Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative Proliferation
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 phosphoryla...
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doaj-9192a9a0cda04901aa08c766517eccaa2020-11-24T21:29:06ZengElsevierCell Reports2211-12472015-08-011261019103110.1016/j.celrep.2015.07.003Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative ProliferationKevin Myant0Xi Qiao1Tuuli Halonen2Christophe Come3Anni Laine4Mahnaz Janghorban5Johanna I. Partanen6John Cassidy7Erinn-Lee Ogg8Patrizia Cammareri9Tiina Laiterä10Juha Okkeri11Juha Klefström12Rosalie C. Sears13Owen J. Sansom14Jukka Westermarck15The Beatson Institute for Cancer Research, Glasgow G61 1BD, UKTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, FinlandTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, FinlandTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, FinlandTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, FinlandDepartment of Molecular and Medical Genetics and Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USAResearch Programs Unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, 00014 Helsinki, FinlandThe Beatson Institute for Cancer Research, Glasgow G61 1BD, UKThe Beatson Institute for Cancer Research, Glasgow G61 1BD, UKThe Beatson Institute for Cancer Research, Glasgow G61 1BD, UKTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, FinlandTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, FinlandResearch Programs Unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, 00014 Helsinki, FinlandDepartment of Molecular and Medical Genetics and Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USAThe Beatson Institute for Cancer Research, Glasgow G61 1BD, UKTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, FinlandAn 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.http://www.sciencedirect.com/science/article/pii/S2211124715007299 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative Proliferation Cell Reports |
author_facet |
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 |
author_sort |
Kevin Myant |
title |
Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative Proliferation |
title_short |
Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative Proliferation |
title_full |
Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative Proliferation |
title_fullStr |
Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative Proliferation |
title_full_unstemmed |
Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative Proliferation |
title_sort |
serine 62-phosphorylated myc associates with nuclear lamins and its regulation by cip2a is essential for regenerative proliferation |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2015-08-01 |
description |
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. |
url |
http://www.sciencedirect.com/science/article/pii/S2211124715007299 |
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