title: Interferon-γ-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)-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.
authors.affiliation: 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.
authors.forename: Fuad
authors.initials: F
authors.lastname: Bahram
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Per
authors.initials: P
authors.lastname: Hydbring
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.|GE Healthcare, Uppsala, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Tronnersjö
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Siti Mariam
authors.initials: SM
authors.lastname: Zakaria
authors.affiliation: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Oliver
authors.initials: O
authors.lastname: Frings
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.|Department of Neuroscience, Swedish Medical Nanoscience Center, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Fahlén
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Pathology, Lund University, Lund, Sweden.
authors.forename: Helén
authors.initials: H
authors.lastname: Nilsson
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jacob
authors.initials: J
authors.lastname: Goodwin
authors.affiliation: Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.|NatScience, Uppsala, Sweden.
authors.forename: Natalie
authors.initials: N
authors.lastname: von der Lehr
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.|Anxun International Co., Limited, Hong Kong, China.
authors.forename: Yingtao
authors.initials: Y
authors.lastname: Su
authors.affiliation: Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Aachen, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lüscher
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Alina
authors.initials: A
authors.lastname: Castell
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars-Gunnar
authors.initials: LG
authors.lastname: Larsson
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D016922:Cellular Senescence / Q000502:physiology; D002522:Chlorocebus aethiops; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007371:Interferon-gamma; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D046988:Proteasome Endopeptidase Complex
keywords: interferon-gamma; oncogene; the cancer genome atlas; tumor suppressor gene; ubiquitin-proteasome system