Genetic Inactivation of the Transcription Factor TIF-IA Leads to Nucleolar Disruption, Cell Cycle Arrest, and p53-Mediated Apoptosis

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),...

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Veröffentlicht in:Molecular cell 2005-07, Vol.19 (1), p.77-87
Hauptverfasser: Yuan, Xuejun, Zhou, Yonggang, Casanova, Emilio, Chai, Minqiang, Kiss, Eva, Gröne, Hermann-Josef, Schütz, Günter, Grummt, Ingrid
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Sprache:eng
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Zusammenfassung: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 p19ARF. 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.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2005.05.023