Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 2003 Mar 15;370(Pt 3):1019–1025. doi: 10.1042/BJ20021503

Early stimulation and late inhibition of peroxisome proliferator-activated receptor gamma (PPAR gamma) gene expression by transforming growth factor beta in human aortic smooth muscle cells: role of early growth-response factor-1 (Egr-1), activator protein 1 (AP1) and Smads.

Mingui Fu 1, Jifeng Zhang 1, Yimin Lin 1, Xiaojun Zhu 1, Luning Zhao 1, Mushtaq Ahmad 1, Markus U Ehrengruber 1, Yuqing E Chen 1
PMCID: PMC1223218  PMID: 12457461

Abstract

Transforming growth factor beta (TGF beta) and peroxisome proliferator-activated receptor gamma (PPAR gamma) play major roles in the development of vascular diseases. It has been documented that PPAR gamma activation inhibits the TGF beta signal pathway in vascular smooth muscle cells (VSMC). Here we examined whether TGF beta can regulate PPAR gamma expression. Northern blot analyses revealed that both TGF beta 1 and 2 exert a biphasic effect (early stimulation and late repression) on PPAR gamma gene expression in VSMC. TGF beta rapidly and transiently induced early growth-response factor-1 (Egr-1) expression through the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 (MEK1)/ERK-mediated pathway. Inhibition of MEK1/ERK by PD98059 not only abrogated the induction of Egr-1 but also abolished the rapid and transient induction of PPAR gamma by TGF beta. Furthermore, overexpression of NAB2, a repressor of Egr-1 activation, also blocked the induction of PPAR gamma by TGF beta in VSMC, suggesting that Egr-1 mediates the rapid and transient induction of PPAR gamma by TGF beta. With regard to the TGF beta repression of PPAR gamma expression, activator protein 1 (AP1) and Smad3/4 dramatically inhibited the PPAR gamma promoter activity in transient-transfection studies. In contrast, adenovirus-mediated overexpression of a dominant-negative form of c-Jun partially rescued the TGF beta-induced PPAR gamma repression in VSMC. Taken together, our data demonstrate that Egr-1, AP1 and Smad are part components of the TGF beta signal transduction pathway that regulates PPAR gamma expression.

