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.
Department of Pathology, College of Medicine, Kyung Hee University, Seoul 130-701, Korea.
Sun
S
Lee
Department of Pathology, College of Medicine, Kyung Hee University, Seoul 130-701, Korea.
Young-Eun
YE
Cho
Department of Pathology, College of Medicine, Kyung Hee University, Seoul 130-701, Korea.
Sang-Hoon
SH
Kim
Department of Pathology, College of Medicine, Kyung Hee University, Seoul 130-701, Korea.
Yong-Jun
YJ
Kim
Department of Pathology, College of Medicine, Kyung Hee University, Seoul 130-701, Korea.
Jae-Hoon
JH
Park
D002466:Cell Nucleolus / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D034622:RNA Interference; D013997:Time Factors; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
C500712:NOP53 protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins; D000090243:Nucleophosmin; D025821:Polyubiquitin
alternative reading frame; degradation; glioma tumor suppressor candidate region gene 2 protein; subcellular localization; translocation