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Modulation of p53 dependent gene expression and cell death through thioredoxin-thioredoxin reductase by the Interferon-Retinoid combination

Oncogene volume 20, pages 4235–4248 (2001)Cite this article

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.

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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

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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.

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Author notes

  1. Edward R Hofmann

    Present address: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

  2. Daniel J Lindner

    Present address: Taussig Cancer Center, Cleveland, OH, USA

Authors and Affiliations

  1. Department of Microbiology & Immunology, Greenebaum Cancer Center, Molecular and Cellular Biology Program, University of Maryland School of Medicine, Baltimore, 21201, Maryland, MD, USA

    Jiadi Hu, Xinrong Ma, Daniel J Lindner, Sreenivasu Karra, Edward R Hofmann & Dhananjaya V Kalvakolanu

  2. Department of Environmental Sciences, The Johns Hopkins University School of Public Health, Baltimore, Maryland, USA

    Sekhar PM Reddy

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Correspondence to Dhananjaya V Kalvakolanu.

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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

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