title: The cellular abundance of the essential transcription termination factor TTF-I regulates ribosome biogenesis and is determined by MDM2 ubiquitinylation.
abstract: The ARF tumour suppressor stabilizes p53 by negatively regulating the E3 ubiquitin ligase MDM2 to promote cell cycle arrest and cell death. However, ARF is also able to arrest cell proliferation by inhibiting ribosome biogenesis. In greater part this is achieved by targeting the transcription termination factor I (TTF-I) for nucleolar export, leading to an inhibition of both ribosomal RNA synthesis and processing. We now show that in the absence of ARF, TTF-I is ubiquitinylated by MDM2. MDM2 interacts directly with TTF-I and regulates its cellular abundance by targeting it for degradation by the proteasome. Enhanced TTF-I levels inhibit ribosome biogenesis by suppressing ribosomal RNA synthesis and processing, strongly suggesting that exact TTF-I levels are critical for efficient ribosome biogenesis. We further show that concomitant with its ability to displace TTF-I from the nucleolus, ARF inhibits MDM2 ubiquitinylation of TTF-I by competitively binding to a site overlapping the MDM2 interaction site. Thus, both the sub-nuclear localization and the abundance of TTF-I are key regulators of ribosome biogenesis.
authors.affiliation: Cancer Research Centre and Department of Molecular Biology, Medical Biochemistry and Pathology of Laval University, CHUQ Research Centre, Pavillon St Patrick, 9 rue McMahon, Québec, G1R 3S3 Québec, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lessard
authors.forename: Victor
authors.initials: V
authors.lastname: Stefanovsky
authors.forename: Michel G
authors.initials: MG
authors.lastname: Tremblay
authors.forename: Tom
authors.initials: T
authors.lastname: Moss
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism*; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; C504004:Ttf1 protein, mouse; D025803:Tumor Suppressor Protein p14ARF; D051736:Proto-Oncogene Proteins c-mdm2