[en] Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays a central
role in whole body metabolism by regulating adipocyte differentiation and energy
storage. Recently, however, PPAR-gamma has also been demonstrated to affect
proliferation, differentiation, and apoptosis of different cell types. As we have
previously shown that BAY 11-7085-induced synovial fibroblast apoptosis is
prevented by PPAR-gamma agonist 15d-PGJ2; the expression of PPAR-gamma in these
cells was studied. Both PPAR-gamma1 and PPAR-gamma2 isoforms were cloned from
synovial fibroblast RNA, but only PPAR-gamma1 was detected by Western blot,
showing constitutive nuclear expression. Within minutes of BAY 11-7085 treatment,
a PPAR-gamma1-specific band was shifted into a form of higher mobility,
suggesting dephosphorylation, as confirmed by phosphatase treatment of cell
extracts. Of interest, BAY 11-7085-induced PPAR-gamma1 dephosphorylation was
followed by PARP and caspase-8 cleavage as well as by PPAR-gamma1 protein
degradation. PPAR-gamma1 dephosphorylation was followed by the loss of PPAR-DNA
binding activity ubiquitously present in synovial fibroblast nuclear extracts.
Unlike the phosphorylated form, dephosphorylated PPAR-gamma1 was found in
insoluble membrane cell fraction and was not ubiquitinated before degradation.
PPAR-gamma1 dephosphorylation coincided with ERK1/2 phosphorylation that
accompanies BAY 11-7085-induced synovial fibroblasts apoptosis. 15d-PGJ2, PGD2,
and partially UO126, down-regulated ERK1/2 phosphorylation, protected cells from
BAY 11-7085-induced apoptosis, and reversed both PPAR-gamma dephosphorylation and
degradation. Furthermore, PPAR-gamma antagonist BADGE induced PPAR-gamma1
degradation, ERK1/2 phosphorylation, and synovial fibroblasts apoptosis. The
results presented suggest an anti-apoptotic role for PPAR-gamma1 in synovial
fibroblasts. Since apoptotic marker PARP is cleaved after PPAR-gamma1
dephosphorylation but before PPAR-gamma1 degradation, dephosphorylation event
might be enough to mediate BAY 11-7085-induced apoptosis in synovial fibroblasts.
Disciplines :
Rheumatology
Author, co-author :
Relic, Biserka ; Université de Liège - ULiège > Rhumatologie
Knouff, C., and Auwerx, J. (2004) Endocr. Rev. 25, 899-910
Rangwala, S. M., and Lazar, M. A. (2004) Trends Pharmacol. Sci. 25, 331-336
Theocharis, S., Margeli, A., Vielh, P., and Kouraklis, G. (2004) Cancer Treat. Rev. 30, 545-554
Eucker, J., Bangeroth, K., Zavrski, I., Krebbel, H., Zang, C., Heider, U., Jakob, C., Elstner, E., Possinger, K., and Sezer, O. (2004) Anticancer Drugs 10, 955-960
Takashima, T., Fujiwara, Y., Hamaguchi, M., Sasaki, E., Tominaga, K., Watanabe, T., Oshitani, N., Higuchi, K., and Arakawa, T. (2005) Oncol. Rep. 13, 601-606
Bren-Mattison, Y., Van Putten, V., Chan, D., Winn, R., Geraci, M. W., and Nemenoff, R. A. (2005) Oncogene 24, 1412-1422
Wang, Y. L., Frauwirth, K. A., Rangwala, S. M., Lazar, M. A., and Thompson, C. B. (2002) J. Biol. Chem. 277, 31781-31788
Scaglia, N., Caviglia, J. M., and Igal, R. A. (2005) Biochim. Biophys. Acta 1687, 141-151
Mukherjee, R., Jow, L., Croston, G. E., and Paterniti, J. R. (1997) J. Biol. Chem. 272, 8071-8076
Mueller, E., Drori, S., Aiyer, A., Yie, J., Sarraf, P., Chen, H., Hauser, S., Rosen, E. D., Ge, K., Roeder, R. G., and Spiegelman, B. M. (2002) J. Biol. Chem. 277, 41925-41930
Sabichi, A. L., Subbarayan, V., Llansa, N., Lippman, S. M., and Menter, D. G. (2004) Cancer Epidemiol. Biomarkers Prev. 13, 1704-1709
