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Requirement of GTP binding for TIF‐90‐regulated ribosomal RNA synthesis and oncogenic activities in human colon cancer cells
Author(s) -
Nguyen Dang Quan,
Hoang Dinh Hoa,
Nelson Michael,
Nigam Lokesh,
Nguyen Vo Thanh Thao,
Zhang Lianjun,
Pham Tram Kim Thi,
Ho Huu Duc,
Nguyen Dai Dong Thi,
Lam Trung Quoc,
Tat Trinh To,
Elhajmoussa Yasmin,
Ly Quoc Trung,
Pichiorri Flavia,
Pullarkat Vinod,
Zhang Bin,
Kuo YaHuei,
Marcucci Guido,
Nguyen Le Xuan Truong
Publication year - 2020
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.29661
Subject(s) - nucleolus , gtp' , microbiology and biotechnology , rna polymerase i , biology , ribosomal rna , rna , pi3k/akt/mtor pathway , 23s ribosomal rna , cell growth , ribosome , rna polymerase , biochemistry , signal transduction , cytoplasm , gene , enzyme
Abstract 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.