Interferon-γ-induced P27KIP1 Binds to and Targets MYC for Proteasome-mediated Degradation

Overview

Journal Oncotarget

Specialty Oncology

Date 2015 Dec 25

PMID 26701207

Citations 7

Authors

Fuad Bahram

Per Hydbring

Susanna Tronnersjo

Siti Mariam Zakaria

Oliver Frings

Sara Fahlen

Helen Nilsson

Jacob Goodwin

Natalie von der Lehr

Yingtao Su

Bernhard Luscher

Alina Castell

Lars-Gunnar Larsson

Affiliations

Soon will be listed here.

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.

Citing Articles

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