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- Title
PPARβ/δ promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling.
- Authors
Zhu, B; Ferry, C H; Blazanin, N; Bility, M T; Khozoie, C; Kang, B-H; Glick, A B; Gonzalez, F J; Peters, J M
- Abstract
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.
- Subjects
PEROXISOME proliferator-activated receptors; HRAS genes; TUMOR suppressor proteins; NEOPLASTIC cell transformation; CELLULAR signal transduction; PHOSPHOINOSITIDE-dependent kinase-1
- Publication
Oncogene, 2014, Vol 33, Issue 46, p5348
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2013.477