The ARF tumor suppressor controls ribosome biogenesis by regulating the RNA polymerase I transcription factor TTF-I.
The p14/p19(ARF) (ARF) product of the CDKN2A gene displays tumor suppressor activity both in the presence and absence of p53/TP53. In p53-negative cells, ARF arrests cell proliferation, at least in part, by suppressing ribosomal RNA synthesis. We show that ARF does this by controlling the subnuclear localization of the RNA polymerase I transcription termination factor, TTF-I. TTF-I shuttles between nucleoplasm and nucleolus with the aid of the chaperone NPM/B23 and a nucleolar localization sequence within its N-terminal regulatory domain. ARF inhibits nucleolar import of TTF-I by binding to this nucleolar localization sequence, causing the accumulation of TTF-I in the nucleoplasm. Depletion of TTF-I recapitulates the effects of ARF on ribosomal RNA synthesis and is rescued by the introduction of a TTF-I transgene. Thus, our data delineate the pathway by which ARF regulates ribosomal RNA synthesis and provide a compelling explanation for the role of NPM.
Cancer Research Centre, Department of Molecular Biology, Medical Biochemistry, and Pathology of Laval University, CHUQ Research Centre, Québec, Québec, Canada.
Frédéric
F
Lessard
Françoise
F
Morin
Stacey
S
Ivanchuk
Frédéric
F
Langlois
Victor
V
Stefanovsky
James
J
Rutka
Tom
T
Moss
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D012318:RNA Polymerase I / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism*; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*
D004268:DNA-Binding Proteins; C504003:TTF1 protein, human; D014157:Transcription Factors; C504004:Ttf1 protein, mouse; D025803:Tumor Suppressor Protein p14ARF; D012318:RNA Polymerase I