Serine 62-phosphorylated MYC Associates with nuclear lamins and its regulation by CIP2A is essential for regenerative proliferation

Kevin Myant, Xi Qiao, Tuuli Halonen, Christophe Come, Anni Laine, Mahnaz Janghorban, Johanna I. Partanen, John Cassidy, Erinn Lee Ogg, Patrizia Cammareri, Tiina Laiterä, Juha Okkeri, Juha Klefström, Rosalie C. Sears, Owen J. Sansom, Jukka Westermarck

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

An understanding of the mechanisms determining MYC's transcriptional and proliferation-promoting activities in vivo could facilitate approaches for MYC targeting. However, post-translational mechanisms that control MYC function in vivo are poorly understood. Here, we demonstrate that MYC phosphorylation at serine 62 enhancesMYC accumulation on Lamin A/C-associated nuclear structures and that the protein phosphatase 2A (PP2A) inhibitor protein CIP2A is required for this process. CIP2A is also critical for serum-induced MYC phosphorylation and for MYC-elicited proliferation induction in vitro. Complementary transgenic approaches and an intestinal regeneration model further demonstrated the in vivo importance of CIP2A and serine 62 phosphorylation forMYCactivity upon DNA damage. However, targeting of CIP2A did not influence the normal function of intestinal crypt cells. These data underline the importance of nuclear organization in the regulation of MYC phosphorylation, leading to an in vivo demonstration of a strategy for inhibiting MYC activity without detrimental physiological effects.

Original languageEnglish (US)
Pages (from-to)1019-1031
Number of pages13
JournalCell Reports
Volume12
Issue number6
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Myant, K., Qiao, X., Halonen, T., Come, C., Laine, A., Janghorban, M., Partanen, J. I., Cassidy, J., Ogg, E. L., Cammareri, P., Laiterä, T., Okkeri, J., Klefström, J., Sears, R. C., Sansom, O. J., & Westermarck, J. (2015). Serine 62-phosphorylated MYC Associates with nuclear lamins and its regulation by CIP2A is essential for regenerative proliferation. Cell Reports, 12(6), 1019-1031. https://doi.org/10.1016/j.celrep.2015.07.003