Abstract
We have shown earlier that the IFN-β and all-trans retinoic acid (RA) combination, but not the single agents, induces death in several tumor cell lines. Employing a genetic technique we have identified several Genes associated with Retinoid-IFN induced Mortality (GRIM). One of the GRIMs was human thioredoxin reductase (TR), a redox enzyme. Since the overexpressed TR augments IFN/RA stimulated cell death, we explored the mechanisms of TR-mediated death. Here we show that TR augments cell death by upregulating the transcriptional activity of p53 tumor suppressor. This process does not involve a physical increase in levels of p53. Using redox inactive mutants of TR and its substrate, thioredoxin (Trx), we demonstrate that IFN/RA-induced regulation of p53 dependent gene expression requires TR and Trx. In contrast-over-expression of wildtype TR or Trx augment the p53 dependent gene expression in response to IFN/RA treatment. Consistent with these results an increased DNA binding activity of p53 was noted in the presence of TR. These studies identify a novel mechanism of p53 mediated cell death regulation involving redox enzymes.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- Cys mut:
-
A TR-mutant lacking the active site cysteines
- GRIM:
-
gene associated with retinoid-IFN induced mortality
- IFN:
-
interferon
- ORF:
-
open reading frame
- PIG:
-
p53 inducible gene
- RA:
-
all trans retinoic acid
- p53RE:
-
p53 responsive element
- TR:
-
thioredoxin reductase
- Trx:
-
thioredoxin
- Trx mut:
-
a mutant Trx1 lacking the critical cysteine residues
References
Akamatsu Y, Ohno T, Hirota K, Kagoshima H, Yodoi J, Shigesada K . 1997 J. Biol. Chem. 272: 14497–14500
Arner ES, Holmgren A . 2000 Eur. J. Biochem. 267: 6102–6109
Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA, Struhl K . 1994 Current Protocols in Molecular Biology A Wiley Interscience Publication: New York
Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B . 1990 Science 249: 912–915
Balcer-Kubiczek EK, Yin J, Lin K, Harrison GH, Abraham JM, Meltzer SJ . 1995 Radiat. Res. 142: 256–262
Bischoff JR, Casso D, Beach D . 1992 Mol. Cell. Biol. 12: 1405–1411
Casso D, Beach D . 1996 Mol. Gen. Genet. 252: 518–529
Cho Y, Gorina S, Jeffrey PD, Pavletich NP . 1994 Science 265: 346–355
Darnell Jr JE, Kerr IM, Stark GR . 1994 Science 264: 1415–1421
Deiss LP, Kimchi A . 1991 Science 252: 117–120
Delphin C, Cahen P, Lawrence JJ, Baudier J . 1994 Eur. J. Biochem. 223: 683–692
Di Leonardo A, Khan SH, Linke SP, Greco V, Seidita G, Wahl GM . 1997 Cancer Res. 57: 1013–1019
Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery Jr CA, Butel JS, Bradley A . 1992 Nature 356: 215–221
el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B . 1993 Cell 75: 817–825
Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Fujii-Kuriyama Y . 1999 EMBO J. 18: 1905–1914
Epstein CB, Attiyeh EF, Hobson DA, Silver AL, Broach JR, Levine AJ . 1998 Oncogene 16: 2115–2122
