Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative Proliferation
| Autor: | Kevin Myant, Tuuli Halonen, Erinn Lee Ogg, John W. Cassidy, Anni Laine, Tiina Laiterä, Rosalie C. Sears, Mahnaz Janghorban, Jukka Westermarck, Owen J. Sansom, Christophe Côme, Juha Klefström, Johanna I. Partanen, Juha Okkeri, Xi Qiao, Patrizia Cammareri |
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| Přispěvatelé: | Research Programs Unit, Medicum, Department of Biochemistry and Developmental Biology, Juha Klefström / Principal Investigator, Translational Cancer Biology (TCB) Research Programme |
| Rok vydání: | 2013 |
| Předmět: |
CANCER-THERAPY
DNA damage Biology Autoantigens Models Biological General Biochemistry Genetics and Molecular Biology Article Serine Proto-Oncogene Proteins c-myc 03 medical and health sciences Mice 0302 clinical medicine medicine C-MYC Animals Phosphorylation lcsh:QH301-705.5 030304 developmental biology Regulation of gene expression Cell Nucleus 0303 health sciences GENE-REGULATION ta1182 Membrane Proteins PROTEIN PHOSPHATASE 2A INTESTINAL REGENERATION Protein phosphatase 2 Lamin Type A Immunohistochemistry Gene Expression Regulation Neoplastic Cell nucleus APC DEFICIENCY medicine.anatomical_structure lcsh:Biology (General) 030220 oncology & carcinogenesis Cancer research Nuclear lamina CELL-GROWTH 3111 Biomedicine STEM-CELLS Lamin ONCOPROTEIN |
| Zdroj: | Cell Reports, Vol 12, Iss 6, Pp 1019-1031 (2015) Myant, K, Qiao, X, Halonen, T, Come, C, Laine, A, Janghorban, M, Partanen, J, Cassidy, J, Ogg, E, Cammareri, P, Laiterä, T, Okkeri, J, Klefström, J, Sears, R, Sansom, O & Westermarck, J 2015, ' Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative Proliferation ', Cell Reports, vol. 12, no. 6, pp. 1019-1031 . https://doi.org/10.1016/j.celrep.2015.07.003 |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2015.07.003 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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