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Tumor-suppressor NFκB2 p100 interacts with ERK2 and stabilizes PTEN mRNA via inhibition of miR-494

Oncogene volume 35, pages 4080–4090 (2016)Cite this article

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Abstract

Emerging evidence from The Cancer Genome Atlas has revealed that nuclear factor κB2 (nfκb2) gene encoding p100 is genetically deleted or mutated in human cancers, implicating NFκB2 as a potential tumor suppressor. However, the molecular mechanism underlying the antitumorigenic action of p100 remains poorly understood. Here we report that p100 inhibits cancer cell anchorage-independent growth, a hallmark of cellular malignancy, by stabilizing the tumor-suppressor phosphatase and tensin homolog (PTEN) mRNA via a mechanism that is independent of p100’s inhibitory role in NFκB activation. We further demonstrate that the regulatory effect of p100 on PTEN expression is mediated by its downregulation of miR-494 as a result of the inactivation of extracellular signal–regulated kinase 2 (ERK2), in turn leading to inhibition of c-Jun/activator protein-1-dependent transcriptional activity. Furthermore, we identify that p100 specifically interacts with non-phosphorylated ERK2 and prevents ERK2 phosphorylation and nuclear translocation. Moreover, the death domain at C-terminal of p100 is identified as being crucial and sufficient for its interaction with ERK2. Taken together, our findings provide novel mechanistic insights into the understanding of the tumor-suppressive role for NFκB2 p100.

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Acknowledgements

We greatly appreciate Dr Han-Fei Ding for his generous gifts about constructs expressing p100 and various deletion mutants of p100. We also appreciate Dr Shao-Cong Sun from the Department of Immunology, University of Texas MD Anderson Cancer Center for the gift of constructs expressing p100Ser866/870Ala or p100ΔDD. This work was supported partially by grants from NIH/NCI CA165980, CA177665 and CA112557, as well as NIH/NIEHS ES000260.

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  1. Y Wang and J Xu: These authors contributed equally to this work.

Authors and Affiliations

  1. Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA

    Y Wang, J Xu, G Gao, J Li, H Huang, H Jin, J Zhu, X Che & C Huang

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Wang, Y., Xu, J., Gao, G. et al. Tumor-suppressor NFκB2 p100 interacts with ERK2 and stabilizes PTEN mRNA via inhibition of miR-494. Oncogene 35, 4080–4090 (2016). https://doi.org/10.1038/onc.2015.470

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