Home LiteratureArticle Details
PMID: 11287611 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Inhibition of cellular proliferation through IkappaB kinase-independent and peroxisome proliferator-activated receptor gamma-dependent repression of cyclin D1.

Molecular and cellular biology ·Vol. 21 ·No. 9 ·2001-05-00 ·Pages 3057-70

Wang C, Fu M, D'Amico M, Albanese C, Zhou JN, Brownlee M, Lisanti MP, Chatterjee VK, Lazar MA, Pestell RG

Abstract

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-regulated nuclear receptor superfamily member. Liganded PPARgamma 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 PPARgamma ligands showed enhancement of tumor growth, raising the possibility that reduced immune function and tumor surveillance may outweigh the direct inhibitory effects of PPARgamma ligands on cellular proliferation. Recent findings that PPARgamma ligands convey PPARgamma-independent activities through IkappaB kinase (IKK) raises important questions about the specific mechanisms through which PPARgamma ligands inhibit cellular proliferation. We investigated the mechanisms regulating the antiproliferative effect of PPARgamma. Herein PPARgamma, liganded by either natural (15d-PGJ(2) and PGD(2)) 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-PGJ(2) was not observed in PPARgamma-deficient cells. Cyclin D1 overexpression reversed the S-phase inhibition by 15d-PGJ(2). Cyclin D1 repression was independent of IKK, as prostaglandins (PGs) which bound PPARgamma but lacked the IKK interactive cyclopentone ring carbonyl group repressed cyclin D1. Cyclin D1 repression by PPARgamma involved competition for limiting abundance of p300, directed through a c-Fos binding site of the cyclin D1 promoter. 15d-PGJ(2) enhanced recruitment of p300 to PPARgamma 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.

