The nuclear receptor peroxisome proliferator-activated receptor-β/ δ (PPARβ/δ) promotes oncogene-induced cellular senescence through repression of endoplasmic reticulum stress

Bokai Zhu, Christina H. Ferry, Lauren K. Markell, Nicholas Blazanin, Adam B. Glick, Frank J. Gonzalez, Jeffrey M. Peters

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Endoplasmic reticulum (ER) stress and ER stress-associated unfolded protein response (UPR) can promote cancer cell survival, but it remains unclear whether they can influence oncogene-induced senescence. The present study examined the role of ER stress in senescence using oncogene-dependent models. Increased ER stress attenuated senescence in part by up-regulating phosphorylated protein kinase B (p-AKT) and decreasing phosphorylated extracellular signal-regulated kinase (p-ERK). A positive feed forward loop between p-AKT, ER stress, and UPR was discovered whereby a transient increase of ER stress caused reduced senescence and promotion of tumorigenesis. Decreased ER stress was further correlated with increased senescence in both mouse and human tumors. Interestingly, H-RAS-expressing Pparβ/δ null cells and tumors having increased cell proliferation exhibited enhanced ER stress, decreased cellular senescence, and/or enhanced tumorigenicity. Collectively, these results demonstrate a new role for ER stress and UPR that attenuates H-RAS-induced senescence and suggest that PPARβ/δ can repress this oncogene-induced ER stress to promote senescence in accordance with its role as a tumor modifier that suppresses carcinogenesis.

Original languageEnglish (US)
Pages (from-to)20102-20119
Number of pages18
JournalJournal of Biological Chemistry
Volume289
Issue number29
DOIs
StatePublished - Jan 1 2014

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Peroxisome Proliferator-Activated Receptors
Endoplasmic Reticulum Stress
Cell Aging
Cytoplasmic and Nuclear Receptors
Oncogenes
Unfolded Protein Response
Tumors
Heat-Shock Proteins
Neoplasms
Carcinogenesis
Null Lymphocytes
Proto-Oncogene Proteins c-akt
Proteins
Extracellular Signal-Regulated MAP Kinases
Cell proliferation
Cell Survival
Cells
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "The nuclear receptor peroxisome proliferator-activated receptor-β/ δ (PPARβ/δ) promotes oncogene-induced cellular senescence through repression of endoplasmic reticulum stress",
abstract = "Endoplasmic reticulum (ER) stress and ER stress-associated unfolded protein response (UPR) can promote cancer cell survival, but it remains unclear whether they can influence oncogene-induced senescence. The present study examined the role of ER stress in senescence using oncogene-dependent models. Increased ER stress attenuated senescence in part by up-regulating phosphorylated protein kinase B (p-AKT) and decreasing phosphorylated extracellular signal-regulated kinase (p-ERK). A positive feed forward loop between p-AKT, ER stress, and UPR was discovered whereby a transient increase of ER stress caused reduced senescence and promotion of tumorigenesis. Decreased ER stress was further correlated with increased senescence in both mouse and human tumors. Interestingly, H-RAS-expressing Pparβ/δ null cells and tumors having increased cell proliferation exhibited enhanced ER stress, decreased cellular senescence, and/or enhanced tumorigenicity. Collectively, these results demonstrate a new role for ER stress and UPR that attenuates H-RAS-induced senescence and suggest that PPARβ/δ can repress this oncogene-induced ER stress to promote senescence in accordance with its role as a tumor modifier that suppresses carcinogenesis.",
author = "Bokai Zhu and Ferry, {Christina H.} and Markell, {Lauren K.} and Nicholas Blazanin and Glick, {Adam B.} and Gonzalez, {Frank J.} and Peters, {Jeffrey M.}",
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The nuclear receptor peroxisome proliferator-activated receptor-β/ δ (PPARβ/δ) promotes oncogene-induced cellular senescence through repression of endoplasmic reticulum stress. / Zhu, Bokai; Ferry, Christina H.; Markell, Lauren K.; Blazanin, Nicholas; Glick, Adam B.; Gonzalez, Frank J.; Peters, Jeffrey M.

In: Journal of Biological Chemistry, Vol. 289, No. 29, 01.01.2014, p. 20102-20119.

Research output: Contribution to journalArticle

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AU - Zhu, Bokai

AU - Ferry, Christina H.

AU - Markell, Lauren K.

AU - Blazanin, Nicholas

AU - Glick, Adam B.

AU - Gonzalez, Frank J.

AU - Peters, Jeffrey M.

PY - 2014/1/1

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N2 - Endoplasmic reticulum (ER) stress and ER stress-associated unfolded protein response (UPR) can promote cancer cell survival, but it remains unclear whether they can influence oncogene-induced senescence. The present study examined the role of ER stress in senescence using oncogene-dependent models. Increased ER stress attenuated senescence in part by up-regulating phosphorylated protein kinase B (p-AKT) and decreasing phosphorylated extracellular signal-regulated kinase (p-ERK). A positive feed forward loop between p-AKT, ER stress, and UPR was discovered whereby a transient increase of ER stress caused reduced senescence and promotion of tumorigenesis. Decreased ER stress was further correlated with increased senescence in both mouse and human tumors. Interestingly, H-RAS-expressing Pparβ/δ null cells and tumors having increased cell proliferation exhibited enhanced ER stress, decreased cellular senescence, and/or enhanced tumorigenicity. Collectively, these results demonstrate a new role for ER stress and UPR that attenuates H-RAS-induced senescence and suggest that PPARβ/δ can repress this oncogene-induced ER stress to promote senescence in accordance with its role as a tumor modifier that suppresses carcinogenesis.

AB - Endoplasmic reticulum (ER) stress and ER stress-associated unfolded protein response (UPR) can promote cancer cell survival, but it remains unclear whether they can influence oncogene-induced senescence. The present study examined the role of ER stress in senescence using oncogene-dependent models. Increased ER stress attenuated senescence in part by up-regulating phosphorylated protein kinase B (p-AKT) and decreasing phosphorylated extracellular signal-regulated kinase (p-ERK). A positive feed forward loop between p-AKT, ER stress, and UPR was discovered whereby a transient increase of ER stress caused reduced senescence and promotion of tumorigenesis. Decreased ER stress was further correlated with increased senescence in both mouse and human tumors. Interestingly, H-RAS-expressing Pparβ/δ null cells and tumors having increased cell proliferation exhibited enhanced ER stress, decreased cellular senescence, and/or enhanced tumorigenicity. Collectively, these results demonstrate a new role for ER stress and UPR that attenuates H-RAS-induced senescence and suggest that PPARβ/δ can repress this oncogene-induced ER stress to promote senescence in accordance with its role as a tumor modifier that suppresses carcinogenesis.

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