Requirement of GTP binding for TIF-90-regulated ribosomal RNA synthesis and oncogenic activities in human colon cancer cells
| Autor: | Quoc Trung Ly, Bin Zhang, Tram Kim Thi Pham, Lokesh Nigam, Trung Quoc Lam, Le Xuan Truong Nguyen, Yasmin Elhajmoussa, Guido Marcucci, Dai Dong Thi Nguyen, Vinod Pullarkat, Vo Thanh Thao Nguyen, Trinh To Tat, Ya-Huei Kuo, Lianjun Zhang, Flavia Pichiorri, Dinh Hoa Hoang, Michael S. Nelson, Dang Quan Nguyen, Huu Duc Ho |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
GTP' Transcription Genetic Physiology Nucleolus Carcinogenesis Clinical Biochemistry DNA Ribosomal 03 medical and health sciences 0302 clinical medicine Transcription (biology) RNA Polymerase I Cell Line Tumor RNA polymerase I Humans Enhancer Ribosomal DNA PI3K/AKT/mTOR pathway Cell Proliferation Chemistry Cell Biology Ribosomal RNA HCT116 Cells Cell biology 030104 developmental biology RNA Ribosomal 030220 oncology & carcinogenesis Colonic Neoplasms Guanosine Triphosphate Ribosomes Signal Transduction Transcription Factors |
| Zdroj: | Journal of cellular physiologyREFERENCES. 235(10) |
| ISSN: | 1097-4652 |
| Popis: | Transcription initiation factor 90 (TIF-90), an alternatively spliced variant of TIF-IA, differs by a 90 base pair deletion of exon 6. TIF-90 has been shown to regulate ribosomal RNA (rRNA) synthesis by interacting with polymerase I (Pol I) during the initiation of ribosomal DNA (rDNA) transcription in the nucleolus. Recently, we showed that TIF-90-mediated rRNA synthesis can play an important role in driving tumorigenesis in human colon cancer cells. Here we show that TIF-90 binds GTP at threonine 310, and that GTP binding is required for TIF-90-enhanced rRNA synthesis. Overexpression of activated AKT induces TIF-90 T310, but not a GTP-binding site (TIF-90 T310N) mutant, to translocate into the nucleolus and increase rRNA synthesis. Complementing this result, treatment with mycophenolic acid (MPA), an inhibitor of GTP production, dissociates TIF-90 from Pol I and hence abolishes AKT-increased rRNA synthesis by way of TIF-90 activation. Thus, TIF-90 requires bound GTP to fulfill its function as an enhancer of rRNA synthesis. Both TIF variants are highly expressed in colon cancer cells, and depletion of TIF-IA expression in these cells results in significant sensitivity to MPA-inhibited rRNA synthesis and reduced cell proliferation. Finally, a combination of MPA and AZD8055 (an inhibitor of both AKT and mTOR) synergistically inhibits rRNA synthesis, in vivo tumor growth, and other oncogenic activities of primary human colon cancer cells, suggesting a potential avenue for the development of therapeutic treatments by targeting the regulation of rRNA synthesis by TIF proteins. |
| Databáze: | OpenAIRE |
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