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

Autor: Bahram F; Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.; Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.; Moreinx AB, Uppsala, Sweden., Hydbring P; Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Tronnersjö S; Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.; GE Healthcare, Uppsala, Sweden., Zakaria SM; Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden., Frings O; Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden., Fahlén S; Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.; Department of Neuroscience, Swedish Medical Nanoscience Center, Karolinska Institutet, Stockholm, Sweden., Nilsson H; Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.; Center for Molecular Pathology, Lund University, Lund, Sweden., Goodwin J; Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden., von der Lehr N; Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.; NatScience, Uppsala, Sweden., Su Y; Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.; Anxun International Co., Limited, Hong Kong, China., Lüscher B; Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Aachen, Germany., Castell A; Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden., Larsson LG; Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
Jazyk: angličtina
Zdroj: Oncotarget [Oncotarget] 2016 Jan 19; Vol. 7 (3), pp. 2837-54.
DOI: 10.18632/oncotarget.6693
Abstrakt: 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 sufficient for IFN-γ-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-γ/p27(KIP1) potentially offers new possibilities for therapeutic intervention in tumors with deregulated Myc.
Databáze: MEDLINE
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