title: Tumor-suppressor NFκB2 p100 interacts with ERK2 and stabilizes PTEN mRNA via inhibition of miR-494.
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.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Gao
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Jin
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: X
authors.initials: X
authors.lastname: Che
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Huang
mesh_terms: D021581:Active Transport, Cell Nucleus; D045325:HCT116 Cells; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D052003:NF-kappa B p52 Subunit / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D020871:RNA Stability; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: C547168:MIRN494 microRNA, human; D035683:MicroRNAs; D052003:NF-kappa B p52 Subunit; C498206:NFKB2 protein, human; D016755:Proto-Oncogene Proteins c-jun; D025521:Tumor Suppressor Proteins; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D051059:PTEN Phosphohydrolase