Full Text

The Full Text of this article is available as a PDF (271.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahdjoudj Souhila, Lasmoles Françoise, Holy Xavier, Zerath Erik, Marie Pierre J. Transforming growth factor beta2 inhibits adipocyte differentiation induced by skeletal unloading in rat bone marrow stroma. J Bone Miner Res. 2002 Apr;17(4):668–677. doi: 10.1359/jbmr.2002.17.4.668. [DOI] [PubMed] [Google Scholar]
  2. Brown P. H., Chen T. K., Birrer M. J. Mechanism of action of a dominant-negative mutant of c-Jun. Oncogene. 1994 Mar;9(3):791–799. [PubMed] [Google Scholar]
  3. Ehrengruber M. U., Muhlebach S. G., Söhrman S., Leutenegger C. M., Lester H. A., Davidson N. Modulation of early growth response (EGR) transcription factor-dependent gene expression by using recombinant adenovirus. Gene. 2000 Nov 27;258(1-2):63–69. doi: 10.1016/s0378-1119(00)00445-5. [DOI] [PubMed] [Google Scholar]
  4. Fajas L., Auboeuf D., Raspé E., Schoonjans K., Lefebvre A. M., Saladin R., Najib J., Laville M., Fruchart J. C., Deeb S. The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem. 1997 Jul 25;272(30):18779–18789. doi: 10.1074/jbc.272.30.18779. [DOI] [PubMed] [Google Scholar]
  5. Fu M., Zhang J., Zhu X., Myles D. E., Willson T. M., Liu X., Chen Y. E. Peroxisome proliferator-activated receptor gamma inhibits transforming growth factor beta-induced connective tissue growth factor expression in human aortic smooth muscle cells by interfering with Smad3. J Biol Chem. 2001 Oct 5;276(49):45888–45894. doi: 10.1074/jbc.M105490200. [DOI] [PubMed] [Google Scholar]
  6. Fu M., Zhu X., Wang Q., Zhang J., Song Q., Zheng H., Ogawa W., Du J., Chen Y. E. Platelet-derived growth factor promotes the expression of peroxisome proliferator-activated receptor gamma in vascular smooth muscle cells by a phosphatidylinositol 3-kinase/Akt signaling pathway. Circ Res. 2001 Nov 23;89(11):1058–1064. doi: 10.1161/hh2301.099642. [DOI] [PubMed] [Google Scholar]
  7. Fu Mingui, Zhang Jifeng, Lin Yiming, Zhu Xiaojun, Ehrengruber Markus U., Chen Yuqing E. Early growth response factor-1 is a critical transcriptional mediator of peroxisome proliferator-activated receptor-gamma 1 gene expression in human aortic smooth muscle cells. J Biol Chem. 2002 May 13;277(30):26808–26814. doi: 10.1074/jbc.M203748200. [DOI] [PubMed] [Google Scholar]
  8. Han J., Hajjar D. P., Tauras J. M., Feng J., Gotto A. M., Jr, Nicholson A. C. Transforming growth factor-beta1 (TGF-beta1) and TGF-beta2 decrease expression of CD36, the type B scavenger receptor, through mitogen-activated protein kinase phosphorylation of peroxisome proliferator-activated receptor-gamma. J Biol Chem. 2000 Jan 14;275(2):1241–1246. doi: 10.1074/jbc.275.2.1241. [DOI] [PubMed] [Google Scholar]
  9. Itami A., Watanabe G., Shimada Y., Hashimoto Y., Kawamura J., Kato M., Hosotani R., Imamura M. Ligands for peroxisome proliferator-activated receptor gamma inhibit growth of pancreatic cancers both in vitro and in vivo. Int J Cancer. 2001 Nov 1;94(3):370–376. doi: 10.1002/ijc.1488. [DOI] [PubMed] [Google Scholar]
  10. Jiang C., Ting A. T., Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998 Jan 1;391(6662):82–86. doi: 10.1038/34184. [DOI] [PubMed] [Google Scholar]
  11. Kintscher Ulrich, Wakino Shu, Bruemmer Dennis, Goetze Stephan, Graf Kristof, Hsueh Willa A., Law Ronald E. TGF-beta(1) induces peroxisome proliferator-activated receptor gamma1 and gamma2 expression in human THP-1 monocytes. Biochem Biophys Res Commun. 2002 Oct 4;297(4):794–799. doi: 10.1016/s0006-291x(02)02264-7. [DOI] [PubMed] [Google Scholar]
  12. Kliewer S. A., Lehmann J. M., Willson T. M. Orphan nuclear receptors: shifting endocrinology into reverse. Science. 1999 Apr 30;284(5415):757–760. doi: 10.1126/science.284.5415.757. [DOI] [PubMed] [Google Scholar]
  13. Law R. E., Goetze S., Xi X. P., Jackson S., Kawano Y., Demer L., Fishbein M. C., Meehan W. P., Hsueh W. A. Expression and function of PPARgamma in rat and human vascular smooth muscle cells. Circulation. 2000 Mar 21;101(11):1311–1318. doi: 10.1161/01.cir.101.11.1311. [DOI] [PubMed] [Google Scholar]
