Nucleolar associated structures: the Perinucleolar Compartment, Sam68 and Cajal bodies

Several sub-nuclear compartments are often associated with nucleoli, including the Cajal and Sam68 bodies, as well as the perinucleolar compartment (PNC). Originally called the nucleolar accessory body, Cajal bodies are often found in close proximity or juxtaposed to nucleoli. Many Cajal body proteins are also found in nucleoli including p80 coilin, fibrillarin and Nopp140. It is believed that Cajal bodies play a role in snRNP biogenesis and in the trafficking of snoRNPs and snRNPs, which appear to move through the Cajal body en route to nucleoli or splicing speckles (respectively) (Sleeman and Lamond 1999) .

The PNC, first described by the localisation of the polypyrimidine tract binding protein (PTB), is a dynamic perinucleolar structure predominately observed in transformed cells (reviewed in Huang et al., 2000). The presence of hnRNP proteins, splicing factors and snRNAs in the PNC suggests that this structure is involved in multiple aspects of RNA metabolism. The PNC is also enriched in RNase MRP and RNase P RNAs, which have been shown to be involved in rRNA processing. Therefore, the PNC may act as a resevoir for these molecules during rRNA biogenesis in transformed cells. Equally enigmatic are the Sam68 bodies, which are also found predominately in transformed cell lines and are implicated in RNA metabolism (Huang et al., 2000). The significance of the association of these bodies with nucleoli is unknown.

The Nucleolus: Storage Site or Cell Cycle Regulator?

Beyond its role in ribosomal RNA biogenesis, the nucleolus appears to act as a storage site or reservoir for a number of proteins that do not have roles in rRNA metabolism (Carmo-Fonseca et al., 2000; Olson et al., 2000) . The nucleolar sequestration of proteins appears to be a common means of cell cycle regulation among eukaryotes. For example, the tumour suppressor ARF, whose expression is upregulated by oncogenic proteins such as RAS , Myc and E1A, is a nucleolar protein (Tao and Levine, 1999). ARF can bind and recruit MDM2 to the nucleolus thereby preventing the MDM2-dependent degredation of p53, which is normally exported to the cytoplasm for degradation in association with MDM2. Increased levels of p53 can lead to cell cycle arrest. Therefore, nucleolar anchoring of MDM2 by ARF provides one means of regulating the cell cycle.

Similarly, in S. cerevisiae the exit from mitosis is regulated by the nucleolar sequestration of the protein phosphatase Cdc14p, which is released from the nucleolus to promote both the degradation of the cyclin subunit Clb and the accumulation of protein-kinase inhibitor during late anaphase (Visintin et al., 1999). However, this mechanism for controlling mitotic exit is specific for lower eukaryotes like yeast, because as discussed above, nucleoli are dispersed during mitosis in metazoan nuclei.

The Nucleolus and Disease

Nucleolar porteins are know to be mutated in a number of disease including TCOF in Treacher Collins (Marsh et al., 1998) and ataxin 7 in a form of spinocerevellar ataxia (Kaytor et al., 1999). In addition, several proteins that localise to the nucleolus are involved in cancer including both the Werner's syndrome (WRN) and the Bloom's syndrome (BLM) gene products, which are DNA helicases that affect genome stability (reviewed in Mohaghegh and Hickson, 2001). Furthermore, nucleolar proteins are common auto-antigens in patients with hepatocellular carcinoma (HCC), gastrointestinal, lung, and ovarian cancers (Imai et al., 1992) .