Inhibition of cellular proliferation through IκB kinase-independent and peroxisome proliferator-activated receptor γ-dependent repression of cyclin D1

C. Wang, M. Fu, M. D'Amico, C. Albanese, J. N. Zhou, M. Brownlee, M. P. Lisanti, V. K K Chatterjee, M. A. Lazar, R. G. Pestell

Research output: Contribution to journalArticle

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Abstract

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-regulated nuclear receptor superfamily member. Liganded PPARγ exerts diverse biological effects, promoting adipocyte differentiation, inhibiting tumor cellular proliferation, and regulating monocyte/macrophage and anti-inflammatory activities in vitro. In vivo studies with PPARγ ligands showed enhancement of tumor growth, raising the possibility that reduced immune function and tumor surveillance may outweigh the direct inhibitory effects of PPARγ ligands on cellular proliferation. Recent findings that PPARγ ligands convey PPARγ-independent activities through IκB kinase (IKK) raises important questions about the specific mechanisms through which PPARγ ligands inhibit cellular proliferation. We investigated the mechanisms regulating the antiproliferative effect of PPARγ. Herein PPARγ, liganded by either natural (15d-PGJ2 and PGD2) or synthetic ligands (BRL49653 and troglitazone), selectively inhibited expression of the cyclin D1 gene. The inhibition of S-phase entry and activity of the cyclin D1-dependent serine-threonine kinase (Cdk) by 15d-PGJ2 was not observed in PPARγ-deficient cells. Cyclin D1 overexpression reversed the S-phase inhibition by 15d-PGJ2. Cyclin D1 repression was independent of IKK, as prostaglandins (PGs) which bound PPARγ but lacked the IKK interactive cyclopentone ring carbonyl group repressed cyclin D1. Cyclin D1 repression by PPARγ involved competition for limiting abundance of p300, directed through a c-Fos binding site of the cyclin D1 promoter. 15d-PGJ2 enhanced recruitment of p300 to PPARγ but reduced binding to c-Fos. The identification of distinct pathways through which eicosanoids regulate anti-inflammatory and antiproliferative effects may improve the utility of COX2 inhibitors.

Original languageEnglish (US)
Pages (from-to)3057-3070
Number of pages14
JournalMolecular and Cellular Biology
Volume21
Issue number9
DOIs
StatePublished - 2001

Fingerprint

Peroxisome Proliferator-Activated Receptors
Cyclin D1
Phosphotransferases
Cell Proliferation
Ligands
rosiglitazone
troglitazone
Cytoplasmic and Nuclear Receptors
S Phase
Anti-Inflammatory Agents
bcl-1 Genes
Prostaglandin D2
Neoplasms
Cyclin-Dependent Kinases
Eicosanoids
Cyclooxygenase 2 Inhibitors
Protein-Serine-Threonine Kinases
Adipocytes
Prostaglandins
Monocytes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Inhibition of cellular proliferation through IκB kinase-independent and peroxisome proliferator-activated receptor γ-dependent repression of cyclin D1. / Wang, C.; Fu, M.; D'Amico, M.; Albanese, C.; Zhou, J. N.; Brownlee, M.; Lisanti, M. P.; Chatterjee, V. K K; Lazar, M. A.; Pestell, R. G.

In: Molecular and Cellular Biology, Vol. 21, No. 9, 2001, p. 3057-3070.

Research output: Contribution to journalArticle

Wang, C, Fu, M, D'Amico, M, Albanese, C, Zhou, JN, Brownlee, M, Lisanti, MP, Chatterjee, VKK, Lazar, MA & Pestell, RG 2001, 'Inhibition of cellular proliferation through IκB kinase-independent and peroxisome proliferator-activated receptor γ-dependent repression of cyclin D1', Molecular and Cellular Biology, vol. 21, no. 9, pp. 3057-3070. https://doi.org/10.1128/MCB.21.9.3057-3070.2001
Wang, C. ; Fu, M. ; D'Amico, M. ; Albanese, C. ; Zhou, J. N. ; Brownlee, M. ; Lisanti, M. P. ; Chatterjee, V. K K ; Lazar, M. A. ; Pestell, R. G. / Inhibition of cellular proliferation through IκB kinase-independent and peroxisome proliferator-activated receptor γ-dependent repression of cyclin D1. In: Molecular and Cellular Biology. 2001 ; Vol. 21, No. 9. pp. 3057-3070.
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AU - D'Amico, M.

AU - Albanese, C.

AU - Zhou, J. N.

AU - Brownlee, M.

AU - Lisanti, M. P.

AU - Chatterjee, V. K K

AU - Lazar, M. A.

AU - Pestell, R. G.

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