A Phosphatidylinositol 3-Kinase-regulated Akt-Independent Signaling Promotes Cigarette Smoke-induced FRA-1 Expression

Zhang, Qin; Adiseshaiah, Pavan P.; Kalvakolanu, Dhananjaya V.; Reddy, Sekhar P.

doi:10.1074/jbc.m513008200

Cited by 35 publications

(32 citation statements)

References 46 publications

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“…It is worth noting that siRNA-mediated knockdown of Akt1 did not lead to AMPK or ACC hyperphosphorylation, in contrast to the hyperphosphorylation effect seen with the PI3K inhibitor wortmannin. We speculate that this difference between the effects of wortmannin versus Akt1 siRNA may reflect Akt-independent signaling downstream of PI3K, perhaps involving the MAPK pathway, as has been proposed in a number of recent reports (52,53). Further studies will be necessary to determine whether AMPK can directly activate eNOS in a pathway that does not involve Akt.…”

Section: Discussionmentioning

confidence: 92%

Agonist-modulated Regulation of AMP-activated Protein Kinase (AMPK) in Endothelial Cells

Levine

Michel

2007

Journal of Biological Chemistry

192

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The endothelial isoform of nitric-oxide synthase (eNOS), a key determinant of vascular homeostasis, is a calcium/calmodulindependent phosphoprotein regulated by diverse cell surface receptors. Vascular endothelial growth factor (VEGF) and sphingosine 1-phosphate (S1P) stimulate eNOS activity through Akt/phosphoinositide 3-kinase and calcium-dependent pathways. AMP-activated protein kinase (AMPK) also activates eNOS in endothelial cells; however, the molecular mechanisms linking agonist-mediated AMPK regulation with eNOS activation remain incompletely understood. We studied the role of AMPK in VEGF-and S1P-mediated eNOS activation and found that both agonists led to a striking increase in AMPK phosphorylation in pathways involving the calcium/calmodulin-dependent protein kinase kinase ␤. Treatment with tyrosine kinase inhibitors or the phosphoinositide 3-kinase inhibitor wortmannin demonstrated differential effects of VEGF versus S1P. Small interfering RNA (siRNA)-mediated knockdown of AMPK␣1 or Akt1 impaired the stimulatory effects of both VEGF and S1P on eNOS activation. AMPK␣1 knockdown impaired agonist-mediated Akt phosphorylation, whereas Akt1 knockdown did not affect AMPK activation, thus suggesting that AMPK lies upstream of Akt in the pathway leading from receptor activation to eNOS stimulation. Importantly, we found that siRNA-mediated knockdown of AMPK␣1 abrogates agonist-mediated activation of the small GTPase Rac1. Conversely, siRNA-mediated knockdown of Rac1 decreased the agonist-mediated phosphorylation of AMPK substrates without affecting that of AMPK, implicating Rac1 as a molecular link between AMPK and Akt in agonist-mediated eNOS activation. Finally, siRNA-mediated knockdown of caveolin-1 significantly enhanced AMPK phosphorylation, suggesting that AMPK is negatively regulated by caveolin-1. Taken together, these results suggest that VEGF and S1P differentially regulate AMPK and establish a central role for an agonist-modulated AMPK 3 Rac1 3 Akt axis in the control of eNOS in endothelial cells.

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Section: Discussionmentioning

confidence: 92%

Agonist-modulated Regulation of AMP-activated Protein Kinase (AMPK) in Endothelial Cells

