The ARF tumor suppressor controls ribosome biogenesis by regulating the RNA polymerase I transcription factor TTF-I

Mol Cell. 2010 May 28;38(4):539-50. doi: 10.1016/j.molcel.2010.03.015.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • NIH 3T3 Cells
  • RNA Polymerase I / metabolism*
  • Ribosomes / metabolism*
  • Transcription Factors
  • Tumor Suppressor Protein p14ARF / metabolism*

Substances

  • DNA-Binding Proteins
  • TTF1 protein, human
  • Transcription Factors
  • Ttf1 protein, mouse
  • Tumor Suppressor Protein p14ARF
  • RNA Polymerase I