Abstract PR03: Serine 62 phosphorylated MYC associates with nuclear lamins and its regulation by CIP2A is essential for proliferation induction in vivo

Targeting MYC function would be highly desirable for hyperproliferative diseases. As MYC itself is refractory to direct chemical inhibition, understanding of the mechanisms determining MYC's transcriptional and proliferation promoting activities in vivo would be critical for generation of alternative targeting strategies. However, despite 30 years of research, it is very poorly documented what post-translational mechanisms control MYC function in vivo. Here we demonstrate for the first time that Lamin A/C association is critical for MYC phosphorylation regulation. MYC phosphorylation at serine 62 enhances MYC recruitment to Lamin A/C-associated nuclear structures and the Protein Phosphatase 2A (PP2A) inhibitor protein CIP2A is required for retaining this phosphorylation and localization. CIP2A is also critical for serum induced MYC phosphorylation, and for MYC-elicited proliferation induction in vitro. Critically, using complementary transgenic approaches, and intestinal regeneration model, we demonstrate the in vivo importance of this mechanism for MYC´s transcriptional and proliferation promoting activities. However, targeting of this mechanism does not influence basal proliferation, or differentiation of intestinal crypt cells or mouse well-being. Together we discover unprecedented importance of nuclear organization of MYC for its phosphorylation regulation; leading to in vivo demonstration of a strategy for targeting of MYC activity without detrimental physiological effects. Citation Format: Kevin Myant, Xi Qiao, Tuuli Halonen, Christophe Come, Anni Laine, Johanna I. Partanen, Erinn-Lee Ogg, Tiina Laiterä, Mahnaz Janghorban, Juha Okkeri, Juha Klefström, Rosalie C. Sears, Owen J. Sansom, Jukka Westermarck. Serine 62 phosphorylated MYC associates with nuclear lamins and its regulation by CIP2A is essential for proliferation induction in vivo. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR03.