Genetic inactivation of the transcription factor TIF-IA leads to nucleolar disruption, cell cycle arrest, and p53-mediated apoptosis

Mol Cell. 2005 Jul 1;19(1):77-87. doi: 10.1016/j.molcel.2005.05.023.


Growth-dependent regulation of rRNA synthesis is mediated by TIF-IA, a basal transcription initiation factor for RNA polymerase I. We inactivated the murine TIF-IA gene by homologous recombination in mice and embryonic fibroblasts (MEFs). TIF-IA-/- embryos die before or at embryonic day 9.5 (E9.5), displaying retardation of growth and development. In MEFs, Cre-mediated depletion of TIF-IA leads to disruption of nucleoli, cell cycle arrest, upregulation of p53, and induction of apoptosis. Elevated levels of p53 after TIF-IA depletion are due to increased binding of ribosomal proteins, such as L11, to MDM2 and decreased interaction of MDM2 with p53 and p19(ARF). RNAi-induced loss of p53 overcomes proliferation arrest and apoptosis in response to TIF-IA ablation. The striking correlation between perturbation of nucleolar function, elevated levels of p53, and induction of cell suicide supports the view that the nucleolus is a stress sensor that regulates p53 activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Cycle*
  • Cell Line, Transformed
  • Cell Nucleolus / metabolism*
  • Cell Nucleolus / ultrastructure
  • Cell Proliferation
  • Cell Transformation, Viral
  • Chromatin Immunoprecipitation
  • Embryo, Mammalian / ultrastructure
  • Fibroblasts / metabolism
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Precipitin Tests
  • RNA, Small Interfering / metabolism
  • Retroviridae / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stem Cells / cytology
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Protein p53 / physiology


  • Nuclear Proteins
  • RNA, Small Interfering
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • transcriptional intermediary factor 1