Retinoids regulate TGFbeta signaling at the level of Smad2 phosphorylation and nuclear accumulation.
Indirect regulation of transforming growth factor (TGF)-beta signaling by retinoids occurs on a long-term timescale, secondary to transcriptional events. Studies by our group show loss of retinoid X receptor (RXR) alpha results in increased TGFbeta2 in the midgestational heart, which may play a role in the cardiac defects seen in this model [S.W. Kubalak, D.R. Hutson, K.K. Scott and R.A. Shannon, Elevated transforming growth factor beta2 enhances apoptosis and contributes to abnormal outflow tract and aortic sac development in retinoic X receptor alpha knockout embryos, Development 129 (2002) 733-746.]. Acute and direct interactions between retinoid and TGFbeta signaling, however, are not clearly understood. Treatment of dispersed hearts and NIH3T3 cells for 1 h with TGFbeta and retinoids (dual treatment) resulted in increased phosphorylated Smad2 and Smad3 when compared to treatment with TGFbeta alone. Of all dual treatments, those with the RXR agonist Bexarotene, resulted in the highest level of phosphorylated Smad2, a 7-fold increase over TGFbeta2 alone. Additionally, during dual treatment phosphorylation of Smad2 occurs via the TGFbeta type I receptor but not by increased activation of the receptor. As loss of RXRalpha results in increased levels of Smad2 phosphorylation in response to TGFbeta treatment and since nuclear accumulation of phosphorylated Smad2 is decreased during dual treatment, we propose that RXRalpha directly regulates the activities of Smad2. These data show retinoid signaling influences the TGFbeta pathway in an acute and direct manner that has been unappreciated until now.
Hoover
Loretta L
LL
Department of Cell Biology and Anatomy, Cardiovascular Developmental Biology Center, Medical University of South Carolina, 173 Ashley Avenue Suite 601BSB Charleston, SC 29425, USA.
Burton
Elizabeth G
EG
O'Neill
Megan L
ML
Brooks
Bonnie A
BA
Sreedharan
Shilpa
S
Dawson
Nineveh A
NA
Kubalak
Steven W
SW
D000818:Animals; D000077610:Bexarotene; D002467:Cell Nucleus / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006321:Heart / Q000502:physiology; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008907:Mink; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000819:agonists / Q000502:physiology; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism; D013347:Subcellular Fractions; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D018125:Receptors, Transforming Growth Factor beta; D047490:Retinoid X Receptor alpha; D012176:Retinoids; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D013764:Tetrahydronaphthalenes; D016212:Transforming Growth Factor beta; D000077610:Bexarotene; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II
Dev Dyn. 2005 Jul;233(3):1091-101
15861408
J Biochem Mol Biol. 2005 Jan 31;38(1):9-16
15715940
Annu Rev Cell Dev Biol. 2005;21:659-93
16212511
Nature. 1997 Oct 9;389(6651):631-5
9335507
Blood. 2003 Jan 15;101(2):498-507
12393416
J Biol Chem. 2005 Dec 2;280(48):40152-60
16204233
Cell. 2003 Jun 13;113(6):685-700
12809600
J Biol Chem. 2006 Dec 29;281(52):40412-9
17085434
Cell. 1998 Dec 11;95(6):779-91
9865696
Cell Growth Differ. 2001 Sep;12(9):457-63
11571228
Anal Biochem. 1994 Feb 1;216(2):276-84
8179182
Mol Biol Cell. 2007 Jun;18(6):2264-73
17429065
Proc Natl Acad Sci U S A. 2001 May 22;98(11):6198-203
11371641
Cytokine Growth Factor Rev. 2001 Mar;12(1):1-8
11312113
Cell Signal. 2002 Dec;14(12):977-88
12359303
Mol Cell. 2000 Dec;6(6):1365-75
11163210
Development. 2002 Feb;129(3):733-46
11830573
FASEB J. 2003 Aug;17(11):1576-8
12824291
Mol Cell. 2002 Aug;10(2):271-82
12191473
ScientificWorldJournal. 2008 Feb 25;8:194-211
18661045
Mol Cell. 2001 Sep;8(3):671-82
11583628
Pharmacol Rev. 2006 Dec;58(4):712-25
17132850
EMBO J. 2001 Feb 1;20(3):480-90
11157754
J Cardiovasc Pharmacol. 2004 Nov;44 Suppl 1:S216-8
15838283
Oncogene. 2003 Nov 6;22(50):8212-20
14603262
J Biol Chem. 1999 Dec 24;274(52):37105-10
10601270
FASEB J. 1996 Jul;10(9):940-54
8801176
Mol Cell Biol. 2000 Nov;20(21):8008-17
11027271
Biochem Soc Symp. 1996;62:143-56
8971347
Mol Endocrinol. 2002 Aug;16(8):1738-51
12145331
EMBO Rep. 2006 Oct;7(10):1030-4
16936639
Pharmacol Rev. 2006 Dec;58(4):760-72
17132853
Cell. 2006 Jun 2;125(5):915-28
16751101
Mol Cell. 2000 Jan;5(1):27-34
10678166
Sci STKE. 2001 Dec 18;2001(113):pe43
11752631
J Nutr Biochem. 2007 Aug;18(8):497-508
17320364
Mol Pharmacol. 2002 Jul;62(1):65-74
12065756
Nat Cell Biol. 1999 Dec;1(8):472-8
10587642