Cellular Stress and Nucleolar Function

Abstract

All organisms sense and respond to conditions that stress their homeostaticmechanisms. Here we review current studies showing that the nucleolus, long regardedas a mere ribosome producing factory, plays a key role in monitoring and respondingto cellular stress. After exposure to extra- or intracellular stress, cells rapidly downregulatethe synthesis of ribosomal RNA. Impairment of nucleolar function in responseto stress is accompanied by perturbation of nucleolar structure, cell cycle arrest andstabilization of p53. The nucleolar target for down-regulation of rDNA transcription isTIF-IA, an essential transcription factor that modulates the activity of RNApolymerase I (Pol I). Upon stress, TIF-IA is phosphorylated by c-Jun N-terminalkinase 2 (JNK2). Phosphorylation prevents TIF-IA from interaction with Pol I,thereby impairing transcription complex formation and rRNA synthesis. Furthermore,stress-induced inactivation of TIF-IA is accompanied by translocation of TIF-IA fromthe nucleolus to the nucleoplasm. These findings, together with other data showingstress-induced release of nucleolar proteins to carry out other regulatory functions,reinforce the growing realization that nucleoli orchestrate the chain of events the celluses to properly respond to stress signals.