PPARβ/δ promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling.
PPARβ/δ promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling.
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Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) inhibits skin tumorigenesis through mechanisms that may be dependent on HRAS signaling. The present study examined the hypothesis that PPARβ/δ promotes HRAS-induced senescence resulting in suppression of tumorigenesis. PPARβ/δ expression increased p-ERK and decreased p-AKT activity. Increased p-ERK activity results from the dampened HRAS-induced negative feedback response mediated in part through transcriptional upregulation of RAS guanyl-releasing protein 1 (RASGRP1) by PPARβ/δ. Decreased p-AKT activity results from repression of integrin-linked kinase (ILK) and phosphoinositide dependent protein kinase-1 (PDPK1) expression. Decreased p-AKT activity in turn promotes cellular senescence through upregulation of p53 and p27 expression. Both over-expression of RASGRP1 and shRNA-mediated knockdown of ILK partially restore cellular senescence in Pparβ/δ-null cells. Higher PPARβ/δ expression is also correlated with increased senescence observed in human benign neurofibromas and colon adenoma lesions in vivo. These results demonstrate that PPARβ/δ promotes senescence to inhibit tumorigenesis and provide new mechanistic insights into HRAS-induced cellular senescence.
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影响因子：
3.6
作者：
Borland MG;Foreman JE;Girroir EE;Zolfaghari R;Sharma AK;Amin S;Gonzalez FJ;Ross AC;Peters JM
通讯作者：
Peters JM
全基因组分析通过过氧化物酶体增殖物激活受体-β/δ（PPARβ/δ）定义了不同的转录调节模式。
影响因子：
3.7
作者：
Adhikary T;Kaddatz K;Finkernagel F;Schönbauer A;Meissner W;Scharfe M;Jarek M;Blöcker H;Müller-Brüsselbach S;Müller R
通讯作者：
Müller R
影响因子：
4.6
作者：
Foreman, Jennifer E.;Chang, Wen-Chi L.;Palkar, Prajakta S.;Zhu, Bokai;Borland, Michael G.;Williams, Jennie L.;Kramer, Lance R.;Clapper, Margie L.;Gonzalez, Frank J.;Peters, Jeffrey M.
通讯作者：
Peters, Jeffrey M.
影响因子：
16
作者：
Kennedy AL;Morton JP;Manoharan I;Nelson DM;Jamieson NB;Pawlikowski JS;McBryan T;Doyle B;McKay C;Oien KA;Enders GH;Zhang R;Sansom OJ;Adams PD
通讯作者：
Adams PD
影响因子：
4.8
作者：
Cao, Xiaoxiao;Xue, Lixiang;Tong, Tanjun
通讯作者：
Tong, Tanjun