TY - JOUR
T1 - Akt kinase targets association of CBP with SMAD 3 to regulate TGFβ-induced expression of plasminogen activator inhibitor-1
AU - Das, Falguni
AU - Ghosh-Choudhury, Nandini
AU - Venkatesan, Balachandar
AU - Li, Xiaonan
AU - Mahimainathan, Lenin
AU - Choudhury, Goutam Ghosh
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2008/2
Y1 - 2008/2
N2 - Transforming growth factor-β (TGFβ) controls expression of plasminogen activator inhibitor type 1 (PAI-1), which regulates degradation of extracellular matrix proteins in fibrotic diseases. The TGFβ receptor-specific Smad 3 has been implicated in the PAI-1 expression. The mechanism by which non-Smad signaling contributes to this process is not known. We studied the cross-talk between Smad 3 and PI 3 kinase/Akt signaling in TGFβ-induced PAI-1 expression in renal mesangial cells. Inhibition of PI 3 kinase and Akt kinase blocked TGFβ- and Smad 3-mediated expression of PAI-1. In contrast, constitutively active PI 3 kinase and Akt kinase increased PAI-1 expression, similar to TGFβ. Inhibition of PI 3 kinase and Akt kinase had no effect on TGFβ-induced Smad 3 phosphorylation and its translocation to the nucleus. Notably, inhibition of PI 3 kinase-dependent Akt kinase abrogated TGFβ-induced PAI-1 transcription, without affecting binding of Smad 3 to the PAI-1 Smad binding DNA element. However, PI 3 kinase inhibition and dominant negative Akt kinase antagonized the association of the transcriptional coactivator CBP with Smad 3 in response to TGFβ, resulting in inhibition of Smad 3 acetylation. Together our findings identify TGFβ-induced PI 3 kinase/Akt signaling as a critical regulator of Smad 3-CBP interaction and Smad 3 acetylation, which cause increased PAI-1 expression.
AB - Transforming growth factor-β (TGFβ) controls expression of plasminogen activator inhibitor type 1 (PAI-1), which regulates degradation of extracellular matrix proteins in fibrotic diseases. The TGFβ receptor-specific Smad 3 has been implicated in the PAI-1 expression. The mechanism by which non-Smad signaling contributes to this process is not known. We studied the cross-talk between Smad 3 and PI 3 kinase/Akt signaling in TGFβ-induced PAI-1 expression in renal mesangial cells. Inhibition of PI 3 kinase and Akt kinase blocked TGFβ- and Smad 3-mediated expression of PAI-1. In contrast, constitutively active PI 3 kinase and Akt kinase increased PAI-1 expression, similar to TGFβ. Inhibition of PI 3 kinase and Akt kinase had no effect on TGFβ-induced Smad 3 phosphorylation and its translocation to the nucleus. Notably, inhibition of PI 3 kinase-dependent Akt kinase abrogated TGFβ-induced PAI-1 transcription, without affecting binding of Smad 3 to the PAI-1 Smad binding DNA element. However, PI 3 kinase inhibition and dominant negative Akt kinase antagonized the association of the transcriptional coactivator CBP with Smad 3 in response to TGFβ, resulting in inhibition of Smad 3 acetylation. Together our findings identify TGFβ-induced PI 3 kinase/Akt signaling as a critical regulator of Smad 3-CBP interaction and Smad 3 acetylation, which cause increased PAI-1 expression.
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U2 - 10.1002/jcp.21236
DO - 10.1002/jcp.21236
M3 - Article
C2 - 17671970
AN - SCOPUS:37349112714
VL - 214
SP - 513
EP - 527
JO - Journal of Cellular Physiology
JF - Journal of Cellular Physiology
SN - 0021-9541
IS - 2
ER -