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Molecular and Cellular Biology, March 2006, p. 1979-1996, Vol. 26, No. 5
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.5.1979-1996.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Interferon-Inducible Protein IFIX1 Functions as a Negative Regulator of HDM2

Department of Molecular and Cellular Oncology, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030,¹ The University of Texas, Graduate School of Biomedical Sciences at Houston, Houston, Texas,² Department of Biochemistry and Molecular Biology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239³

Received 15 July 2005/ Returned for modification 21 August 2005/ Accepted 16 December 2005

The 200-amino-acid repeat (HIN-200) gene family with the hematopoietic interferon (IFN)-inducible nuclear protein encodes highly homologous proteins involved in cell growth, differentiation, autoimmunity, and tumor suppression. IFIX is the newest member of the human HIN-200 family and is often downregulated in breast tumors and breast cancer cell lines. The expression of the longest isoform of IFIX gene products, IFIX1, is associated with growth inhibition, suppression of transformation, and tumorigenesis. However, the mechanism underlying the tumor suppression activity of IFIX1 is not well understood. Here, we show that IFIX1 downregulates HDM2, a principal negative regulator of p53, at the posttranslational level. IFIX1 destabilizes HDM2 protein and promotes its ubiquitination. The E3 ligase activity of HDM2 appears to be required for this IFIX1 effect. Importantly, HDM2 downregulation is required for the IFIX1-mediated increase of p53 protein levels, transcriptional activity, and nuclear localization, suggesting that IFIX1 positively regulates p53 by acting as a negative regulator of HDM2. We found that IFIX1 interacts with HDM2. Interestingly, the signature motif of the HIN-200 gene family, i.e., the 200-amino-acid HIN domain of IFIX1, is sufficient not only for binding HDM2 but also for downregulating it, leading to p53 activation. Finally, we show that IFIX mediates HDM2 downregulation in an IFN-inducible system. Together, these results suggest that IFIX1 functions as a tumor suppressor by repressing HDM2 function.

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