Fan S, Smith ML, Rivet DJ, Duba D, Zhan Q, Kohn KW, Fornace AJ, O'Connor PM . 1995 Cancer Res. 55: 1649–1654
Gaiddon C, Moorthy NC, Prives C . 1999 EMBO J. 18: 5609–5621
Glass CK, Rose DW, Rosenfeld MG . 1997 Curr. Opin. Cell. Biol. 9: 222–232
Green DR, Reed JC . 1998 Science 281: 1309–1311
Gross A, Jockel J, Wei MC, Korsmeyer SJ . 1998 EMBO J. 17: 3878–3885
Gutterman JU . 1994 Proc. Natl. Acad. Sci. USA 91: 1198–1205
Hainaut P, Milner J . 1993 Cancer Res. 53: 4469–4473
Hartman H, Wu M, Buchanan BB, Gerhart JC . 1993 Proc. Natl. Acad. Sci. USA 90: 2271–2275
Hayashi T, Ueno Y, Okamoto T . 1993 J. Biol. Chem. 268: 11380–11388
Hirota K, Matsui M, Iwata S, Nishiyama A, Mori K, Yodoi J . 1997 Proc. Natl. Acad. Sci. USA 94: 3633–3638
Hofmann ER, Boyanapalli M, Lindner DJ, Weihua X, Hassel BA, Jagus R, Gutierrez PL, Kalvakolanu DV . 1998 Mol. Cell. Biol. 18: 6493–6504
Holtschke T, Lohler J, Kanno Y, Fehr T, Giese N, Rosenbauer F, Lou J, Knobeloch KP, Gabriele L, Waring J, Bachmann MF, Zinkernagel RM, Morse HC, Ozato K, Horak I . 1996 Cell 87: 307–317
Jayaraman L, Prives C . 1999 Cell. Mol. Life Sci. 55: 76–87
Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, Schreiber RD . 1998 Proc. Natl. Acad. Sci. USA 95: 7556–7561
Kern SE, Pietenpol JA, Thiagalingam S, Seymour A, Kinzler WK, Vogelstein B . 1992 Science 256: 827–830
Kessis TD, Slebos RJ, Nelson WG, Kastan MB, Plunkett BS, Han SM, Lorinez AT, Hedrick L, Cho KR . 1993 Proc. Natl. Acad. Sci. USA 90: 3988–3992
Kurooka H, Kato K, Minoguchi S, Takahashi Y, Ikeda J, Habu S, Osawa N, Buchberg AM, Moriwaki K, Shisa H, Honjo T . 1997 Genomics 39: 331–339
Kuwata T, Wang IM, Tamura T, Ponnamperuma RM, Levine R, Holmes KL, Morse HC, de Luca LM, Ozato K . 2000 Blood 95: 3349–3356
Lee KK, Murakawa M, Takahashi S, Tsubuki S, Kawashima S, Sakamaki K, Yonehara S . 1998 J. Biol. Chem. 273: 19160–19166
Lee SR, Kim JR, Kwon KS, Yoon HW, Levine RL, Ginsburg A, Rhee SG . 1999 J. Biol. Chem. 274: 4722–4734
Li H, Kolluri SK, Gu J, Dawson MI, Cao X, Hobbs PD, Lin B, Chen G, Lu J, Lin F, Xie Z, Fontana JA, Reed JC, Zhang X . 2000 Science 289: 1159–1164
Lindner DJ, Borden EC, Kalvakolanu DV . 1997 Clin. Cancer Res. 3: 931–937
Liu R, Takayama S, Zheng Y, Froesch B, Chen GQ, Zhang X, Reed JC, Zhang XK . 1998 J. Biol. Chem. 273: 16985–16992
Lotan R . 1996 FASEB J. 10: 1031–1039
Love JM, Gudas LJ . 1994 Curr. Opin. Cell. Biol. 6: 825–831
Ma X et al . 2001 J. Biol. Chem. in press
Mangelsdorf DJ, Evans RM . 1995 Cell 83: 841–850
Matsui M, Oshima M, Oshima H, Takaku K, Maruyama T, Yodoi J, Taketo MM . 1996 Dev. Biol. 178: 179–185
Miyashita T, Reed JC . 1995 Cell 80: 293–299
Moore DM, Kalvakolanu DV, Lippman SM, Kavanagh JJ, Hong WK, Borden EC, Paredes-Espinoza M, Krakoff IH . 1994 Semin. Hematol. 31: 31–37
Nagy L, Thomazy VA, Heyman RA, Davies PJ . 1998 Cell Death Differ. 5: 11–19
Nechushtan A, Smith CL, Hsu YT, Youle RJ . 1999 EMBO J. 18: 2330–2341
Pearson GD, Merrill GF . 1998 J. Biol. Chem. 273: 5431–5434
Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B . 1997 Nature 389: 300–305
Potapova O, Gorospe M, Dougherty RH, Dean NM, Gaarde WA, Holbrook NJ . 2000 Mol. Cell. Biol. 20: 1713–1722
Raveh T, Hovanessian AG, Meurs EF, Sonenberg N, Kimchi A . 1996 J. Biol. Chem. 271: 25479–25484
Resnitzky D, Tiefenbrun N, Berissi H, Kimchi A . 1992 Proc. Natl. Acad. Sci. USA 89: 402–406
Rubartelli A, Bonifaci N, Sitia R . 1995 Cancer Res. 55: 675–680
Salz HK, Flickinger TW, Mittendorf E, Pellicena-Palle A, Petschek JP, Albrecht EB . 1994 Genetics 136: 1075–1086
Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM . 1990 Cell 63: 1129–1136
Somasundaram K, Zhang H, Zeng YX, Houvras Y, Peng Y, Zhang H, Wu GS, Licht JD, Weber BL, El-Deiry WS . 1997 Nature 389: 187–190
Spyrou G, Enmark E, Miranda-Vizuete A, Gustafsson J . 1997 J. Biol. Chem. 272: 2936–2941
Sun QA, Wu Y, Zappacosta F, Jeang KT, Lee BJ, Hatfield DL, Gladyshev VN . 1999a J. Biol. Chem. 274: 24522–24530
Sun SY, Yue P, Mao L, Dawson MI, Shroot B, Lamph WW, Heyman RA, Chandraratna RA, Shudo K, Hong WK, Lotan R . 2000 Clin. Cancer Res. 6: 1563–1573
Sun SY, Yue P, Wu GS, El-Deiry WS, Shroot B, Hong WK, Lotan R . 1999b Oncogene 18: 2357–2365
Taniguchi T, Lamphier MS, Tanaka N . 1997 Biochim. Biophys. Acta 1333: M9–M17
Tiefenbrun N, Melamed D, Levy N, Resnitzky D, Hoffman I, Reed SI, Kimchi A . 1996 Mol. Cell. Biol. 16: 3934–3944
Tsukada T, Tomooka Y, Takai S, Ueda Y, Nishikawa S, Yagi T, Tokunaga T, Takeda N, Suda Y, Abe S et al . 1993 Oncogene 8: 3313–3322
Ueno M, Masutani H, Arai RJ, Yamauchi A, Hirota K, Sakai T, Inamoto T, Yamaoka Y, Yodoi J, Nikaido T . 1999 J. Biol. Chem. 274: 35809–35815
Vander Heiden MG, Chandel NS, Williamson EK, Schumacker PT, Thompson CB . 1997 Cell 91: 627–637
Vogelstein B, Lane D, Levine AJ . 2000 Nature 408: 307–310
Wagner P, Grimaldi M, Jenkins JR . 1993 Eur. J. Biochem. 217: 731–736
Weihua X, Kolla V, Kalvakolanu DV . 1997 Proc. Natl. Acad. Sci. USA 94: 103–108
Acknowledgements
These studies are supported by the National Cancer Institute grants CA 78282 and CA 71401 to DV Kalvakolanu and National Institutes of Health grant HL-58122 to SPM Reddy. We thank B Vogelstein, K Kinzler and C Prives, for providing p53 related plasmids; AJ Fornace for MCF-7 cells expressing HPV-E6 gene, Junji Yodoi for providing Trx1 and its mutants used in this study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hu, J., Ma, X., Lindner, D. et al. Modulation of p53 dependent gene expression and cell death through thioredoxin-thioredoxin reductase by the Interferon-Retinoid combination. Oncogene 20, 4235–4248 (2001). https://doi.org/10.1038/sj.onc.1204585
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204585
Keywords
This article is cited by
-
Antioxidant enzymes in oligodendroglial brain tumors: association with proliferation, apoptotic activity and survival
Journal of Neuro-Oncology (2006)
-
Thioredoxin reductase regulates AP-1 activity as well as thioredoxin nuclear localization via active cysteines in response to ionizing radiation
Oncogene (2002)