Levine

Michel

2007

Journal of Biological Chemistry

192

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“…However, none of these studies suggested the role of PAK-1 in mediating the cross talk between growth factors and Wnt signaling. In human bronchial epithelial cells, cigarette smoke-induced epidermal growth factor receptor-mediated activation of FRA-1 expression is carried out by the PI3K-(PAK-1)-(Raf)-MEK-ERK signaling cascade, without the participation of Akt (Li et al, 2005;Zhang et al, 2006). In addition, Qiao et al (2004) reported that IGF-1 stimulates the activity of the transcription factor RUNX2, through a PI3K-dependent but Akt-independent signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

et al. 2009

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Hyperinsulinemia and type II diabetes are associated with an increased risk of developing colorectal tumors. We found previously that in intestinal cells, insulin or insulinlike growth factor-1 stimulates c-Myc and cyclin D1 protein expression through both Akt-dependent and Aktindependent mechanisms. The effect of Akt is attributed to the stimulation of c-Myc translation by mammalian target of rapamycin. However, Akt-independent stimulation was, associated with an increase in b-catenin (b-cat) in the nucleus and an increased association between b-cat and T-cell factor binding sites on the c-Myc promoter, detected by chromatin immunoprecipitation. In this study, we show that insulin stimulated the phosphorylation/ activation of p-21-activated protein kinase-1 (PAK-1) in an Akt-independent manner in vitro and in an in vivo hyperinsulinemic mouse model. Significantly, shRNA (small hairpin RNA)-mediated PAK-1 knockdown attenuated both basal and insulin-stimulated c-Myc and cyclin D1 expression, associated with a marked reduction in extracellular signal-regulated kinase activation and b-cat phosphorylation at Ser675. Furthermore, PAK-1 silencing led to a complete blockade of insulin-stimulated b-cat binding to the c-Myc promoter and cellular growth. Finally, inhibition of MEK, a downstream target of PAK-1, blocked insulin-stimulated nuclear b-cat accumulation and c-Myc expression. Our observations suggest that PAK-1 serves as an important linker between insulin and Wnt signaling pathways.

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“…Genetic deletion of TLR4 or genes encoding its adapter molecules should reveal whether TLR4 functions in chemotherapy-induced lung injury. It is also noteworthy that cigarette smoking reportedly induces Fra-1 expression (Zhang et al, 2006) and could also promote interstitial lung disease.…”

Section: Discussionmentioning

confidence: 99%

Interstitial lung disease induced by gefitinib and Toll-like receptor ligands is mediated by Fra-1

et al. 2011

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The role of the AP-1 transcription factor Fra-1 (encoded by Fosl1) in inflammatory responses associated with lung disease is largely unknown. Here, we show that Fra-1 overexpression in mice reduced proinflammatory cytokine production in response to injection of lipopolysaccharide (LPS), a Toll-like receptor (TLR)-ligand. Unexpectedly, Fra-1 transgenic mice died rapidly following LPS treatment, showing severe interstitial lung disease and displaying massive accumulation of macrophages and overproduction of several chemokines, including macrophage chemoattractant protein-1 (MCP-1, encoded by Ccl2). To assess the clinical relevance of Fra-1 in lung pathology, mice were treated with the anticancer drug gefitinib (Iressa), which can lead to interstitial lung disease in patients. Gefitinib-treated mice showed increased Fosl1 and Ccl2 expression and developed interstitial lung disease in response to LPS, endogenous TLR ligands and chemotherapy. Moreover, deletion of Fra-1 or blocking MCP-1 receptor signaling in mice attenuated gefitinib-enhanced lethality in response to LPS. Importantly, human alveolar macrophages showed enhanced LPS-induced FOSL1 and CCL2 expression after gefitinib treatment. These results indicate that Fra-1 is an important mediator of interstitial lung disease following gefitinib treatment.

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A Phosphatidylinositol 3-Kinase-regulated Akt-Independent Signaling Promotes Cigarette Smoke-induced FRA-1 Expression

Cited by 35 publications

References 46 publications

Agonist-modulated Regulation of AMP-activated Protein Kinase (AMPK) in Endothelial Cells

Agonist-modulated Regulation of AMP-activated Protein Kinase (AMPK) in Endothelial Cells

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

Interstitial lung disease induced by gefitinib and Toll-like receptor ligands is mediated by Fra-1

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