SUMMARY 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 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 normal function of intestinal crypt cells. The data underline the importance of nuclear organization in the regulation of MYC phosphorylation, leading to in vivo demonstration of a strategy for inhibiting MYC activity without detrimental physiological effects.
Containment in cell membranes is essential for all contemporary life, and apparently even the earliest life forms had to be somehow contained. It has been postulated that random enclosure of replicating molecules inside of spontaneously assembled vesicles would have formed the initial cellular ancestors. However, completely random re-formation or division of such primitive vesicles would have abolished the heritability of their contents, nullifying any selective advantage to them. We propose that the containment of the early replicators in membranous vesicles was adopted only after the invention of genetically encoded proteins, and that selective enclosure of target molecules was mediated by specific proteins. A similar containment process is still utilised by various RNA- and retroviruses to isolate their replication complexes from the host's intracellular environment. Such selective encapsulation would have protected the replicators against competitor and parasitic sequences, and provided a strong positive selection within the replicator communities.
Targeting MYC function would be highly desirable for hyperproliferative diseases. As MYC itself is refractory to direct chemical inhibition, understanding of the mechanisms determining MYC's transcriptional and proliferation promoting activities in vivo would be critical for generation of alternative targeting strategies. However, despite 30 years of research, it is very poorly documented what post-translational mechanisms control MYC function in vivo. Here we demonstrate for the first time that Lamin A/C association is critical for MYC phosphorylation regulation. MYC phosphorylation at serine 62 enhances MYC recruitment to Lamin A/C-associated nuclear structures and the Protein Phosphatase 2A (PP2A) inhibitor protein CIP2A is required for retaining this phosphorylation and localization. CIP2A is also critical for serum induced MYC phosphorylation, and for MYC-elicited proliferation induction in vitro. Critically, using complementary transgenic approaches, and intestinal regeneration model, we demonstrate the in vivo importance of this mechanism for MYC´s transcriptional and proliferation promoting activities. However, targeting of this mechanism does not influence basal proliferation, or differentiation of intestinal crypt cells or mouse well-being. Together we discover unprecedented importance of nuclear organization of MYC for its phosphorylation regulation; leading to in vivo demonstration of a strategy for targeting of MYC activity without detrimental physiological effects. Citation Format: Kevin Myant, Xi Qiao, Tuuli Halonen, Christophe Come, Anni Laine, Johanna I. Partanen, Erinn-Lee Ogg, Tiina Laiterä, Mahnaz Janghorban, 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 proliferation induction in vivo. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR03.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.