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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

TNFα and RANKL stimulation activate the Akt and mTOR pathway.Western blot analysis of the expression of phospho-Akt, Akt, phospho-S6, and S6 from whole cell lysates of Pkd1 wild-type and Pkd1  MEK cells treated with TNFα (20 ng/ml) (A) and RANKL (100 ng/ml) (B). The numbers at the bottom indicate the intensities of p-Akt relative to total Akt and p-S6 relative to total S6.
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pone.0131043.g003: TNFα and RANKL stimulation activate the Akt and mTOR pathway.Western blot analysis of the expression of phospho-Akt, Akt, phospho-S6, and S6 from whole cell lysates of Pkd1 wild-type and Pkd1 MEK cells treated with TNFα (20 ng/ml) (A) and RANKL (100 ng/ml) (B). The numbers at the bottom indicate the intensities of p-Akt relative to total Akt and p-S6 relative to total S6.

Mentions: TNFα and RANKL have been found to activate PI3K in osteoclasts [26]. Activation of PI3K allows phosphoinositide-dependent kinase 1 (PDK1) to access and phosphorylate Thr308 in the activation loop of Akt [27]. The activation of Akt results in the phosphorylation and activation of mTOR in cancer and PKD [28, 29]. The activated mTOR has been found to regulate Id2 expression in mammary epithelial cells [30]. We found that TNFα and RANKL treatment induced the phosphorylation of Thr308 of Akt in Pkd1 wild type and mutant MEK cells (Fig 3A and 3B). Phosphorylation of Akt activates mTOR, which induces the activation of p70 S6 kinase at and the subsequent phosphorylation of S6 ribosomal protein [31]. We found that TNFα and RANKL treatment also induced phosphorylation of S6 in Pkd1 wild type and mutant MEK cells (Fig 3A and 3B).


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)

TNFα and RANKL stimulation activate the Akt and mTOR pathway.Western blot analysis of the expression of phospho-Akt, Akt, phospho-S6, and S6 from whole cell lysates of Pkd1 wild-type and Pkd1  MEK cells treated with TNFα (20 ng/ml) (A) and RANKL (100 ng/ml) (B). The numbers at the bottom indicate the intensities of p-Akt relative to total Akt and p-S6 relative to total S6.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131043.g003: TNFα and RANKL stimulation activate the Akt and mTOR pathway.Western blot analysis of the expression of phospho-Akt, Akt, phospho-S6, and S6 from whole cell lysates of Pkd1 wild-type and Pkd1 MEK cells treated with TNFα (20 ng/ml) (A) and RANKL (100 ng/ml) (B). The numbers at the bottom indicate the intensities of p-Akt relative to total Akt and p-S6 relative to total S6.
Mentions: TNFα and RANKL have been found to activate PI3K in osteoclasts [26]. Activation of PI3K allows phosphoinositide-dependent kinase 1 (PDK1) to access and phosphorylate Thr308 in the activation loop of Akt [27]. The activation of Akt results in the phosphorylation and activation of mTOR in cancer and PKD [28, 29]. The activated mTOR has been found to regulate Id2 expression in mammary epithelial cells [30]. We found that TNFα and RANKL treatment induced the phosphorylation of Thr308 of Akt in Pkd1 wild type and mutant MEK cells (Fig 3A and 3B). Phosphorylation of Akt activates mTOR, which induces the activation of p70 S6 kinase at and the subsequent phosphorylation of S6 ribosomal protein [31]. We found that TNFα and RANKL treatment also induced phosphorylation of S6 in Pkd1 wild type and mutant MEK cells (Fig 3A and 3B).

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