The nucleolus as a stress sensor: JNK2 inactivates the transcription factor TIF-IA and down-regulates rRNA synthesis.
Cells respond to a variety of extracellular and intracellular forms of stress by down-regulating rRNA synthesis. We have investigated the mechanism underlying stress-dependent inhibition of RNA polymerase I (Pol I) transcription and show that the Pol I-specific transcription factor TIF-IA is inactivated upon stress. Inactivation is due to phosphorylation of ... TIF-IA by c-Jun N-terminal kinase (JNK) at a single threonine residue (Thr 200). Phosphorylation at Thr 200 impairs the interaction of TIF-IA with Pol I and the TBP-containing factor TIF-IB/SL1, thereby abrogating initiation complex formation. Moreover, TIF-IA is translocated from the nucleolus into the nucleoplasm. Substitution of Thr 200 by valine as well as knock-out of Jnk2 prevent inactivation and translocation of TIF-IA, leading to stress-resistance of Pol I transcription. Our data identify TIF-IA as a downstream target of the JNK pathway and suggest a critical role of JNK2 to protect rRNA synthesis against the harmful consequences of cellular stress.
Mesh Terms:
Animals, Cell Nucleolus, Chromatin Immunoprecipitation, Fluorescent Antibody Technique, Gene Expression Regulation, Enzymologic, Immunoblotting, Immunoprecipitation, Mice, Mitogen-Activated Protein Kinase 9, Phosphorylation, Pol1 Transcription Initiation Complex Proteins, RNA Polymerase I, RNA, Ribosomal, Threonine, Transfection, Tumor Cells, Cultured
Animals, Cell Nucleolus, Chromatin Immunoprecipitation, Fluorescent Antibody Technique, Gene Expression Regulation, Enzymologic, Immunoblotting, Immunoprecipitation, Mice, Mitogen-Activated Protein Kinase 9, Phosphorylation, Pol1 Transcription Initiation Complex Proteins, RNA Polymerase I, RNA, Ribosomal, Threonine, Transfection, Tumor Cells, Cultured
Genes Dev.
Date: Apr. 15, 2005
PubMed ID: 15805466
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