title: Retinoids regulate TGFbeta signaling at the level of Smad2 phosphorylation and nuclear accumulation.
abstract: 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.
authors.affiliation: Department of Cell Biology and Anatomy, Cardiovascular Developmental Biology Center, Medical University of South Carolina, 173 Ashley Avenue Suite 601BSB Charleston, SC 29425, USA.
authors.forename: Loretta L
authors.initials: LL
authors.lastname: Hoover
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Burton
authors.forename: Megan L
authors.initials: ML
authors.lastname: O'Neill
authors.forename: Bonnie A
authors.initials: BA
authors.lastname: Brooks
authors.forename: Shilpa
authors.initials: S
authors.lastname: Sreedharan
authors.forename: Nineveh A
authors.initials: NA
authors.lastname: Dawson
authors.forename: Steven W
authors.initials: SW
authors.lastname: Kubalak
mesh_terms: 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*
chemical_list: 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
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