MeSH Terms
Binding Sites Cell Division Cyclin D1/genetics,metabolism G1 Phase Gene Expression Regulation/drug effects Growth Inhibitors/genetics,metabolism HeLa Cells Humans I-kappa B Kinase Ligands Mitogen-Activated Protein Kinases/metabolism Nitric Oxide Synthase/metabolism Nitric Oxide Synthase Type II Nuclear Proteins/genetics,metabolism Promoter Regions, Genetic Prostaglandin D2/analogs & derivatives,metabolism,pharmacology Protein Serine-Threonine Kinases/metabolism Receptors, Cytoplasmic and Nuclear/genetics,metabolism Response Elements Trans-Activators/metabolism Transcription Factor AP-1/metabolism Transcription Factors/genetics,metabolism Tumor Cells, Cultured
Chemicals
Growth Inhibitors Ligands Nuclear Proteins Receptors, Cytoplasmic and Nuclear Trans-Activators Transcription Factor AP-1 Transcription Factors Cyclin D1 9-deoxy-delta-9-prostaglandin D2 NOS2 protein, human Nitric Oxide Synthase Nitric Oxide Synthase Type II Protein Serine-Threonine Kinases CHUK protein, human I-kappa B Kinase IKBKB protein, human IKBKE protein, human Mitogen-Activated Protein Kinases Prostaglandin D2
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Wang C
Departments of Developmental and Molecular Biology and Medicine, The Albert Einstein Cancer Center, Bronx, New York 10461, USA.
Fu M
D'Amico M
Albanese C
Zhou J N
Brownlee M
Lisanti M P
Chatterjee V K
Lazar M A
Pestell R G
References (70)
70 references, click to expand
  1. Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-kappaB-dependent pathway.
    J Biol Chem. 1999 Sep 3;274(36):25245-9 PMID: 10464245
  2. p300 and CBP: partners for life and death.
    J Cell Physiol. 1999 Nov;181(2):218-30 PMID: 10497301
  3. Peroxisome proliferator-activated receptors: nuclear control of metabolism.
    Endocr Rev. 1999 Oct;20(5):649-88 PMID: 10529898
  4. Activation of the cyclin D1 gene by the E1A-associated protein p300 through AP-1 inhibits cellular apoptosis.
    J Biol Chem. 1999 Nov 26;274(48):34186-95 PMID: 10567390
  5. Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway.
    Mol Cell Biol. 2000 Jan;20(2):672-83 PMID: 10611246
  6. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase.
    Nature. 2000 Jan 6;403(6765):103-8 PMID: 10638762
  7. Transcriptional regulation of adipogenesis.
    Genes Dev. 2000 Jun 1;14(11):1293-307 PMID: 10837022
  8. Peroxisome proliferator-activated receptor-gamma activators inhibit IFN-gamma-induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells.
    J Immunol. 2000 Jun 15;164(12):6503-8 PMID: 10843708
  9. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors.
    Cell. 1996 May 3;85(3):403-14 PMID: 8616895
  10. Angiotensin II activation of cyclin D1-dependent kinase activity.
    J Biol Chem. 1996 Sep 13;271(37):22570-7 PMID: 8798425
  11. Induction of cyclin D1 by simian virus 40 small tumor antigen.
    Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):12861-6 PMID: 8917510
  12. Convergence of mitogenic signalling cascades from diverse classes of receptors at the cyclin D-cyclin-dependent kinase-pRb-controlled G1 checkpoint.
    Mol Cell Biol. 1996 Dec;16(12):6917-25 PMID: 8943347
  13. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma.
    Science. 1996 Dec 20;274(5295):2100-3 PMID: 8953045
  14. Inhibition of IkappaB kinase and IkappaB phosphorylation by 15-deoxy-Delta(12,14)-prostaglandin J(2) in activated murine macrophages.
    Mol Cell Biol. 2000 Mar;20(5):1692-8 PMID: 10669746
  15. A dominant-negative peroxisome proliferator-activated receptor gamma (PPARgamma) mutant is a constitutive repressor and inhibits PPARgamma-mediated adipogenesis.
    J Biol Chem. 2000 Feb 25;275(8):5754-9 PMID: 10681562
  16. The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling.
    Semin Immunol. 2000 Feb;12(1):85-98 PMID: 10723801
  17. 15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway.
    Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4844-9 PMID: 10781090
  18. Analysis of domains in the IKKalpha and IKKbeta proteins that regulate their kinase activity.
    J Biol Chem. 2000 May 12;275(19):14752-9 PMID: 10747982
  19. Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators.
    Annu Rev Pharmacol Toxicol. 2000;40:491-518 PMID: 10836145
  20. Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site.
    J Biol Chem. 1997 Feb 21;272(8):5128-32 PMID: 9030579
  21. Hyperexpression of mitogen-activated protein kinase in human breast cancer.
    J Clin Invest. 1997 Apr 1;99(7):1478-83 PMID: 9119990
  22. Regulation of peroxisome proliferator-activated receptor gamma activity by mitogen-activated protein kinase.
    J Biol Chem. 1997 Apr 18;272(16):10811-6 PMID: 9099735
  23. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta.
    Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4312-7 PMID: 9113986
  24. Ligand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor gamma (PPARgamma). Differential activity of PPARgamma1 and -2 isoforms and influence of insulin.
    J Biol Chem. 1997 Aug 8;272(32):20230-5 PMID: 9242701
  25. PPARgamma induces cell cycle withdrawal: inhibition of E2F/DP DNA-binding activity via down-regulation of PP2A.
    Genes Dev. 1997 Aug 1;11(15):1987-98 PMID: 9271121
  26. Isolation and characterization of PBP, a protein that interacts with peroxisome proliferator-activated receptor.
    J Biol Chem. 1997 Oct 10;272(41):25500-6 PMID: 9325263
  27. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation.
    Nature. 1998 Jan 1;391(6662):79-82 PMID: 9422508
  28. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines.
    Nature. 1998 Jan 1;391(6662):82-6 PMID: 9422509
  29. Epidermal growth factor induction of the c-jun promoter by a Rac pathway.
    Mol Cell Biol. 1998 Feb;18(2):1065-73 PMID: 9448004
  30. Amyloid beta-peptide stimulates nitric oxide production in astrocytes through an NFkappaB-dependent mechanism.
    Proc Natl Acad Sci U S A. 1998 May 12;95(10):5795-800 PMID: 9576964
  31. Inhibition of cyclin D1 kinase activity is associated with E2F-mediated inhibition of cyclin D1 promoter activity through E2F and Sp1.
    Mol Cell Biol. 1998 Jun;18(6):3212-22 PMID: 9584162
