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

Myant, K. et al. (2015) Serine 62-phosphorylated MYC associates with nuclear lamins and its regulation by CIP2A is essential for regenerative proliferation. Cell Reports, 12(6), pp. 1019-1031. (doi:10.1016/j.celrep.2015.07.003) (PMID:26235622)

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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 enhances MYC 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 for MYC activity 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Myant, Dr Kevin and Cammareri, Dr Patrizia and Sansom, Professor Owen
Authors: 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., and Westermarck, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Reports
Publisher:Elsevier
ISSN:2211-1247
ISSN (Online):2211-1247
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Cell Reports 12(6):1019-1031
Publisher Policy:Reproduced under a Creative Commons License

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