Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis*
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Cell Cycle*
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Cell Line, Transformed
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Cell Nucleolus / metabolism*
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Cell Nucleolus / ultrastructure
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Cell Proliferation
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Cell Transformation, Viral
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Chromatin Immunoprecipitation
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Embryo, Mammalian / ultrastructure
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Fibroblasts / metabolism
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Immunohistochemistry
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Mice
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Mice, Transgenic
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Models, Biological
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Precipitin Tests
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RNA, Small Interfering / metabolism
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Retroviridae / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Stem Cells / cytology
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Protein p53 / physiology
Substances
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Nuclear Proteins
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RNA, Small Interfering
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Transcription Factors
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Tumor Suppressor Protein p53
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transcriptional intermediary factor 1