| First Author | Zhu B | Year | 2014 |
| Journal | Oncogene | Volume | 33 |
| Issue | 46 | Pages | 5348-59 |
| PubMed ID | 24213576 | Mgi Jnum | J:216271 |
| Mgi Id | MGI:5608578 | Doi | 10.1038/onc.2013.477 |
| Citation | Zhu B, et al. (2014) PPARbeta/delta promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling. Oncogene 33(46):5348-59 |
| abstractText | Peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) inhibits skin tumorigenesis through mechanisms that may be dependent on HRAS signaling. The present study examined the hypothesis that PPARbeta/delta promotes HRAS-induced senescence resulting in suppression of tumorigenesis. PPARbeta/delta 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 PPARbeta/delta. 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 Pparbeta/delta-null cells. Higher PPARbeta/delta expression is also correlated with increased senescence observed in human benign neurofibromas and colon adenoma lesions in vivo. These results demonstrate that PPARbeta/delta promotes senescence to inhibit tumorigenesis and provide new mechanistic insights into HRAS-induced cellular senescence. |
