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), 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.
Division of Molecular Biology of the Cell II, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Xuejun
X
Yuan
Yonggang
Y
Zhou
Emilio
E
Casanova
Minqiang
M
Chai
Eva
E
Kiss
Hermann-Josef
HJ
Gröne
Günter
G
Schütz
Ingrid
I
Grummt
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002461:Cell Line, Transformed; D002466:Cell Nucleolus / Q000378:metabolism* / Q000648:ultrastructure; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D047369:Chromatin Immunoprecipitation; D004622:Embryo, Mammalian / Q000648:ultrastructure; D005347:Fibroblasts / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011233:Precipitin Tests; D034741:RNA, Small Interfering / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C093517:transcriptional intermediary factor 1