Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative Proliferation
Open accessAbstract
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.
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CIP2A deficiency inhibits MYC activity and Her2-driven mammary tumorigenesis in vivo.
“CIP2A deficiency inhibits MYC activity, and Her2-driven mammary tumorigenesis in vivo [11,22]”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [22]
The Results section reports that CIP2A-deficient mice had reduced MYC phosphorylation and MYC-target expression during intestinal regeneration, supporting the in vivo MYC-activity part of the claim. The paper does not report an experiment showing that CIP2A deficiency inhibits Her2-driven mammary tumorigenesis; its Introduction refers instead to a separate murine breast-cancer study. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAmong oncogenic CIP2A-regulated PP2A targets, the best-known is MYC.
“Among the oncogenic CIP2A-regulated PP2A targets, the best-known is MYC5,21,25.”
From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [25]
The Introduction (page not provided) identifies MYC among proteins whose phosphorylation and activity CIP2A regulates, and the Results examine CIP2A’s regulation of MYC. The paper does not establish the comparative claim that MYC is the best-known of those targets. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCIP2A deficiency does not compromise normal mouse development or growth, except for a defect in spermatogenesis.
“it does not compromise normal mouse development or growth, except for a defect in spermatogenesis [11,22,23]”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [22]
CIP2A impacts oncogenic RAS signaling and MYC activity in vivo.
“Impact of CIP2A on both oncogenic RAS signaling [10,13,36] and MYC activity in vivo [10,12,22]”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [22]
A CIP2A-deficient mouse model lacks detrimental normal tissue homeostasis effects.
“without lack of any detrimental normal tissue homeostasis effects in a CIP2A-deficient mouse model [11,22,23]”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [22]
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Non-genomic mechanisms of protein phosphatase 2A (PP2A) regulation in cancer
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Self-citationOncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56
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Self-citationStructural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A
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“The data show that the CIP2A(1-560) residues cross-linked to B56α are located primarily in the N-terminal head domain (K18, K21, E23, E34, K40) with an additional residue at the C-terminus (K490) (Fig.”
BackgroundMethodInfluentialSelf-citation
- 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. J., & Westermarck, J.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- Åbo Akademi University (FI)
- Oregon Health & Science University (US)
- University of Helsinki (FI)
- Corresponding author
- Sansom, Owen J.
- Westermarck, Jukka
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 12
- Issue
- 6
- Pages
- 1019-1031
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4535171
- OpenAlex
- W1560204041
- Cited by
- 59
- References
- 52
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 6 · 2022: 2 · 2021: 6 · 2020: 12 · 2019: 6 · 2018: 12 · 2017: 2 · 2016: 4 · 2015: 1
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Funders
- Finnish Cancer Institute
- Cancer Research UK (A12481, 21139)
- European Commission (278568)
- Academy of Finland (137687)
- National Institutes of Health
- National Cancer Institute (R01CA129040, R01CA100855, R01CA186241)
- National Institute of General Medical Sciences (T32GM071338)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- c-Myc, CIP2A, nuclear lamins, lamin A/C, protein phosphatase 2A, post-translational regulation, nuclear organization, intestinal regeneration, DNA damage response, cell proliferation, MYC inhibitors
- MeSH terms
- Animals, Autoantigens, Cell Nucleus, Immunohistochemistry, Membrane Proteins, Models, Biological, Phosphorylation, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, Lamin Type A, Mice
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