scholarly journals Phosphatidylinositol 3-Kinase/Akt Pathway Targets Acetylation of Smad3 through Smad3/CREB-binding Protein Interaction

2009 ◽  
Vol 284 (36) ◽  
pp. 23912-23924 ◽  
Author(s):  
Lassad Oussaief ◽  
Aurélie Hippocrate ◽  
Vanessa Ramirez ◽  
Aurore Rampanou ◽  
Wei Zhang ◽  
...  
2006 ◽  
Vol 282 (7) ◽  
pp. 4830-4840 ◽  
Author(s):  
Mélanie Sanchez ◽  
Karine Sauvé ◽  
Nathalie Picard ◽  
André Tremblay

The hormonal response of estrogen receptors (ER) α and ERβ is controlled by a number of cofactors, including the general transcriptional coactivator CREB-binding protein (CBP). Growing evidence suggests that specific kinase signaling events also modulate the formation and activity of the ER coactivation complex. Here we show that ERβ activity and target gene expression are decreased upon activation of ErbB2/ErbB3 receptors despite the presence of CBP. This inhibition of ERβ involved activation of the phosphatidylinositol 3-kinase/Akt pathway, abrogating the potential of CBP to facilitate ERβ response to estrogen. Such reduced activity was associated with an impaired ability of ERβ to recruit CBP upon activation of Akt. Mutation of serine 255, an Akt consensus site contained in the hinge region of ERβ, prevented the release of CBP and rendered ERβ transcriptionally more responsive to CBP coactivation, suggesting that Ser-255 may serve as a regulatory site to restrain ERβ activity in Akt-activated cells. In contrast, we found that CBP intrinsic activity was increased by Akt through threonine 1872, a consensus site for Akt in the cysteine- and histidine-rich 3 domain of CBP, indicating that such enhanced transcriptional potential of CBP did not serve to activate ERβ. Interestingly, nuclear receptors sharing a conserved Akt consensus site with ERβ also exhibit a reduced ability to be coactivated by CBP, whereas others missing that site were able to benefit from the activation of CBP by Akt. These results therefore outline a regulatory mechanism by which the phosphatidylinositol 3-kinase/Akt pathway may discriminate nuclear receptor response through coactivator transcriptional competence.


2008 ◽  
Vol 29 (1) ◽  
pp. 58-68 ◽  
Author(s):  
Abraham Jacob ◽  
Tina X. Lee ◽  
Brian A. Neff ◽  
Shyra Miller ◽  
Bradley Welling ◽  
...  

2016 ◽  
Vol 291 (43) ◽  
pp. 22841-22841
Author(s):  
Mei Sun ◽  
Lin Yang ◽  
Richard I. Feldman ◽  
Xia-meng Sun ◽  
Kapil N. Bhalla ◽  
...  

Endocrinology ◽  
2006 ◽  
Vol 147 (5) ◽  
pp. 2383-2391 ◽  
Author(s):  
Catherine Mounier ◽  
Victor Dumas ◽  
Barry I. Posner

The expression of IGF-binding protein-1 (IGFBP-1) is induced in rat liver by dexamethasone and glucagon and is completely inhibited by 100 nm insulin. Various studies have implicated phosphatidylinositol 3-kinase, protein kinase B (Akt), phosphorylation of the transcription factors forkhead in rhabdomyosarcoma 1 (Foxo1)/Foxo3, and the mammalian target of rapamycin (mTOR) in insulin’s effect. In this study we examined insulin regulation of IGFBP-1 in both subconfluent and confluent hepatocytes. In subconfluent hepatocytes, insulin inhibition of IGFBP-1 mRNA levels was blocked by inhibiting PI3 kinase activation, and there was a corresponding inhibition of Foxo1/Foxo3 phosphorylation. In these same cells, inhibition of the insulin effect by rapamycin occurred in the presence of insulin-induced Foxo1/Foxo3 phosphorylation. In confluent hepatocytes, insulin could not activate the phosphatidylinositol 3-kinase (PI3 kinase)-Akt-Foxo1/Foxo3 pathway, but still inhibited IGFBP-1 gene expression in an mTOR-dependent manner. In subconfluent hepatocytes, the serine/threonine phosphatase inhibitor okadaic acid (100 nm) partially inhibited IGFBP-1 gene expression by 40%, but did not produce phosphorylation of either Akt or Foxo proteins. In contrast, 1 nm insulin inhibited the IGFBP-1 mRNA level by 40% and correspondingly activated Akt and Foxo1/Foxo3 phosphorylation to a level comparable to that observed with 100 nm insulin. These results suggest a potential role for a serine/threonine phosphatase(s) in the regulation of IGFBP-1 gene transcription, which is not downstream of mTOR and is independent of Akt. In conclusion, we have found that in rat liver, insulin inhibition of IGFBP-1 mRNA levels can occur in the absence of the phosphorylation of Foxo1/Foxo3, whereas activation of the mTOR pathway is both necessary and sufficient.


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