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.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Lessard F,Stefanovsky V,Tremblay MG,Moss Tdoi
10.1093/nar/gks198subject
Has Abstractpub_date
2012-07-01 00:00:00pages
5357-67issue
12eissn
0305-1048issn
1362-4962pii
gks198journal_volume
40pub_type
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