GLTSCR2 promotes the nucleoplasmic translocation and subsequent degradation of nucleolar ARF.

The alternative reading frame protein (p14ARF/ARF) is a key determinant of cell fate, acting as a potent tumor suppressor through a p53/MDM2-dependent pathway or promoting apoptosis in a p53-independent manner. The ARF protein is mainly expressed in the nucleolus and sequestered by nucleophosmin (NPM), whereas ARF-binding proteins, including p53 and MDM2, predominantly reside in the nucleoplasm. This raises the question of how nucleolar ARF binds nucleoplasmic signaling proteins to suppress tumor growth or inhibit cell cycle progression. GLTSCR2 (also known as PICT-1) is a nucleolar protein involved in both tumor suppression and oncogenesis in concert with p53, NPM, and/or MYC. Here, we show that GLTSCR2 increases nucleoplasmic ARF translocation and its degradation. Specifically, GLTSCR2 bound to ARF, and GLTSCR2-ARF complexes were released to the nucleoplasm, where GLTSCR2 increased the binding affinity of ARF for ULF/TRIP12 (a nucleoplasmic E3-ubiquitin ligase of ARF) and enhanced ARF degradation through the polyubiquitination pathway. Our results demonstrate that nucleolar/nucleoplasmic GLTSCR2 is a strong candidate for promoting the subcellular localization and protein stability of ARF.