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Oncogene ; 34(19): 2516-26, 2015 May 07.
Article in English | MEDLINE | ID: mdl-24998852

ABSTRACT

Tumor Progression Locus 2 (TPL2) is widely recognized as a cytoplasmic mitogen-activated protein 3 kinase with a prominent role in the regulation of inflammatory and oncogenic signal transduction. Herein we report that TPL2 may also operate in the nucleus as a physical and functional partner of nucleophosmin (NPM/B23), a major nucleolar phosphoprotein with diverse cellular activities linked to malignancy. We demonstrate that TPL2 mediates the phosphorylation of a fraction of NPM at threonine 199, an event required for its proteasomal degradation and maintenance of steady-state NPM levels. Upon exposure to ultraviolet C, Tpl2 is required for the translocation of de-phosphorylated NPM from the nucleolus to the nucleoplasm. NPM is an endogenous inhibitor of HDM2:p53 interaction and knockdown of TPL2 was found to result in reduced binding of NPM to HDM2, with concomitant defects in p53 accumulation following genotoxic or ribosomal stress. These findings expand our understanding of the function of TPL2 as a negative regulator of carcinogenesis by defining a nuclear role for this kinase in the topological sequestration of NPM, linking p53 signaling to the generation of threonine 199-phosphorylated NPM.


Subject(s)
Active Transport, Cell Nucleus/radiation effects , MAP Kinase Kinase Kinases/metabolism , Nuclear Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Cell Line , Cell Nucleus/metabolism , Cell Proliferation , Cell Transformation, Neoplastic , HEK293 Cells , Humans , MAP Kinase Kinase Kinases/genetics , MAP Kinase Kinase Kinases/radiation effects , Mice , Nucleolus Organizer Region/metabolism , Nucleophosmin , Phosphorylation , Protein Binding/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/radiation effects , Proto-Oncogene Proteins c-mdm2/metabolism , RNA Interference , RNA, Small Interfering , Signal Transduction/genetics , Ultraviolet Rays
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