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Antitumor activity of IFIX, a novel interferon-inducible HIN-200 gene, in breast cancer

Oncogene volume 23, pages 4556–4566 (2004)Cite this article

Abstract

We identified IFIX as a new member of the hematopoietic interferon (IFN)-inducible nuclear protein with the 200-amino-acid repeat (HIN-200) family. Six different alternatively spliced forms of mRNA are transcribed from the IFIX gene, which are predicted to encode six different isoforms of IFIX proteins (IFIXα1, α2, β1, β2, γ1, and γ2). The IFIX proteins are primarily localized in the nucleus. They share a common N-terminal region that contains a predicted pyrin domain and a putative nuclear localization signal. Unlike IFIXα and IFIXβ, IFIXγ isoforms do not have the 200-amino-acid signature motif. Interestingly, the expression of IFIX was reduced in most human breast tumors and breast cancer cell lines. Expression of IFIXα1, the longest isoform of IFIX, in human breast cancer cell lines reduced their anchorage-dependent and -independent growth in vitro and tumorigenicity in nude mice. Moreover, a liposome-mediated IFIXα1 gene transfer suppressed the growth of already-formed tumors in a breast cancer xenograft model. IFIXα1 appears to suppress the growth of breast cancer cells in a pRB- and p53-independent manner by increasing the expression of the cyclin-dependent kinase inhibitor p21CIP1, which leads to the reduction of the kinase activity of both Cdk2 and p34Cdc2. Together, our results show that IFIXα1 possesses a tumor-suppressor activity and suggest IFIXα1 may be used as a therapeutic agent in cancer treatment.

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Acknowledgements

We thank Drs Mien-Chie Hung, Funda Meric, Naoto Ueno, Dihua Yu, Mong-Hong Lee, and Nancy Poindexter for providing the reagents used in this study. This work was supported in part by grants from the Department of Defense (DAMD17- 99-1-9270), Texas Advanced Technology Program (003657-0082-1999), and an Institutional Research Grant from The University of Texas, MD Anderson Cancer Center (to DHY), and Cancer Center Core Grant CA16672 from the NIH. YD is the recipient of a post-doctoral fellowship from the Department of Defense (DAMD17-02-1-0451).

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Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, 77030, TX, USA

    Yi Ding, Li Wang, Li-Kuo Su, Jennifer A Frey, Ruping Shao & Duen-Hwa Yan

  2. Department of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, 77030, TX, USA

    Kelly K Hunt & Duen-Hwa Yan

  3. The University of Texas Graduate School of Biomedical Sciences at Houston, USA

    Li-Kuo Su, Jennifer A Frey & Duen-Hwa Yan

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  1. Yi Ding
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Correspondence to Duen-Hwa Yan.

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Note added in proof

During the preparation of this manuscript, a partial amino acid sequence of the N-terminal domain of IFIX protein (referred to as IFI16-like protein 1) was published (Liepinsh et al., 2003).

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Ding, Y., Wang, L., Su, LK. et al. Antitumor activity of IFIX, a novel interferon-inducible HIN-200 gene, in breast cancer. Oncogene 23, 4556–4566 (2004). https://doi.org/10.1038/sj.onc.1207592

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