Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar RPL11

Global Centers of Excellence Program, Akita University Graduate School of Medicine, Akita, Japan.
Nature medicine (Impact Factor: 27.36). 07/2011; 17(8):944-51. DOI: 10.1038/nm.2392
Source: PubMed


PICT1 (also known as GLTSCR2) is considered a tumor suppressor because it stabilizes phosphatase and tensin homolog (PTEN), but individuals with oligodendrogliomas lacking chromosome 19q13, where PICT1 is located, have better prognoses than other oligodendroglioma patients. To clarify the function of PICT1, we generated Pict1-deficient mice and embryonic stem (ES) cells. Pict1 is a nucleolar protein essential for embryogenesis and ES cell survival. Even without DNA damage, Pict1 loss led to p53-dependent arrest of cell cycle phase G(1) and apoptosis. Pict1-deficient cells accumulated p53, owing to impaired Mdm2 function. Pict1 binds Rpl11, and Rpl11 is released from nucleoli in the absence of Pict1. In Pict1-deficient cells, increased binding of Rpl11 to Mdm2 blocks Mdm2-mediated ubiquitination of p53. In human cancer, individuals whose tumors express less PICT1 have better prognoses. When PICT1 is depleted in tumor cells with intact P53 signaling, the cells grow more slowly and accumulate P53. Thus, PICT1 is a potent regulator of the MDM2-P53 pathway and promotes tumor progression by retaining RPL11 in the nucleolus.

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    • "In another study, three (L5, L11, and L26) out of fourteen MDM2-binding RPs were reported to interact with Pict1, a novel MDM2-p53 pathway regulator. Sasaki et al. carried out siRNA-mediated knockdown against four MDM2-binding RPs (RPL5, RPL11, RPL23, and RPS7), and found that RPL11 is the only RP that is crucial for the inhibition of MDM2 function in doxycycline-treated mouse ES cells [69]. "
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    ABSTRACT: Ribosomal proteins (RPs) have gained much attention for their extraribosomal functions particularly with respect to p53 regulation. To date, about fourteen RPs have shown to bind to MDM2 and regulate p53. Upon binding to MDM2, the RPs suppress MDM2 E3 ubiquitin ligase activity resulting in the stabilization and activation of p53. Of the RPs that bind to MDM2, RPL5 and RPL11 are the most studied and RPL11 appears to have the most significant role in p53 regulation. Considering that more than 17% of RP species have been shown to interact with MDM2, one of the questions remains unresolved is why so many RPs bind MDM2 and modulate p53. Genes encoding RPs are widely dispersed on different chromosomes in both mice and humans. As components of ribosome, RP expression is tightly regulated to meet the appropriate stoichiometric ratio between RPs and rRNAs. Once genomic instability (e.g. aneuploidy) occurs, transcriptional and translational changes due to change of DNA copy number can result in an imbalance in the expression of RPs including those that bind to MDM2. Such an imbalance in RP expression could lead to failure to assemble functional ribosomes resulting in ribosomal stress. We propose that RPs have evolved ability to regulate MDM2 in response to genomic instability as an additional layer of p53 regulation. Full understanding of the biological roles of RPs could potentially establish RPs as a novel class of therapeutic targets in human diseases such as cancer.
    Oncotarget 02/2014; 5(4). DOI:10.18632/oncotarget.1784 · 6.36 Impact Factor
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    • "The lethal phenotypes of both Mdm2 and Mdm4 knockout mice can be completely rescued by p53 null mice, demonstrating that p53 is involved in the developmental lethality of Mdm2 and Mdm4 knockout mice. Similar rescue and partial rescue phenotypes were observed in mES cells, blastocysts, or mice with knockouts of other genes, such as Brca1 [23-25], Brca2 [26], Rad51 [27], Cdc7 [28], Pict1 [29], L11 [30], Aurora kinase A [31], or Tsg101 [32]. Most of these genes are involved in DNA repair, cell cycle regulation, and nucleolar stress. "
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    ABSTRACT: The viability and subtle developmental defects of p53 knockout mice suggest that p53 does not play major role in development. However, contradictory evidence also exists. This discrepancy mainly results from the lack of molecular and cellular mechanisms and the general fact that p53 activation requires stresses. Recent studies of p53 in mouse and human ES cells and induced pluripotent stem (iPS) cells shed new light on the mechanisms of the developmental roles of p53. This review summarizes these new studies that support the developmental roles of p53, highlights the possible underlying molecular mechanisms, and discusses the potential relationship between the developmental roles and the tumor suppressive function of p53. In summary, the molecular mechanisms underlying the developmental roles of p53 are emerging, and the developmental roles and tumor suppressive function of p53 may be closely related.
    Cell and Bioscience 10/2013; 3(1). DOI:10.1186/2045-3701-3-42 · 3.63 Impact Factor
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    • "We recently reported that PICT1 is a novel oncogene that regulates the MDM2-TP53 pathway (Sasaki et al, 2011). "
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    ABSTRACT: Background: The TP53 pathway is frequently inactivated in human cancers. PICT1 (also known as GLTSCR2) is a novel regulator of the MDM2-TP53 pathway via its interaction with the ribosomal protein RPL11 in the nucleolus. However, the clinical significance of PICT1 in gastric cancer remains unknown. Methods: To evaluate PICT1 function, we used shRNA to inhibit PICT1 expression in gastric cancer cells that expressed wild-type TP53. PICT1 expression and TP53 mutation status were quantified in 110 cases of primary gastric cancer to explore the impact of PICT1 expression levels on gastric cancer. Results: Deficiency of PICT1 significantly impaired cell proliferation and colony formation via TP53-mediated cell cycle arrest. Following induction of PICT1 deficiency, RPL11 translocated out of the nucleolus. Of the 110 gastric cancer samples tested, 70 (63.6%) and 40 (36.4%) tumours expressed wild-type and mutant TP53, respectively. In gastric cancer patients with wild-type TP53 tumours, patients with relatively low PICT1 expression levels had a better prognosis compared with high expression level patients (P=0.046). Conclusion: The findings suggest that PICT1 has a crucial role in gastric cancer progression by regulating the MDM2-TP53 pathway through RPL11. Clinically, PICT1 expression is a novel prognostic parameter in gastric cancer patients with wild-type TP53 tumours.
    British Journal of Cancer 09/2013; 109(8). DOI:10.1038/bjc.2013.561 · 4.84 Impact Factor
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