TY - JOUR
T1 - Retinoids regulate TGFβ signaling at the level of Smad2 phosphorylation and nuclear accumulation
AU - Hoover, Loretta L.
AU - Burton, Elizabeth G.
AU - O'Neill, Megan L.
AU - Brooks, Bonnie A.
AU - Sreedharan, Shilpa
AU - Dawson, Nineveh A.
AU - Kubalak, Steven W.
N1 - Funding Information:
The authors would like to thank Dr. Rifkin for generously providing the stably transfected MLEC line and Mr. Jarrett Walsh for helpful discussions regarding this work. This work was supported by NIH Grant Number C06 RR018823 and C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources, NIH T32 HL07260 (LLH) and NIH/NHLBI R01 HL83116 (SWK).
PY - 2008/12
Y1 - 2008/12
N2 - Indirect regulation of transforming growth factor (TGF)-β 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 TGFβ2 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 TGFβ signaling, however, are not clearly understood. Treatment of dispersed hearts and NIH3T3 cells for 1 h with TGFβ and retinoids (dual treatment) resulted in increased phosphorylated Smad2 and Smad3 when compared to treatment with TGFβ alone. Of all dual treatments, those with the RXR agonist Bexarotene, resulted in the highest level of phosphorylated Smad2, a 7-fold increase over TGFβ2 alone. Additionally, during dual treatment phosphorylation of Smad2 occurs via the TGFβ type I receptor but not by increased activation of the receptor. As loss of RXRα results in increased levels of Smad2 phosphorylation in response to TGFβ treatment and since nuclear accumulation of phosphorylated Smad2 is decreased during dual treatment, we propose that RXRα directly regulates the activities of Smad2. These data show retinoid signaling influences the TGFβ pathway in an acute and direct manner that has been unappreciated until now.
AB - Indirect regulation of transforming growth factor (TGF)-β 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 TGFβ2 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 TGFβ signaling, however, are not clearly understood. Treatment of dispersed hearts and NIH3T3 cells for 1 h with TGFβ and retinoids (dual treatment) resulted in increased phosphorylated Smad2 and Smad3 when compared to treatment with TGFβ alone. Of all dual treatments, those with the RXR agonist Bexarotene, resulted in the highest level of phosphorylated Smad2, a 7-fold increase over TGFβ2 alone. Additionally, during dual treatment phosphorylation of Smad2 occurs via the TGFβ type I receptor but not by increased activation of the receptor. As loss of RXRα results in increased levels of Smad2 phosphorylation in response to TGFβ treatment and since nuclear accumulation of phosphorylated Smad2 is decreased during dual treatment, we propose that RXRα directly regulates the activities of Smad2. These data show retinoid signaling influences the TGFβ pathway in an acute and direct manner that has been unappreciated until now.
KW - Nuclear accumulation
KW - Phosphorylation
KW - Retinoic acid
KW - Retinoid X receptor
KW - Smad
KW - Transforming growth factor-β
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U2 - 10.1016/j.bbamcr.2008.07.028
DO - 10.1016/j.bbamcr.2008.07.028
M3 - Article
C2 - 18773928
AN - SCOPUS:55049117137
SN - 0167-4889
VL - 1783
SP - 2279
EP - 2286
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
IS - 12
ER -