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Interferon-?-induced p27KIP1 binds to and targets MYC for proteasome-mediated degradation.

ABSTRACT: The Myc oncoprotein is tightly regulated at multiple levels including ubiquitin-mediated protein turnover. We recently demonstrated that inhibition of Cdk2-mediated phosphorylation of Myc at Ser-62 pharmacologically or through interferon (IFN)-?-induced expression of p27(Kip1) (p27) repressed Myc's activity to suppress cellular senescence and differentiation. In this study we identified an additional activity of p27 to interfere with Myc independent of Ser-62 phosphorylation. p27 is required and sufficient for IFN-?-induced turnover of Myc. p27 interacted with Myc in the nucleus involving the C-termini of the two proteins, including Myc box 4 of Myc. The C-terminus but not the Cdk2 binding fragment of p27 was sufficient for inducing Myc degradation. Protein expression data of The Cancer Genome Atlas breast invasive carcinoma set revealed significantly lower Myc protein levels in tumors with highly expressed p27 lacking phosphorylation at Thr-157--a marker for active p27 localized in the nucleus. Further, these conditions correlated with favorable tumor stage and patient outcome. This novel regulation of Myc by IFN-?/p27(KIP1) potentially offers new possibilities for therapeutic intervention in tumors with deregulated Myc.

SUBMITTER: Bahram F

PROVIDER: S-EPMC4823075 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Interferon-γ-induced p27KIP1 binds to and targets MYC for proteasome-mediated degradation.

Bahram Fuad F Hydbring Per P Tronnersjö Susanna S Zakaria Siti Mariam SM Frings Oliver O Fahlén Sara S Nilsson Helén H Goodwin Jacob J von der Lehr Natalie N Su Yingtao Y Lüscher Bernhard B Castell Alina A Larsson Lars-Gunnar LG

Oncotarget 20160101 3

The Myc oncoprotein is tightly regulated at multiple levels including ubiquitin-mediated protein turnover. We recently demonstrated that inhibition of Cdk2-mediated phosphorylation of Myc at Ser-62 pharmacologically or through interferon (IFN)-γ-induced expression of p27(Kip1) (p27) repressed Myc's activity to suppress cellular senescence and differentiation. In this study we identified an additional activity of p27 to interfere with Myc independent of Ser-62 phosphorylation. p27 is required and ...[more]

PMID: 26701207

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Project description:BACKGROUND:Type I interferons (IFN-?/?) have broad and potent immunoregulatory and antiproliferative activities. However, it is still known whether the dietary flavonoids exhibit their antiviral and anticancer properties by modulating the function of type I IFNs. OBJECTIVE:This study aimed at determining the role of apigenin, a dietary plant flavonoid abundant in common fruits and vegetables, on the type I IFN-mediated inhibition of cancer cell viability. DESIGN:Inhibitory effect of apigenin on human 26S proteasome, a known negative regulator of type I IFN signaling, was evaluated in vitro. Molecular docking was conducted to know the interaction between apigenin and subunits of 26S proteasome. Effects of apigenin on JAK/STAT pathway, 26S proteasome-mediated interferon receptor stability, and cancer cells viability were also investigated. RESULTS:Apigenin was identified to be a potent inhibitor of human 26S proteasome in a cell-based assay. Apigenin inhibited the chymotrypsin-like, caspase-like, and trypsin-like activities of the human 26S proteasome and increased the ubiquitination of endogenous proteins in cells. Results from computational modeling of the potential interactions of apigenin with the chymotrypsin site (?5 subunit), caspase site (?1 subunit), and trypsin site (?2 subunit) of the proteasome were consistent with the observed proteasome inhibitory activity. Apigenin enhanced the phosphorylation of signal transducer and activator of transcription proteins (STAT1 and STAT2) and promoted the endogenous IFN-?-regulated gene expression. Apigenin inhibited the IFN-?-stimulated ubiquitination and degradation of type I interferon receptor 1 (IFNAR1). Apigenin also sensitized the inhibitory effect of IFN-? on viability of cervical carcinoma HeLa cells. CONCLUSION:These results suggest that apigenin potentiates the inhibitory effect of IFN-? on cancer cell viability by activating JAK/STAT signaling pathway through inhibition of 26S proteasome-mediated IFNAR1 degradation. This may provide a novel mechanism for increasing the efficacy of IFN-?/?.

Dataset Information

Interferon-?-induced p27KIP1 binds to and targets MYC for proteasome-mediated degradation.

Publications

Interferon-γ-induced p27KIP1 binds to and targets MYC for proteasome-mediated degradation.

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