Requirement of GTP binding for TIF-90-regulated ribosomal RNA synthesis and oncogenic activities in human colon cancer cells.
Carcinogenesis
/ genetics
Cell Line, Tumor
Cell Proliferation
/ genetics
Colonic Neoplasms
/ genetics
DNA, Ribosomal
/ genetics
Guanosine Triphosphate
/ genetics
HCT116 Cells
Humans
RNA Polymerase I
/ genetics
RNA, Ribosomal
/ genetics
Ribosomes
/ genetics
Signal Transduction
/ genetics
Transcription Factors
/ genetics
Transcription, Genetic
/ genetics
GTP
MPA
TIF-90
TIF-IA
rRNA synthesis
Journal
Journal of cellular physiology
ISSN: 1097-4652
Titre abrégé: J Cell Physiol
Pays: United States
ID NLM: 0050222
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
05
08
2019
accepted:
13
02
2020
pubmed:
12
3
2020
medline:
5
3
2021
entrez:
12
3
2020
Statut:
ppublish
Résumé
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.
Substances chimiques
DNA, Ribosomal
0
RNA, Ribosomal
0
Transcription Factors
0
Guanosine Triphosphate
86-01-1
RNA Polymerase I
EC 2.7.7.6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7567-7579Subventions
Organisme : National Foundation for Science and Technology Development
ID : 106-YS.02-2015.60
Informations de copyright
© 2020 Wiley Periodicals, Inc.
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