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

Bahram, Fuad; Hydbring, Per; Tronnersjö, Susanna; Zakaria, Siti Mariam; Frings, Oliver; Fahlén, Sara; Nilsson, Helén LU ; Goodwin, Jacob; von der Lehr, Natalie and Su, Yingtao, et al. (2016) In Oncotarget 7(3). p.2837-2854
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 p27Kip1 (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... (More)
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 p27Kip1 (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/p27KIP1 potentially offers new possibilities for therapeutic intervention in tumors with deregulated Myc. (Less)
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type
Contribution to journal
publication status
published
subject
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Oncotarget
volume
7
issue
3
pages
2837 - 2854
publisher
Impact Journals, LLC
external identifiers
  • PMID:26701207
  • Scopus:84962221857
ISSN
1949-2553
DOI
10.18632/oncotarget.6693
language
English
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yes
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9296c3f2-8ddc-4a76-8181-e356e2431eeb (old id 8503771)
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http://www.ncbi.nlm.nih.gov/pubmed/26701207?dopt=Abstract
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2016-01-06 13:16:26
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2016-11-13 04:27:30
@misc{9296c3f2-8ddc-4a76-8181-e356e2431eeb,
  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 p27Kip1 (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/p27KIP1 potentially offers new possibilities for therapeutic intervention in tumors with deregulated Myc.},
  author       = {Bahram, Fuad and Hydbring, Per and Tronnersjö, Susanna and Zakaria, Siti Mariam and Frings, Oliver and Fahlén, Sara and Nilsson, Helén and Goodwin, Jacob and von der Lehr, Natalie and Su, Yingtao and Lüscher, Bernhard and Castell, Alina and Larsson, Lars-Gunnar},
  issn         = {1949-2553},
  language     = {eng},
  number       = {3},
  pages        = {2837--2854},
  publisher    = {ARRAY(0x92370d0)},
  series       = {Oncotarget},
  title        = {Interferon-γ-induced p27KIP1 binds to and targets MYC for proteasome-mediated degradation.},
  url          = {http://dx.doi.org/10.18632/oncotarget.6693},
  volume       = {7},
  year         = {2016},
}