Limits...
PPARβ/δ promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling.

Zhu B, Ferry CH, Blazanin N, Bility MT, Khozoie C, Kang BH, Glick AB, Gonzalez FJ, Peters JM - Oncogene (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary and Biomedical Sciences, The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA.

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- 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.

Show MeSH

Related in: MedlinePlus

PPARβ/δ promotes HRAS-induced senescence by potentiating p-ERK and repressing p-AKT. HRAS-induced senescence is promoted by RAF/MEK/ERK pathway and inhibited by the PI3K/AKT pathway. The end result is increased expression of proteins that mediate senescence including p16, p21, p27 and p53. PPARβ/δ promotes senescence by inhibiting the PI3K/AKT pathway allowing for increased RAF/MEK/ERK activity. This is mediated by PPARβ/δ-dependent modulation of RASGRP1, PDPK1 and ILK expression.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4017002&req=5

Figure 8: PPARβ/δ promotes HRAS-induced senescence by potentiating p-ERK and repressing p-AKT. HRAS-induced senescence is promoted by RAF/MEK/ERK pathway and inhibited by the PI3K/AKT pathway. The end result is increased expression of proteins that mediate senescence including p16, p21, p27 and p53. PPARβ/δ promotes senescence by inhibiting the PI3K/AKT pathway allowing for increased RAF/MEK/ERK activity. This is mediated by PPARβ/δ-dependent modulation of RASGRP1, PDPK1 and ILK expression.

Mentions: Results from these studies are the first to show that PPARβ/δ promotes HRAS-induced senescence in keratinocytes and skin tumors. PPARβ/δ promotes senescence by enhancing the RAF/MEK/ERK pathway and inhibiting the PI3K/AKT pathway during HRAS-induced neoplastic transformation. These studies also demonstrated that increased p-ERK and decreased p-AKT activities are both required to facilitate senescence. This conclusion is supported by several studies that showed that higher pERK activity could trigger senescence by upregulating expression of p16 and p21 20, 39, 40. This is consistent with data from the present studies showing that higher PPARβ/δ expression in benign tumors is associated with higher expression of p16. Further, results from the present studies are consistent with other studies showing that high PI3K/AKT activity can prevent HRAS-induced senescence by inhibiting FOXO activity and increasing MDM2 activity that collectively cause reduced expression of p27, p21 and p53 27, 41. Among these senescence markers, the most robust change observed in Pparβ/δ- keratinocytes was the marked reduction of p27. p27 has been previously shown to promote senescence in multiple tissues and loss of p27 expression led to down-regulation of senescence and progression of cancer 21, 42–44. Collectively, these results suggest that PPARβ/δ inhibits AKT activity causing: 1) increased FOXO activity thereby preventing down-regulation of p27 and p21 caused by activation of HRAS, and 2) decreased p-MDM2 activity thereby preventing down-regulation of p53 mediated by activation of HRAS (Figure 8). Higher PI3K/AKT signaling can also counteract senescence by stimulating cell survival by phosphorylation of many substrates 45. The fact that inhibition of AKT didn’t promote senescence in wild-type HRAS-expressing keratinocytes, whereas inhibition of AKT in Pparβ/δ- keratinocytes did promote senescence suggests that there may be different threshold levels of p-AKT required for promoting pro-survival versus an anti-senescence function of p-AKT.


PPARβ/δ promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling.

Zhu B, Ferry CH, Blazanin N, Bility MT, Khozoie C, Kang BH, Glick AB, Gonzalez FJ, Peters JM - Oncogene (2013)

PPARβ/δ promotes HRAS-induced senescence by potentiating p-ERK and repressing p-AKT. HRAS-induced senescence is promoted by RAF/MEK/ERK pathway and inhibited by the PI3K/AKT pathway. The end result is increased expression of proteins that mediate senescence including p16, p21, p27 and p53. PPARβ/δ promotes senescence by inhibiting the PI3K/AKT pathway allowing for increased RAF/MEK/ERK activity. This is mediated by PPARβ/δ-dependent modulation of RASGRP1, PDPK1 and ILK expression.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4017002&req=5

Figure 8: PPARβ/δ promotes HRAS-induced senescence by potentiating p-ERK and repressing p-AKT. HRAS-induced senescence is promoted by RAF/MEK/ERK pathway and inhibited by the PI3K/AKT pathway. The end result is increased expression of proteins that mediate senescence including p16, p21, p27 and p53. PPARβ/δ promotes senescence by inhibiting the PI3K/AKT pathway allowing for increased RAF/MEK/ERK activity. This is mediated by PPARβ/δ-dependent modulation of RASGRP1, PDPK1 and ILK expression.
Mentions: Results from these studies are the first to show that PPARβ/δ promotes HRAS-induced senescence in keratinocytes and skin tumors. PPARβ/δ promotes senescence by enhancing the RAF/MEK/ERK pathway and inhibiting the PI3K/AKT pathway during HRAS-induced neoplastic transformation. These studies also demonstrated that increased p-ERK and decreased p-AKT activities are both required to facilitate senescence. This conclusion is supported by several studies that showed that higher pERK activity could trigger senescence by upregulating expression of p16 and p21 20, 39, 40. This is consistent with data from the present studies showing that higher PPARβ/δ expression in benign tumors is associated with higher expression of p16. Further, results from the present studies are consistent with other studies showing that high PI3K/AKT activity can prevent HRAS-induced senescence by inhibiting FOXO activity and increasing MDM2 activity that collectively cause reduced expression of p27, p21 and p53 27, 41. Among these senescence markers, the most robust change observed in Pparβ/δ- keratinocytes was the marked reduction of p27. p27 has been previously shown to promote senescence in multiple tissues and loss of p27 expression led to down-regulation of senescence and progression of cancer 21, 42–44. Collectively, these results suggest that PPARβ/δ inhibits AKT activity causing: 1) increased FOXO activity thereby preventing down-regulation of p27 and p21 caused by activation of HRAS, and 2) decreased p-MDM2 activity thereby preventing down-regulation of p53 mediated by activation of HRAS (Figure 8). Higher PI3K/AKT signaling can also counteract senescence by stimulating cell survival by phosphorylation of many substrates 45. The fact that inhibition of AKT didn’t promote senescence in wild-type HRAS-expressing keratinocytes, whereas inhibition of AKT in Pparβ/δ- keratinocytes did promote senescence suggests that there may be different threshold levels of p-AKT required for promoting pro-survival versus an anti-senescence function of p-AKT.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary and Biomedical Sciences, The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA.

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- 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.

Show MeSH
Related in: MedlinePlus