process as reduction of ATP levels prevents nucleolar localization. In addition, p53 sub-nucleolar accumulation is abolished when cells are subjected to various types of genotoxic stress. Furthermore, we show that monoubiquitination of p53, which causes it to localize to the cytoplasm and nucleoplasm, does not prevent the association of p53 with the nucleolus after MG132 treatment. Importantly, we demonstrate that p53 nucleolar association occurs in lung and bladder carcinomas. Journal of Cell Science ATP-dependent p53 sub-nucleolar localizationThe nucleolus is the site of rRNA transcription, processing and ribosome assembly (Andersen et al., 2005; Carmo-Fonseca et al., 2000;Lam et al., 2005;Lamond and Sleeman, 2003;Leung et al., 2003;Olson and Dundr, 2005). As diagrammed in Fig. 1A the nucleolus consists of at least three morphologically distinct regions: the fibrillar center (FC), a dense fibrillar center (DFC) and a granular component (GC) (Scheer and Hock, 1999). Although, still not fully described, several studies indicate that the FC or the FC-DFC boundaries are the sites of pre-rRNA transcription (reviewed by Boisvert et al., 2007;Lamond and Sleeman, 2003). Ribosomal proteins and assembly factors are found in the GCs (Huang, 2002;Koberna et al., 2002;Lamond and Sleeman, 2003). FCs are particularly enriched in Pol I, topoisomerase I and the upstream binding factor (UBF, an activator of Pol I), whereas most processing molecules localize to the DFC and/or GC including nucleolin, nucleophosmin and fibrillarin [Casafont et al. (Casafont et al., 2007) and references therein].In a previous study we showed that p53 accumulation in the nucleolus, after proteasome inhibition, requires two regions within the carboxyl terminus of p53 (Karni-Schmidt et al., 2007). We show now that after proteasome inhibition, p53 can associate with a discrete sub-nucleolar component, the FC. We demonstrate that p53 association with the FC is ATP dependent and it is abrogated by genotoxic stress. Our results also suggest that monoubiquitination of p53 does not preclude its association with nucleoli. Perhaps most relevantly we have found that p53 associates with nucleoli in human bladder and lung carcinomas. Resultsp53 associates with a discrete sub-nucleolar compartment after MG132 treatment To extend our observations and those of others that the treatment of cells with a proteasome inhibitor causes nucleolar localization of p53 (Karni-Schmidt et al., 2007; Klibanov et al., 2001;Latonen et al., 2003;Pokrovskaja et al., 2001) we examined the precise location of ectopic p53 within the nucleolus. H1299 cells were transfected with a construct expressing wild-type p53 and after 24 hours, cells were treated with different concentrations of MG132 for various times or left untreated. The levels of transfected p53 either did not change or were modestly reduced by treatment with H1299 cells were transfected with wild-type p53 and after 24 hours were treated with different doses (5 μM, 10 μM and 20 μM for 6-10 hours and 1 μM, 5 μM and 10 μM f...
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