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

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.

SUBMITTER: Park J

PROVIDER: S-EPMC2040422 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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

Park Junsoo J Kim Kwangsoo K Lee Eun-Ju EJ Seo Yun-Jee YJ Lim Si-Nae SN Park Kyoungsook K Rho Seung Bae SB Lee Seung-Hoon SH Lee Je-Ho JH

Proceedings of the National Academy of Sciences of the United States of America 20071017 43

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 SU ...[more]

PMID: 17942705

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Project description:Hydrogen has been used to suppress tumor growth with considerable efficacy. Inhalation of hydrogen gas and oral ingestion of hydrogen-rich saline are two common systemic routes of hydrogen administration. We have developed a topical delivery method of hydrogen at targeted sites through the degradation of magnesium-based biomaterials. However, the underlying mechanism of hydrogen's role in cancer treatment remains ambiguous. Here, we investigate the mechanism of tumor cell apoptosis triggered by the hydrogen released from magnesium-based biomaterials. We find that the localized release of hydrogen increases the expression level of P53 tumor suppressor proteins, as demonstrated by the in vitro RNA sequencing and protein expression analysis. Then, the P53 proteins disrupt the membrane potential of mitochondria, activate autophagy, suppress the reactive oxygen species in cancer cells, and finally result in tumor suppression. The anti-tumor efficacy of magnesium-based biomaterials is further validated in vivo by inserting magnesium wire into the subcutaneous tumor in a mouse. We also discovered that the minimal hydrogen concentration from magnesium wires to trigger substantial tumor apoptosis is 91.2 μL/mm3 per day, which is much lower than that required for hydrogen inhalation. Taken together, these findings reveal the release of H2 from magnesium-based biomaterial exerts its anti-tumoral activity by activating the P53-mediated lysosome-mitochondria apoptosis signaling pathway, which strengthens the therapeutic potential of this biomaterial as localized anti-tumor treatment. Graphical abstract Image 1 Highlights • The feasibility of using Mg implants is explored for localized delivery of hydrogen against colorectal tumors.• This approach is advantageous over conventional chemotherapy/H2 inhalation due to the portability, high H2-loading capacity and efficient delivery of H2 gas to tumors.• We provide a molecularly detailed and mechanistic understanding of how H2 could activate the antitumor pathway above certain threshold concentrations of H2, which inspires more effective therapy against tumors.

Dataset Information

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

Publications

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

Similar Datasets

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