker GE, Savage JJ, Kiratipranon P, Toomey KS, Beach LR, Colvin SC, Sloop KW, Rhodes SJ
    Regulation of the follicle-stimulating hormone beta gene by the LHX3 LIM-homeodomain transcription factor. Endocrinology 2004 Nov;145(11):4866-79
  22. Bailey JS, Rave-Harel N, McGillivray SM, Coss D, Mellon PL
    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
  23. Suszko MI, Balkin DM, Chen Y, Woodruff TK
    Smad3 mediates activin-induced transcription of follicle-stimulating hormone beta-subunit gene. Molecular endocrinology (Baltimore, Md.) 2005 Jul;19(7):1849-58
  24. Johnson AL, Bridgham JT, Woods DC
    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
  25. Coss D, Thackray VG, Deng CX, Mellon PL
    Activin regulates luteinizing hormone beta-subunit gene expression through Smad-binding and homeobox elements. Molecular endocrinology (Baltimore, Md.) 2005 Oct;19(10):2610-23
  26. Niswender GD
    Molecular control of luteal secretion of progesterone. Reproduction (Cambridge, England) 2002 Mar;123(3):333-9

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