Limits...
TNFα signaling regulates cystic epithelial cell proliferation through Akt/mTOR and ERK/MAPK/Cdk2 mediated Id2 signaling.

Zhou JX, Fan LX, Li X, Calvet JP, Li X - PLoS ONE (2015)

Bottom Line: However, the cross-talk between TNFα and PKD associated signaling pathways remains elusive.In this study, we found that stimulation of renal epithelial cells with TNFα or RANKL (receptor activator of NF-κB ligand), a member of the TNFα cytokine family, activated either the PI3K pathway, leading to AKT and mTOR mediated the increase of Id2 protein, or MAPK and Cdk2 to induce Id2 nuclear translocation.The effects of TNFα/RANKL on increasing Id2 protein and its nuclear translocation caused significantly decreased mRNA and protein levels of the Cdk inhibitor p21, allowing increased cell proliferation.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, United States of America; Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160, United States of America.

ABSTRACT
Tumor necrosis factor alpha (TNFα) is present in cyst fluid and promotes cyst growth in autosomal dominant polycystic kidney disease (ADPKD). However, the cross-talk between TNFα and PKD associated signaling pathways remains elusive. In this study, we found that stimulation of renal epithelial cells with TNFα or RANKL (receptor activator of NF-κB ligand), a member of the TNFα cytokine family, activated either the PI3K pathway, leading to AKT and mTOR mediated the increase of Id2 protein, or MAPK and Cdk2 to induce Id2 nuclear translocation. The effects of TNFα/RANKL on increasing Id2 protein and its nuclear translocation caused significantly decreased mRNA and protein levels of the Cdk inhibitor p21, allowing increased cell proliferation. TNFα levels increase in cystic kidneys in response to macrophage infiltration and thus might contribute to cyst growth and enlargement during the progression of disease. As such, this study elucidates a novel mechanism for TNFα signaling in regulating cystic renal epithelial cell proliferation in ADPKD.

No MeSH data available.


Related in: MedlinePlus

Inhibition of PI3K blocks the activation of mTOR and Cdk2 induced by TNFα and RANKL.Pkd1 wild type MEK cells were pretreated with PI3K inhibitor, LY294002 (20 μM, mark as LY), for 1 hour, and then stimulated by TNFα (20 ng/ml) (A) or RANKL (100 ng/ml) (B) for 30 minutes. The expression of phospho-Akt, Akt, phospho-S6 and S6, phospho-Cdk2 and Cdk2 from whole cell lysates was analyzed by western blot. The numbers at the bottom indicate the intensities of p-Akt relative to total Akt, p-S6 relative to total S6 and p-Cdk2 relative to total Cdk2.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4482222&req=5

pone.0131043.g005: Inhibition of PI3K blocks the activation of mTOR and Cdk2 induced by TNFα and RANKL.Pkd1 wild type MEK cells were pretreated with PI3K inhibitor, LY294002 (20 μM, mark as LY), for 1 hour, and then stimulated by TNFα (20 ng/ml) (A) or RANKL (100 ng/ml) (B) for 30 minutes. The expression of phospho-Akt, Akt, phospho-S6 and S6, phospho-Cdk2 and Cdk2 from whole cell lysates was analyzed by western blot. The numbers at the bottom indicate the intensities of p-Akt relative to total Akt, p-S6 relative to total S6 and p-Cdk2 relative to total Cdk2.

Mentions: Last, we found that treatment with TNFα or RANKL in the presence of LY294002, an inhibitor of PI3K, decreased the phosphorylation of AKT and S6 but not the levels of AKT and S6 in Pkd1 wild type MEK cells compared with cells treated with TNFα or RANKL alone (Fig 5A and 5B). These results suggested that TNFα and RANKL regulate the expression of Id2 through PI3K to activate the Akt/mTOR pathway.


TNFα signaling regulates cystic epithelial cell proliferation through Akt/mTOR and ERK/MAPK/Cdk2 mediated Id2 signaling.

Zhou JX, Fan LX, Li X, Calvet JP, Li X - PLoS ONE (2015)

Inhibition of PI3K blocks the activation of mTOR and Cdk2 induced by TNFα and RANKL.Pkd1 wild type MEK cells were pretreated with PI3K inhibitor, LY294002 (20 μM, mark as LY), for 1 hour, and then stimulated by TNFα (20 ng/ml) (A) or RANKL (100 ng/ml) (B) for 30 minutes. The expression of phospho-Akt, Akt, phospho-S6 and S6, phospho-Cdk2 and Cdk2 from whole cell lysates was analyzed by western blot. The numbers at the bottom indicate the intensities of p-Akt relative to total Akt, p-S6 relative to total S6 and p-Cdk2 relative to total Cdk2.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482222&req=5

pone.0131043.g005: Inhibition of PI3K blocks the activation of mTOR and Cdk2 induced by TNFα and RANKL.Pkd1 wild type MEK cells were pretreated with PI3K inhibitor, LY294002 (20 μM, mark as LY), for 1 hour, and then stimulated by TNFα (20 ng/ml) (A) or RANKL (100 ng/ml) (B) for 30 minutes. The expression of phospho-Akt, Akt, phospho-S6 and S6, phospho-Cdk2 and Cdk2 from whole cell lysates was analyzed by western blot. The numbers at the bottom indicate the intensities of p-Akt relative to total Akt, p-S6 relative to total S6 and p-Cdk2 relative to total Cdk2.
Mentions: Last, we found that treatment with TNFα or RANKL in the presence of LY294002, an inhibitor of PI3K, decreased the phosphorylation of AKT and S6 but not the levels of AKT and S6 in Pkd1 wild type MEK cells compared with cells treated with TNFα or RANKL alone (Fig 5A and 5B). These results suggested that TNFα and RANKL regulate the expression of Id2 through PI3K to activate the Akt/mTOR pathway.

Bottom Line: However, the cross-talk between TNFα and PKD associated signaling pathways remains elusive.In this study, we found that stimulation of renal epithelial cells with TNFα or RANKL (receptor activator of NF-κB ligand), a member of the TNFα cytokine family, activated either the PI3K pathway, leading to AKT and mTOR mediated the increase of Id2 protein, or MAPK and Cdk2 to induce Id2 nuclear translocation.The effects of TNFα/RANKL on increasing Id2 protein and its nuclear translocation caused significantly decreased mRNA and protein levels of the Cdk inhibitor p21, allowing increased cell proliferation.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, United States of America; Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160, United States of America.

ABSTRACT
Tumor necrosis factor alpha (TNFα) is present in cyst fluid and promotes cyst growth in autosomal dominant polycystic kidney disease (ADPKD). However, the cross-talk between TNFα and PKD associated signaling pathways remains elusive. In this study, we found that stimulation of renal epithelial cells with TNFα or RANKL (receptor activator of NF-κB ligand), a member of the TNFα cytokine family, activated either the PI3K pathway, leading to AKT and mTOR mediated the increase of Id2 protein, or MAPK and Cdk2 to induce Id2 nuclear translocation. The effects of TNFα/RANKL on increasing Id2 protein and its nuclear translocation caused significantly decreased mRNA and protein levels of the Cdk inhibitor p21, allowing increased cell proliferation. TNFα levels increase in cystic kidneys in response to macrophage infiltration and thus might contribute to cyst growth and enlargement during the progression of disease. As such, this study elucidates a novel mechanism for TNFα signaling in regulating cystic renal epithelial cell proliferation in ADPKD.

No MeSH data available.


Related in: MedlinePlus