This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow An erratum has been published
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hofman, E. R.
Right arrow Articles by Kalvakolanu, D. V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hofman, E. R.
Right arrow 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 expression of genes involved in antiviral, antitumor, and immunomodulatory actions. Retinoids exert their cell growth-regulatory effects via nuclear receptors, which also function as transcription factors. Although these ligands act through distinct mechanisms, several studies have shown that the combination of IFNs and retinoids synergistically inhibits cell growth. We have previously reported that IFN-beta -all-trans-retinoic acid (RA) combination is a more potent growth suppressor of human tumor xenografts in vivo than either agent alone. Furthermore, the IFN-RA combination causes cell death in several tumor cell lines in vitro. However, the molecular basis for these growth-suppressive actions is unknown. It has been suggested that certain gene products, which mediate the antiviral actions of IFNs, are also responsible for the antitumor actions of the IFN-RA combination. However, we did not find a correlation between their activities and cell death. Therefore, we have used an antisense knockout approach to directly identify the gene products that mediate cell death and have isolated several genes associated with retinoid-IFN-induced mortality (GRIM). In this investigation, we characterized one of the GRIM cDNAs, GRIM-12. Sequence analysis suggests that the GRIM-12 product is identical to human thioredoxin reductase (TR). TR is posttranscriptionally induced by the IFN-RA combination in human breast carcinoma cells. Overexpression of GRIM-12 causes a small amount of cell death and further enhances the susceptibility of cells to IFN-RA-induced death. Dominant negative inhibitors directed against TR inhibit its cell death-inducing functions. Interference with TR enzymatic activity led to growth promotion in the presence of the IFN-RA combination. Thus, these studies identify a novel function for TR in cell growth regulation.

* Corresponding author. Mailing address: Department of Microbiology & Immunology, Greenebaum Cancer Center, University of Maryland School 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:

  • (2009). Identification of LIV1, a Putative Zinc Transporter Gene Responsible for HDACi-Induced Apoptosis, Using a Functional Gene Screen Approach. Molecular Cancer Therapeutics 8: 3108-3116  
  • 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]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»