  32. Transactivation by retinoid X receptor-peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimers: intermolecular synergy requires only the PPARgamma hormone-dependent activation function.
    Mol Cell Biol. 1998 Jun;18(6):3483-94 PMID: 9584188
  33. Terminal differentiation of human breast cancer through PPAR gamma.
    Mol Cell. 1998 Feb;1(3):465-70 PMID: 9660931
  34. Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice.
    Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8806-11 PMID: 9671760
  35. Fos family members induce cell cycle entry by activating cyclin D1.
    Mol Cell Biol. 1998 Sep;18(9):5609-19 PMID: 9710644
  36. Differentiation and reversal of malignant changes in colon cancer through PPARgamma.
    Nat Med. 1998 Sep;4(9):1046-52 PMID: 9734398
  37. Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice.
    Nat Med. 1998 Sep;4(9):1053-7 PMID: 9734399
  38. Activators of the nuclear receptor PPARgamma enhance colon polyp formation.
    Nat Med. 1998 Sep;4(9):1058-61 PMID: 9734400
  39. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma.
    Nature. 1998 Sep 10;395(6698):137-43 PMID: 9744270
  40. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages.
    J Biol Chem. 1998 Oct 2;273(40):25573-80 PMID: 9748221
  41. Activation of PPARgamma leads to inhibition of anchorage-independent growth of human colorectal cancer cells.
    Gastroenterology. 1998 Nov;115(5):1049-55 PMID: 9797355
  42. Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation.
    Genes Dev. 1998 Nov 1;12(21):3357-68 PMID: 9808623
  43. Interdomain communication regulating ligand binding by PPAR-gamma.
    Nature. 1998 Nov 26;396(6709):377-80 PMID: 9845075
  44. Transcriptional regulation of the cyclin D1 promoter by STAT5: its involvement in cytokine-dependent growth of hematopoietic cells.
    EMBO J. 1999 Mar 1;18(5):1367-77 PMID: 10064602
  45. pp60(v-src) induction of cyclin D1 requires collaborative interactions between the extracellular signal-regulated kinase, p38, and Jun kinase pathways. A role for cAMP response element-binding protein and activating transcription factor-2 in pp60(v-src) signaling in breast cancer cells.
    J Biol Chem. 1999 Mar 12;274(11):7341-50 PMID: 10066798
  46. p300 interacts with the N- and C-terminal part of PPARgamma2 in a ligand-independent and -dependent manner, respectively.
    J Biol Chem. 1999 Mar 19;274(12):7681-8 PMID: 10075656
  47. Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene.
    Mol Cell Biol. 2000 Jul;20(13):4699-707 PMID: 10848596
  48. Discrete roles for peroxisome proliferator-activated receptor gamma and retinoid X receptor in recruiting nuclear receptor coactivators.
    Mol Cell Biol. 2000 Nov;20(21):8008-17 PMID: 11027271
  49. Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators.
    J Biol Chem. 2000 Oct 27;275(43):33201-4 PMID: 10944516
  50. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation.
    Nat Med. 2001 Jan;7(1):48-52 PMID: 11135615
  51. NF-kappaB and cell-cycle regulation: the cyclin connection.
    Cytokine Growth Factor Rev. 2001 Mar;12(1):73-90 PMID: 11312120
  52. Ras regulation of cyclin-dependent immunoprecipitation kinase assays.
    Methods Enzymol. 2001;333:127-38 PMID: 11400330
  53. Prostaglandins with antiproliferative activity induce the synthesis of a heat shock protein in human cells.
    Proc Natl Acad Sci U S A. 1989 Nov;86(21):8407-11 PMID: 2813398
  54. Analysis with specific polyclonal antiserum indicates that the E1A-associated 300-kDa product is a stable nuclear phosphoprotein that undergoes cell cycle phase-specific modification.
    Mol Cell Biol. 1991 Nov;11(11):5389-97 PMID: 1833633
  55. Expression and amplification of cyclin genes in human breast cancer.
    Oncogene. 1993 Aug;8(8):2127-33 PMID: 8336939
  56. Distinct roles for cyclin-dependent kinases in cell cycle control.
    Science. 1993 Dec 24;262(5142):2050-4 PMID: 8266103
  57. Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system.
    Mol Cell Biol. 1994 Mar;14(3):1669-79 PMID: 8114703
  58. Activation of cAMP and mitogen responsive genes relies on a common nuclear factor.
    Nature. 1994 Jul 21;370(6486):226-9 PMID: 8028671
  59. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer.
    Genes Dev. 1994 May 15;8(10):1224-34 PMID: 7926726
  60. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor.
    Cell. 1994 Dec 30;79(7):1147-56 PMID: 8001151
  61. Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions.
    J Biol Chem. 1995 Oct 6;270(40):23589-97 PMID: 7559524
  62. Differential activation of peroxisome proliferator-activated receptors by eicosanoids.
    J Biol Chem. 1995 Oct 13;270(41):23975-83 PMID: 7592593
  63. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma.
    Cell. 1995 Dec 1;83(5):803-12 PMID: 8521497
  64. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation.
    Cell. 1995 Dec 1;83(5):813-9 PMID: 8521498
  65. Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation.
    Science. 1999 Apr 9;284(5412):309-13 PMID: 10195894
  66. BRCA1 inhibition of estrogen receptor signaling in transfected cells.
    Science. 1999 May 21;284(5418):1354-6 PMID: 10334989
  67. Protein kinase Cdelta inhibition of S-phase transition in capillary endothelial cells involves the cyclin-dependent kinase inhibitor p27(Kip1).
    J Biol Chem. 1999 Jul 23;274(30):20805-11 PMID: 10409620
  68. NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1.
    Mol Cell Biol. 1999 Aug;19(8):5785-99 PMID: 10409765
  69. The cyclins and cyclin-dependent kinase inhibitors in hormonal regulation of proliferation and differentiation.
    Endocr Rev. 1999 Aug;20(4):501-34 PMID: 10453356
  70. Stat3 as an oncogene.
    Cell. 1999 Aug 6;98(3):295-303 PMID: 10458605
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.21.9.3057-3070.2001
Published
2001-05-00
Pages
3057-70
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC86934
Subset
IM
Grants
NCI NIH HHS · R01 CA075503 · United States
NCI NIH HHS · R01 CA77552 · United States
NCI NIH HHS · R01CA75503 · United States
NCI NIH HHS · R01CA70897 · United States
NCI NIH HHS · P30 CA013330 · United States
NCI NIH HHS · 5-P30-CA13330-26 · United States
External Links
PubMed source DOI: 10.1128/MCB.21.9.3057-3070.2001 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2