Akt interacts directly with Smad3 to regulate the sensitivity to TGF-β-induced apoptosis

Conery, Andrew R.; Cao, Yanna; Thompson, E. Aubrey; Townsend, Courtney M.; Ko, Tien C.; Luo, Kunxin

doi:10.1038/ncb1117

Cited by 364 publications

(316 citation statements)

References 28 publications

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“…However, both basal and TGFb-induced release of nuclear histones were inhibited in RIE/Evi1 cells relative to RIE/pBabe. We have previously reported that induction of apoptosis in RIE cells involves Smad3 (Conery et al, 2004), and, consistent with these data, RIE/dnSmad3 cells are resistant to induction of nuclear histone release by TGFb (Figure 4c). However, unlike Evi1, dnSmad3 had no effect on basal apoptosis in RIE cells.…”

Section: Evi1 Inhibits Tgfb-mediated Apoptosis In Intestinal Epithelisupporting

confidence: 90%

“…We have shown that the apoptotic response to TGFb can be influenced by crosstalk between Smad3 and AKT (Conery et al, 2004), and several reports indicate that activation of PI3K/AKT signaling suppresses TGFbmediated apoptosis (Chen et al, 1998(Chen et al, , 1999Shih et al, 2000). Our data demonstrate that Evi1 activates PI3K/ AKT signaling, and suppresses TGFb-mediated apoptosis.…”

Section: Discussionsupporting

confidence: 63%

“…TGFb-mediated inhibition of RIE cell growth in culture is due, in part, to induction of apoptosis (Conery et al, 2004 ). As shown in Figure 4a, TGFb treatment of RIE/ pBabe cells resulted in a decrease in total caspase 3 and a corresponding increase in cleaved caspase 3 (Casp3*).…”

Section: Evi1 Inhibits Tgfb-mediated Apoptosis In Intestinal Epithelimentioning

confidence: 98%

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Evi1 is a survival factor which conveys resistance to both TGFβ- and taxol-mediated cell death via PI3K/AKT

Liu

Chen

et al. 2006

Oncogene

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Section: Evi1 Inhibits Tgfb-mediated Apoptosis In Intestinal Epithelisupporting

confidence: 90%

Section: Discussionsupporting

confidence: 63%

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Evi1 is a survival factor which conveys resistance to both TGFβ- and taxol-mediated cell death via PI3K/AKT

Liu

Chen

et al. 2006

Oncogene

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“…We thus hypothesized that the increased interaction of lithium-induced pCREB Ser133 with the transcriptional coactivators CBP/p300 concurrently suppresses Smad3/4-dependent gene transcription due to the sequestration of CBP/p300 by activated pCREB Ser133 . Recent studies demonstrate that AKT can directly interact with nonphosphorylated Smad3, promoting the sequestration of Smad3 in the cytoplasm and thereby impairing Smad3-dependent transcriptional activity (Conery et al, 2004;Remy et al, 2004). Although Smad3 phosphorylation is not affected by lithium treatment in cultured cortical neurons (unpublished data), we have not investigated whether lithium treatment alters AKTSmad3 interaction or Smad3 nuclear translocation.…”

Section: Discussionmentioning

confidence: 88%

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Liang¹,

Wendland²,

Chuang³

2008

Molecular and Cellular Neuroscience

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Smad proteins are intracellular transducers for transforming growth factor-β (TGF-β signaling and play a critical role in differentiation, tissue repair and apoptosis of the central nervous system. Both TGF-β and its regulated gene, plasminogen activator inhibitor type-1 (PAI-1), have been implicated in the etiology and progression of neurodegenerative diseases and mood disorders. We previously reported that GSK-3β protein depletion suppresses Smad3/4-dependent gene transcription and causes a reduction in PAI-1 expression. Here, we provide evidence that lithium, the drug for the treatment and prophylaxis of bipolar disorder, inhibits Smad-dependent signaling by regulating cAMP-protein kinase A (PKA), AKT-glycogen synthase kinase-3β (GSK-3β), and CRE-dependent signaling pathways in neuron-enriched cerebral cortical cultures of rats. We demonstrate that lithium-induced activation of these pathways inhibits Smad3/4-dependent gene transcription through an increase in pCREB Ser133 protein levels, an enhanced interaction between pCREB Ser133 and p300/CBP, which causes Smad3/4-p300/CBP complex disruption and transcriptional suppression of Smad3/4-dependent genes. Therapeutic implications of our findings are discussed.

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“…PI 3-kinase in turn phosphorylates phosphatidylinositides on the 3' position to produce phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P 2 and 3,4-triphosphate (PtdIns3,4)P 3 [46]. PtdIns(3,4)P 2 preferentially activates the Akt/PKB serine/ threonine kinase signaling pathway [4], which inactivates SMAD3 by sequestering unphosphorylated SMAD3 in the cytoplasm, thus preventing SMAD3 phosphorylation and nuclear translocation [6,37]. Sequestration of unphosphorylated SMAD3 inhibits TGFb1-induced, SMAD3-mediated transcription and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Fas Death Pathway in Sarcomas Correlates with Epidermal Growth Factor Transcription

Joyner

Aboulafia

Damron

et al. 2008

Clin Orthop Relat Res

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Modulation of apoptosis may influence sarcoma pathogenesis and/or aggressiveness. The Fas death pathway, mediated by FasL or TGFb, is one of two apoptotic pathways. Recent studies report that EGF can modulate TGFb and/or FasL expression/activity; thus, EGF has the potential to influence activation of the Fas pathway. EGF is not always detectable in mesenchymal tumors; therefore, we hypothesized EGF would define which Fas ligand predominates. We assayed 57 surgically removed human sarcomas for 10 genes involved in the Fas pathway. Skeletal muscle biopsies from eight patients served as controls. Sample transcripts were detected by real-time RT-PCR. We attempted to identify relevant predictor variables. The 57 sarcomas were segregated into two categories defined by EGF mRNA content: (1) 23 tumors with EGF concentrations that approximated muscle EGF transcript levels (high-EGF tumors); and (2) 34 tumors that either lacked EGF mRNA, or whose mRNA levels were very low and frequently undetected by PCR (low-EGF tumors). TGFb1 expression best predicted Fas transcript concentrations in the 34 low-EGF sarcomas, while FasL predicted Fas mRNA levels in the remaining 23 high-EGF sarcomas. The results suggest ligand activity in the Fas death pathway correlates with EGF transcription in sarcomas.

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Akt interacts directly with Smad3 to regulate the sensitivity to TGF-β-induced apoptosis

Cited by 364 publications

References 28 publications

Evi1 is a survival factor which conveys resistance to both TGFβ- and taxol-mediated cell death via PI3K/AKT

Evi1 is a survival factor which conveys resistance to both TGFβ- and taxol-mediated cell death via PI3K/AKT

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Fas Death Pathway in Sarcomas Correlates with Epidermal Growth Factor Transcription

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