c-Jun N-terminal kinase regulates the nucleoplasmic translocation and stability of nucleolar GLTSCR2 protein.

Glioblastoma tumor suppressive candidate region gene 2 (GLTSCR2) is a nucleolar protein that participates in critical cellular processes including the DNA damage response, cell cycle regulation, and inhibition of MYC-induced transforming activity. Irrespective of these important physiological and pathological functions, the mechanisms that regulate GLTSCR2 expression, and its nucleolar-nucleoplasmic translocation, are largely unknown. HeLa cells were treated with various protein kinase inhibitors and subjected to immunocytochemical or immunoblot assays for GLTSCR2. Protein stability was determined by the cycloheximide chase or ubiquitination assays. Oligomer status was analyzed by immunoprecipitation. Inhibiting c-jun N-terminal kinase (JNK) phosphorylation activity on c-jun by SP600125, or adding a c-jun peptide, induced the nucleoplasmic translocation of GLTSCR2 from the nucleolus and enhanced protein degradation through the proteasome-polyubiquitination pathway. These effects may have resulted from reducing the binding affinity between GLTSCR2 monomers. These data indicate that JNK, and its phosphorylation target c-jun, are prerequisites for the nucleolar distribution of GLTSCR2 and maintenance of its protein stability. Overall, GLTSCR2 is crucial for normal cellular function as well as for preventing the development or progression of cancer. The JNK-c-jun axis is indispensible for regulating the activities of GLTSCR2.