title: Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative Proliferation.
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.
authors.affiliation: The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Myant
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Department of Pathology, University of Turku, 20520 Turku, Finland.
authors.forename: Xi
authors.initials: X
authors.lastname: Qiao
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Tuuli
authors.initials: T
authors.lastname: Halonen
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Come
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Anni
authors.initials: A
authors.lastname: Laine
authors.affiliation: Department of Molecular and Medical Genetics and Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Janghorban
authors.affiliation: Research Programs Unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Johanna I
authors.initials: JI
authors.lastname: Partanen
authors.affiliation: The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors.forename: John
authors.initials: J
authors.lastname: Cassidy
authors.affiliation: The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors.forename: Erinn-Lee
authors.initials: EL
authors.lastname: Ogg
authors.affiliation: The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Cammareri
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Laiterä
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Okkeri
authors.affiliation: Research Programs Unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Klefström
authors.affiliation: Department of Molecular and Medical Genetics and Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Rosalie C
authors.initials: RC
authors.lastname: Sears
authors.affiliation: The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK. Electronic address: o.sansom@beatson.gla.ac.uk.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Department of Pathology, University of Turku, 20520 Turku, Finland. Electronic address: jukwes@utu.fi.
authors.forename: Jukka
authors.initials: J
authors.lastname: Westermarck
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D007150:Immunohistochemistry; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism
chemical_list: D001324:Autoantigens; C573112:KIAA1524 protein, mouse; D034904:Lamin Type A; D008565:Membrane Proteins; D016271:Proto-Oncogene Proteins c-myc