Pescadillo Is Essential for Nucleolar Assembly, Ribosome Biogenesis, and Mammalian Cell Proliferation

Abstract

Mutation of the zebrafish pescadillo gene blocks expansion of a number of tissues in the developing embryo, suggesting roles for its gene product in controlling cell proliferation. We report that levels of the pescadillo protein increase in rodent hepatocytes as they enter the cell cycle. Pescadillo protein localizes to distinct substructures of the interphase nucleus including nucleoli, the site of ribosome biogenesis. During mitosis pescadillo closely associates with the periphery of metaphase chromosomes and by late anaphase is associated with nucleolus-derived foci and prenucleolar bodies. Blastomeres in mouse embryos lacking pescadillo arrest at morula stages of development, the nucleoli fail to differentiate and accumulation of ribosomes is inhibited. We propose that in mammalian cells pescadillo is essential for ribosome biogenesis and nucleologenesis and that disruption to its function results in cell cycle arrest.

Role of pescadillo in the transformation and immortalization of mammalian cells

“…Pes1 interacts (by coimmunoprecipitation) with both the SV40 T antigen and IRS-1, each of which can transform MEFs expressing an IGF-I receptor . These findings are a logical extension of previous reports that deletion of pescadillo/Pes1 leads to inhibition of embryonic growth (Lerch-Gaggl et al, 2002) and that PES1 is highly expressed in certain human tumor cells (Kinoshita et al, 2001). Our findings show for the first time that overexpression of Pes1 actually causes transformation of cells in culture (colony formation in soft agar).…”

“…The commercially available antibody to Pes1 is mouse specific (Lerch-Gaggl et al, 2002). We have confirmed it on AR5 cells that are of human origin.…”

“…Its expression was dramatically elevated in malignant human astrocytomas. Lerch-Gaggl et al (2002) reported that Pes1 levels increased in cells stimulated to grow, and that the protein localizes to the nucleoli and, more precisely, co-localizes with nucleolin. PesÀ/À embryos failed to develop and the authors concluded that pescadillo/PES1 is necessary for ribosome biogenesis and nucleologenesis, and that disruption of its function results in growth arrest.…”

Inactivation of the RRB1-Pescadillo pathway involved in ribosome biogenesis induces chromosomal instability

“…The analysis of the human nucleolus proteome recently demonstrated that GRWD, Pescadillo and Bop1 are present in the nucleolus, the cellular site of ribosome biogenesis (Scherl et al, 2002) and we confirmed the former localization of GRWD by immunocytochemistry. Furthermore, the involvement of Pescadillo and Bop1 in ribosome biogenesis has been documented clearly in mammalian cells (Strezoska et al, 2000;Lerch-Gaggl et al, 2002).…”

“…The fact that ORC6, a key protein in DNA replication, physically and genetically interacts with YPH1 and RRB1 (Du and Stillman, 2002; this study) strongly suggests a link between DNA replication and ribosome biogenesis. Interestingly, YPH1, like RRB1, is differentially expressed in response to nocodazole treatment (Velculescu et al, 1997), is involved in ribosome biogenesis (Lerch-Gaggl et al, 2002) and is essential for a proper metaphase/anaphase transition (Kinoshita et al, 2001) and chromosomal segregation. Third, we showed that transient depletion of their human homologues GRWD, Rpl3, Pescadillo and Bop1 increases the percentage of abnormal mitoses, as already observed for Orc6L protein (Prasanth et al, 2002).…”