  14. Law R. E., Meehan W. P., Xi X. P., Graf K., Wuthrich D. A., Coats W., Faxon D., Hsueh W. A. Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia. J Clin Invest. 1996 Oct 15;98(8):1897–1905. doi: 10.1172/JCI118991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Li A. C., Brown K. K., Silvestre M. J., Willson T. M., Palinski W., Glass C. K. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2000 Aug;106(4):523–531. doi: 10.1172/JCI10370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Marx N., Schönbeck U., Lazar M. A., Libby P., Plutzky J. Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res. 1998 Nov 30;83(11):1097–1103. doi: 10.1161/01.res.83.11.1097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Massagué J. TGF-beta signal transduction. Annu Rev Biochem. 1998;67:753–791. doi: 10.1146/annurev.biochem.67.1.753. [DOI] [PubMed] [Google Scholar]
  18. Massagué J., Wotton D. Transcriptional control by the TGF-beta/Smad signaling system. EMBO J. 2000 Apr 17;19(8):1745–1754. doi: 10.1093/emboj/19.8.1745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. McCaffrey T. A. TGF-betas and TGF-beta receptors in atherosclerosis. Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):103–114. doi: 10.1016/s1359-6101(99)00034-9. [DOI] [PubMed] [Google Scholar]
  20. Miano J. M., Berk B. C. NAB2: a transcriptional brake for activated gene expression in the vessel wall? Am J Pathol. 1999 Oct;155(4):1009–1012. doi: 10.1016/S0002-9440(10)65200-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nabel E. G., Shum L., Pompili V. J., Yang Z. Y., San H., Shu H. B., Liptay S., Gold L., Gordon D., Derynck R. Direct transfer of transforming growth factor beta 1 gene into arteries stimulates fibrocellular hyperplasia. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10759–10763. doi: 10.1073/pnas.90.22.10759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nikol S., Isner J. M., Pickering J. G., Kearney M., Leclerc G., Weir L. Expression of transforming growth factor-beta 1 is increased in human vascular restenosis lesions. J Clin Invest. 1992 Oct;90(4):1582–1592. doi: 10.1172/JCI116027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nishimura R., Kato Y., Chen D., Harris S. E., Mundy G. R., Yoneda T. Smad5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal precursor cell line C2C12. J Biol Chem. 1998 Jan 23;273(4):1872–1879. doi: 10.1074/jbc.273.4.1872. [DOI] [PubMed] [Google Scholar]
  24. Pasceri V., Wu H. D., Willerson J. T., Yeh E. T. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators. Circulation. 2000 Jan 25;101(3):235–238. doi: 10.1161/01.cir.101.3.235. [DOI] [PubMed] [Google Scholar]
  25. Pouponnot C., Jayaraman L., Massagué J. Physical and functional interaction of SMADs and p300/CBP. J Biol Chem. 1998 Sep 4;273(36):22865–22868. doi: 10.1074/jbc.273.36.22865. [DOI] [PubMed] [Google Scholar]
  26. Ricote M., Li A. C., Willson T. M., Kelly C. J., Glass C. K. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998 Jan 1;391(6662):79–82. doi: 10.1038/34178. [DOI] [PubMed] [Google Scholar]
  27. Sasaki Hidefumi, Tanahashi Masayuki, Yukiue Haruhiro, Moiriyama Satoru, Kobayashi Yoshihiro, Nakashima Yoshiaki, Kaji Masahiro, Kiriyama Masanobu, Fukai Ichiro, Yamakawa Yosuke. Decreased perioxisome proliferator-activated receptor gamma gene expression was correlated with poor prognosis in patients with lung cancer. Lung Cancer. 2002 Apr;36(1):71–76. doi: 10.1016/s0169-5002(01)00449-4. [DOI] [PubMed] [Google Scholar]
  28. Silverman E. S., Du J., Williams A. J., Wadgaonkar R., Drazen J. M., Collins T. cAMP-response-element-binding-protein-binding protein (CBP) and p300 are transcriptional co-activators of early growth response factor-1 (Egr-1). Biochem J. 1998 Nov 15;336(Pt 1):183–189. doi: 10.1042/bj3360183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Tontonoz P., Hu E., Spiegelman B. M. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994 Dec 30;79(7):1147–1156. doi: 10.1016/0092-8674(94)90006-x. [DOI] [PubMed] [Google Scholar]
  30. Vo N., Goodman R. H. CREB-binding protein and p300 in transcriptional regulation. J Biol Chem. 2001 Mar 8;276(17):13505–13508. doi: 10.1074/jbc.R000025200. [DOI] [PubMed] [Google Scholar]
  31. Wakefield Lalage M., Roberts Anita B. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev. 2002 Feb;12(1):22–29. doi: 10.1016/s0959-437x(01)00259-3. [DOI] [PubMed] [Google Scholar]
  32. Wolf Y. G., Rasmussen L. M., Ruoslahti E. Antibodies against transforming growth factor-beta 1 suppress intimal hyperplasia in a rat model. J Clin Invest. 1994 Mar;93(3):1172–1178. doi: 10.1172/JCI117070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Yamamura Y., Hua X., Bergelson S., Lodish H. F. Critical role of Smads and AP-1 complex in transforming growth factor-beta -dependent apoptosis. J Biol Chem. 2000 Nov 17;275(46):36295–36302. doi: 10.1074/jbc.M006023200. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES