Thioredoxin Reductase Mediates Cell Death Effects of the Combination of Beta Interferon and Retinoic Acid

This Article

	Full Text
	Full Text (PDF)
	An erratum has been published
	Alert me when this article is cited
	Alert me if a correction is posted

Services

	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new issues of the journal
	Download to citation manager
	Reprints and Permissions
	Copyright Information
	Books from ASM Press
	MicrobeWorld

Citing Articles

	Citing Articles via HighWire
	Citing Articles via Google Scholar

Google Scholar

	Articles by Hofman, E. R.
	Articles by Kalvakolanu, D. V.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Hofman, E. R.
	Articles by Kalvakolanu, D. V.

Previous Article | Next Article

Molecular and Cellular Biology, November 1998, p. 6493-6504, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Thioredoxin Reductase Mediates Cell Death Effects of the Combination of Beta Interferon and Retinoic Acid

Edward R. Hofman,¹ Madanamohan Boyanapalli,¹^,² Daniel J. Lindner,¹^,² Xiao Weihua,¹^,² Bret A. Hassel,¹^,² Rosemary Jagus,³ Peter L. Gutierrez,² and Dhananjaya V. Kalvakolanu¹^,²^,⁴^,⁵^,^*

Department of Microbiology & Immunoogy,¹ Greenebaum Cancer Center,² Molecular and Cellular Biology Program,⁴ and Program in Oncology,⁵ School of Medicine, and Center of Marine Biotechnology,³ University of Maryland, Baltimore, Maryland 21201

Received 12 March 1998/Returned for modification 5 May 1998/Accepted 3 August 1998

Interferons (IFNs) and retinoids are potent biological response modifiers. By using JAK-STAT pathways, IFNs regulate the expressionof genes involved in antiviral, antitumor, and immunomodulatoryactions. Retinoids exert their cell growth-regulatory effectsvia nuclear receptors, which also function as transcription factors.Although these ligands act through distinct mechanisms, severalstudies have shown that the combination of IFNs and retinoidssynergistically inhibits cell growth. We have previously reportedthat IFN- $beta$ -all-trans-retinoic acid (RA) combination is a morepotent growth suppressor of human tumor xenografts in vivo thaneither agent alone. Furthermore, the IFN-RA combination causescell death in several tumor cell lines in vitro. However, themolecular basis for these growth-suppressive actions is unknown.It has been suggested that certain gene products, which mediatethe antiviral actions of IFNs, are also responsible for the antitumoractions of the IFN-RA combination. However, we did not find acorrelation between their activities and cell death. Therefore,we have used an antisense knockout approach to directly identifythe gene products that mediate cell death and have isolated severalgenes associated with retinoid-IFN-induced mortality (GRIM). Inthis investigation, we characterized one of the GRIM cDNAs, GRIM-12.Sequence analysis suggests that the GRIM-12 product is identicalto human thioredoxin reductase (TR). TR is posttranscriptionallyinduced by the IFN-RA combination in human breast carcinoma cells.Overexpression of GRIM-12 causes a small amount of cell deathand further enhances the susceptibility of cells to IFN-RA-induceddeath. Dominant negative inhibitors directed against TR inhibitits cell death-inducing functions. Interference with TR enzymaticactivity led to growth promotion in the presence of the IFN-RAcombination. Thus, these studies identify a novel function forTR in cell growth regulation.

^* Corresponding author. Mailing address: Department of Microbiology & Immunology, Greenebaum Cancer Center, University of MarylandSchool of Medicine, Baltimore, MD 21201. Phone: (410) 328-1396.Fax: (410) 328-1397. E-mail: dkalvako{at}umaryland.edu.

Molecular and Cellular Biology, November 1998, p. 6493-6504, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

This article has been cited by other articles:

Kalakonda, S., Nallar, S. C., Gong, P., Lindner, D. J., Goldblum, S. E., Reddy, S. P., Kalvakolanu, D. V. (2007). Tumor Suppressive Protein Gene Associated with Retinoid-Interferon-Induced Mortality (GRIM)-19 Inhibits src-Induced Oncogenic Transformation at Multiple Levels. Am. J. Pathol. 171: 1352-1368 [Abstract] [Full Text]
Nalvarte, I., Damdimopoulos, A. E., Nystom, C., Nordman, T., Miranda-Vizuete, A., Olsson, J. M., Eriksson, L., Bjornstedt, M., Arner, E. S. J., Spyrou, G. (2004). Overexpression of Enzymatically Active Human Cytosolic and Mitochondrial Thioredoxin Reductase in HEK-293 Cells: EFFECT ON CELL GROWTH AND DIFFERENTIATION. J. Biol. Chem. 279: 54510-54517 [Abstract] [Full Text]
Huang, G., Lu, H., Hao, A., Ng, D. C. H., Ponniah, S., Guo, K., Lufei, C., Zeng, Q., Cao, X. (2004). GRIM-19, a Cell Death Regulatory Protein, Is Essential for Assembly and Function of Mitochondrial Complex I. Mol. Cell. Biol. 24: 8447-8456 [Abstract] [Full Text]
Damdimopoulos, A. E., Miranda-Vizuete, A., Treuter, E., Gustafsson, J.-A., Spyrou, G. (2004). An Alternative Splicing Variant of the Selenoprotein Thioredoxin Reductase Is a Modulator of Estrogen Signaling. J. Biol. Chem. 279: 38721-38729 [Abstract] [Full Text]
Wittke, I., Wiedemeyer, R., Pillmann, A., Savelyeva, L., Westermann, F., Schwab, M. (2003). Neuroblastoma-Derived Sulfhydryl Oxidase, a New Member of the Sulfhydryl Oxidase/Quiescin6 Family, Regulates Sensitization to Interferon {gamma}-Induced Cell Death in Human Neuroblastoma Cells. Cancer Res. 63: 7742-7752 [Abstract] [Full Text]
Rishi, A. K., Zhang, L., Boyanapalli, M., Wali, A., Mohammad, R. M., Yu, Y., Fontana, J. A., Hatfield, J. S., Dawson, M. I., Majumdar, A. P. N., Reichert, U. (2003). Identification and Characterization of a Cell Cycle and Apoptosis Regulatory Protein-1 as a Novel Mediator of Apoptosis Signaling by Retinoid CD437. J. Biol. Chem. 278: 33422-33435 [Abstract] [Full Text]
Zhang, J., Yang, J., Roy, S. K., Tininini, S., Hu, J., Bromberg, J. F., Poli, V., Stark, G. R., Kalvakolanu, D. V. (2003). The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3. Proc. Natl. Acad. Sci. USA 100: 9342-9347 [Abstract] [Full Text]
Anestal, K., Arner, E. S. J. (2003). Rapid Induction of Cell Death by Selenium-compromised Thioredoxin Reductase 1 but Not by the Fully Active Enzyme Containing Selenocysteine. J. Biol. Chem. 278: 15966-15972 [Abstract] [Full Text]
Xia, L., Nordman, T., Olsson, J. M., Damdimopoulos, A., Bjorkhem-Bergman, L., Nalvarte, I., Eriksson, L. C., Arner, E. S. J., Spyrou, G., Bjornstedt, M. (2003). The Mammalian Cytosolic Selenoenzyme Thioredoxin Reductase Reduces Ubiquinone. A NOVEL MECHANISM FOR DEFENSE AGAINST OXIDATIVE STRESS. J. Biol. Chem. 278: 2141-2146 [Abstract] [Full Text]
Lindner, D. J., Ma, X., Hu, J., Karra, S., Kalvakolanu, D. V. (2002). Thioredoxin Reductase Plays a Critical Role in IFN Retinoid-mediated Tumor-Growth Control in Vivo. Clin. Cancer Res. 8: 3210-3218 [Abstract] [Full Text]
Seo, T., Lee, D., Shim, Y. S., Angell, J. E., Chidambaram, N. V., Kalvakolanu, D. V., Choe, J. (2002). Viral Interferon Regulatory Factor 1 of Kaposi's Sarcoma-Associated Herpesvirus Interacts with a Cell Death Regulator, GRIM19, and Inhibits Interferon/Retinoic Acid-Induced Cell Death. J. Virol. 76: 8797-8807 [Abstract] [Full Text]
Ma, X., Hu, J., Lindner, D. J., Kalvakolanu, D. V. (2002). Mutational Analysis of Human Thioredoxin Reductase 1. EFFECTS ON p53-MEDIATED GENE EXPRESSION AND INTERFERON AND RETINOIC ACID-INDUCED CELL DEATH. J. Biol. Chem. 277: 22460-22468 [Abstract] [Full Text]
Fearnley, I. M., Carroll, J., Shannon, R. J., Runswick, M. J., Walker, J. E., Hirst, J. (2001). GRIM-19, a Cell Death Regulatory Gene Product, Is a Subunit of Bovine Mitochondrial NADH:Ubiquinone Oxidoreductase (Complex I). J. Biol. Chem. 276: 38345-38348 [Abstract] [Full Text]
Guo, X., Nanus, D. M, Ruiz, A., Rando, R. R, Bok, D., Gudas, L. J (2001). Reduced Levels of Retinyl Esters and Vitamin A in Human Renal Cancers. Cancer Res. 61: 2774-2781 [Abstract] [Full Text]
Menter, D. G., Sabichi, A. L., Lippman, S. M. (2000). Selenium Effects on Prostate Cell Growth. Cancer Epidemiol. Biomarkers Prev. 9: 1171-1182 [Abstract] [Full Text]
Sun, Q.-A., Wu, Y., Zappacosta, F., Jeang, K.-T., Lee, B. J., Hatfield, D. L., Gladyshev, V. N. (1999). Redox Regulation of Cell Signaling by Selenocysteine in Mammalian Thioredoxin Reductases. J. Biol. Chem. 274: 24522-24530 [Abstract] [Full Text]
Gudkov, A. V., Roninson, I. B., Brown;, R., Kimchi, A., Cohen, O., Kissil, J., Raveh, T., Inbal, B., Levy-Strumpf, N., Berissi, H., Deiss;, L. (1999). Functional Approaches to Gene Isolation in Mammalian Cells. Science 285: 299a-299 [Full Text]
Angell, J. E., Lindner, D. J., Shapiro, P. S., Hofmann, E. R., Kalvakolanu, D. V. (2000). Identification of GRIM-19, a Novel Cell Death-regulatory Gene Induced by the Interferon-beta and Retinoic Acid Combination, Using a Genetic Approach. J. Biol. Chem. 275: 33416-33426 [Abstract] [Full Text]
Ma, X., Karra, S., Guo, W., Lindner, D. J., Hu, J., Angell, J. E., Hofmann, E. R., Reddy, S. P. M., Kalvakolanu, D. V. (2001). Regulation of Interferon and Retinoic Acid-induced Cell Death Activation through Thioredoxin Reductase. J. Biol. Chem. 276: 24843-24854 [Abstract] [Full Text]

J. Bacteriol.	J. Virol.	Eukaryot. Cell

Microbiol. Mol. Biol. Rev.	Clin. Vaccine Immunol.	All ASM Journals