Elevated level of SUMOylated IRF-1 in tumor cells interferes with IRF-1-mediated apoptosis

Molecular Therapy Research Center, Sungkyunkwan University, Seoul 135-710, Korea.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2007; 104(43):17028-33. DOI: 10.1073/pnas.0609852104
Source: PubMed

ABSTRACT SUMOylation of transcription factors often attenuates transcription activity. This regulation of protein activity allows more diversity in the control of gene expression. Interferon regulatory factor-1 (IRF-1) was originally identified as a regulator of IFN-alpha/beta, and its expression is induced by viral infection or IFN stimulation. Accumulating evidence supports the theory that IRF-1 functions as a tumor suppressor and represses the transformed phenotype. Here we report that the level of SUMOylated IRF-1 is elevated in tumors. Site-directed mutagenesis experiments disclose that the SUMOylation sites of IRF-1 are identical to the major ubiquitination sites. Consequently, SUMOylated IRF-1 displays enhanced resistance to degradation. SUMOylation of IRF-1 attenuates its transcription activity, and SUMOylated IRF-1 inhibits apoptosis by repression of its transcriptional activity. These data support a mechanism whereby SUMOylation of IRF-1 inactivates its tumor suppressor function, which facilitates resistance to the immune response.

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Available from: Seung-Hoon Lee, Mar 04, 2014
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    • "Increasing evidence supports the theory that IRF-1 functions as a tumor suppressor and represses the transformed phenotype. In human tumors, IRF-1 is deactivated to prevent apoptosis and cell cycle arrest by genetic mechanisms [9]. "
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    ABSTRACT: Many traditional Chinese medicine (TCM) formulae have been used in cancer therapy. The JIN formula is an ancient herbal formula recorded in the classic TCM book Jin Kui Yao Lue (Golden Chamber). The JIN formula significantly delayed the growth of subcutaneous human H460 xenografted tumors in vivo compared with the growth of mock controls. Gene array analysis of signal transduction in cancer showed that the JIN formula acted on multiple targets such as the mitogen-activated protein kinase, hedgehog, and Wnt signaling pathways. The coformula treatment of JIN and diamminedichloroplatinum (DDP) affected the stress/heat shock pathway. Proteomic analysis showed 36 and 84 differentially expressed proteins between the mock and DDP groups and between the mock and JIN groups, respectively. GoMiner analysis revealed that the differentially expressed proteins between the JIN and mock groups were enriched during cellular metabolic processes, and so forth. The ones between the DDP and mock groups were enriched during protein-DNA complex assembly, and so forth. Most downregulated proteins in the JIN group were heat shock proteins (HSPs) such as HSP90AA1 and HSPA1B, which could be used as markers to monitor responses to the JIN formula therapy. The mechanism of action of the JIN formula on HSP proteins warrants further investigation.
    Evidence-based Complementary and Alternative Medicine 08/2013; 2013:160168. DOI:10.1155/2013/160168 · 1.88 Impact Factor
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    • "A mechanism associated with the human papilloma virus (HPV) 16-encoded E7 oncoprotein has also been reported (26). In addition, previous studies indicate that SUMOylated IRF-1 inhibits apoptosis by repression of transcriptional activity (27). Finally, numerous reports reveal low expression levels of IRF-1 mRNA in specific forms of cancer, including breast cancer and hepatocellular carinoma (28,29). "
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    ABSTRACT: The present review focuses on recent advances in the understanding of the molecular mechnisms by which interferon regulatory factor (IRF)-1 inhibits oncogenesis. IRF-1 is associated with regulation of interferon α and β transcription. In addition, numerous clinical studies have indicated that IRF-1 gene deletion or rearrangement correlates with development of specific forms of human cancer. IRF-1 has been revealed to exhibit marked functional diversity in the regulation of oncogenesis. IRF-1 activates a set of target genes associated with regulation of the cell cycle, apoptosis and the immune response. The role of IRF-1 in the regulation of various types of human tumor has important implications for understanding the susceptibility and progression of cancer. In addition, an improved understanding of the role of IRF-1 in the pathological processes that lead to human malignant diseases may aid development of novel therapeutic strategies.
    Oncology letters 02/2013; 5(2):417-423. DOI:10.3892/ol.2012.1051 · 1.55 Impact Factor
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    • "IRFs control expression of cytokines, growth factors, cell adhesion molecules, chemokines and regulate a large number of genes in a variety of cells and tissues under diverse conditions (Ozato et al. 2007). Dysregulation of IRFs by gene mutation (Nishio et al. 2001), differential expression (Choo et al. 2006), alternative splicing of the mRNAs (Maratheftis et al. 2006), post-translational modifi cation and proteolytic processing (Park et al. 2007) during various pathological conditions and diseases have been reported. IRF-1 and IRF-2, the two founding members of IRF family, provide examples of both positive and negative regulators of transcription of genes during immune response (Colonna 2007), cell growth (Masumi et al. 2003), differentiation (Chung and Kawamoto 2004) and cancer (Wang et al. 2007). "
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