Tontonoz, P., Hu, E., Graves, R. A., Budavari, A. I., and Spiegelman, B. M. (1994) Genes Dev. 8, 1224-1234
Liu, H., and Pope, R. M. (2003) Curr. Opin. Pharmacol. 3, 317-322
Baier, A., Meineckel, I., Gay, S., and Pap, T. (2003) Curr. Opin. Rheumatol. 15, 274-279
Liu, H., and Pope, R. M. (2004) Rheum. Dis. Clin. North Am. 30, 603-625
Relic, B., Benoit, V., Franchimont, N., Ribbens, C., Kaiser, M. J., Gillet, P., Merville, M. P., Bours, V., and Malaise, M. G. (2004) J. Biol. Chem. 279, 22399-22403
Dejardin, E., Bonizzi, G., Bellahcene, A., Castronovo, V., Merville, M. P., and Bours, V. (1995) Oncogene 11, 1835-1841
Buttke, T. M., McCubrey, J. A., and Owen, T. C. (1993) J. Immunol. Methods 157, 233-240
Ward, C. L., Omura, S., and Kopito, R. R. (1995) Cell 83, 121-127
Biggs, J. R., Zhang, Y., Peterson, L. F., Garcia, M., Zhang, D. E., and Kraft, A. S. (2005) Mol. Cancer Res. 3, 391-401
Ohshima, T., Koga, H., and Shimotohno, K. (2004) J. Biol. Chem. 279, 29551-29557
Hauser, S., Adelmant, G., Sarraf, P., Wright, H. M., Mueller, E., and Spiegelman, B. M. (2000) J. Biol. Chem. 275, 18527-18533
Laney, J. D., and Hochstrasser, M. (1999) Cell 97, 427-430
Bossis, G., Ferrara, P., Acquaviva, C., Jariel-Encontre, I., and Piechaczyk, M. (2003) Mol. Cell. Biol. 23, 7425-7436
Davis, S., Vanhoutte, P., Pages, C., Caboche, J., and Laroche, S. (2000) J. Neurosci. 20, 4563-4572
Smith, T. G., Sweetman, D., Patterson, M., Keyse, S. M., and Munsterberg, A. (2005) Development (Camb.) 132, 1305-1314
Wright, H. M., Clish, C. B., Mikami, T., Hauser, S., Yanagi, K., Hiramatsu, R., Serhan, C. N., and Spiegelman, B. M. (2000) J. Biol. Chem. 275, 1873-1877
Yamasaki, S., Nakashima, T., Kawakami, A., Miyashita, T., Ida, H., Migita, K., Nakata, K., and Eguchi, K. (2002) Clin. Exp. Immunol. 129, 379-384
Simonin, M. A., Bordji, K., Boyault, S., Bianchi, A., Gouze, E., Becuwe, P., Dauca, M., Netter, P., and Terlain, B. (2002) Am. J. Physiol. 282, C125-C133
Shiojiri, T., Wada, K., Nakajima, A., Katayama, K., Shibuya, A., Kudo, C., Kadowaki, T., Mayumi, T., Yura, Y., and Kamisaki, Y. (2002) Eur. J. Pharmacol. 448, 231-238
Tanabe, Y., and Nakayama, K. (2004) Nippon Yakurigaku Zasshi. 124, 337-344
Hu, E., Kim, J. B., Sarraf, P., and Spiegelman, B. M. (1996) Science 274, 2100-2103
Adams, M., Reginato, M. J., Shao, D., Lazar, M. A., and Chatterjee, V. K. (1997) J. Biol. Chem. 272, 5128-5132
Varley, C. L., Stahlschmidt, J., Lee, W. C., Holder, J., Diggle, C., Selby, P. J., Trejdosiewicz, L. K., and Southgate, J. (2004) J. Cell Sci. 117, 2029 -2036
Al-Rasheed, N. M., Chana, R. S., Baines, R. J., Willars, G. B., and Brunskill, N. J. (2004) J. Biol. Chem. 279, 49747-49754
Jiang, C., Ting, A. T., and Seed, B. (1998) Nature 391, 82-86
Zingarelli, B., and Cook, J. A. (2005) Shock 23, 393-399
Desmet, C., Warzee, B., Gosset, P., Melotte, D., Rongvaux, A., Gillet, L., Fievez, L., Seumois, G., Vanderplasschen, A., Staels, B., Lekeux, P., and Bureau, F. (2005) Biochem. Pharmacol. 69, 255-265
Appel, S., Mirakaj, V., Bringmann, A., Weck, M. M., Grunebach, F., and Brossart, P. (2005) Blood 106, 3888-3894
Gardner, O. S., Dewar, B. J., Earp, H. S., Samet, J. M., and Graves, L. M. (2003) J. Biol. Chem. 278, 46261-46269
Compe, E., Drane, P., Laurent, C., Diderich, K., Braun, C., Hoeijmakers, J. H., and Egly, J. M. (2005) Mol. Cell. Biol. 25, 6065-6076
Klotz, L., Schmidt, M., Giese, T., Sastre, M., Knolle, P., Klockgether, T., and Heneka, M. T. (2005) J. Immunol. 175, 4948-4955
