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.
Mayer
Christine
C
Division of Molecular Biology of the Cell II, German Cancer Research Center, D-69120 Heidelberg, Germany. Christine.Mayer@dkfz.de
Bierhoff
Holger
H
Grummt
Ingrid
I
D000818:Animals; D002466:Cell Nucleolus / Q000378:metabolism / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D035463:Pol1 Transcription Initiation Complex Proteins / Q000378:metabolism*; D012318:RNA Polymerase I / Q000037:antagonists & inhibitors*; D012335:RNA, Ribosomal / Q000096:biosynthesis*; D013912:Threonine / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; D013912:Threonine; D048056:Mitogen-Activated Protein Kinase 9; D012318:RNA Polymerase I