Article

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: 28.05). 07/2011; 17(8):944-51. DOI: 10.1038/nm.2392
Source: PubMed

ABSTRACT 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.

1 Follower
 · 
116 Views
  • Source
    [Show abstract] [Hide abstract]
    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 · 4.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Glioma tumor-suppressor candidate region gene2 (GLTSCR2) is a recently identified nucleolus-localized protein participating in the regulation of cell cycle progression and apoptosis. Down-regulation of GLTSCR2 in several types of cancers and increased transforming activity in GLTSCR2-downregulated cancer cells indicated its tumor suppressive potential. The aim of this study was to evaluate GLTSCR2 expression in breast cancer and to investigate the question of whether reduced expression of GLTSCR2 may have any pathological significance in breast cancer development or progression. In this study, we performed quantitative RT-PCR and immunohistochemistry to evaluate the expression of GLTSCR2 and relevance with clinicopathological factors in the invasive ductal carcinoma (IDC). GLTSCR2 expression was reduced in 48% of IDC (n=426) by a semi-quantitative scoring system using tissue microarray. GLTSCR2 mRNA was significantly reduced by 0.16 fold in 15 out of 17 (88%) cases of IDC. Reduction of GLTSCR2 was significantly correlated with increased histological grade (p<0.005), increased tumor size (p<0.001), axillary lymph node involvement (p<0.001) and decreased disease free survival (p<0.025). In addition, we show that upregulation of GLTSCR2 decreases the invasive potential of breast cancer cells. Taken together, our data suggest that GLTCR2 may play a role in the tumorigenesis, progression and biological behavior in breast cancer.
    Pathology - Research and Practice 08/2013; DOI:10.1016/j.prp.2013.07.010 · 1.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: GLTSCR2 is a nuclear/nucleolar protein that translocates to the nucleoplasm, suppressed and mutated in human cancers. Our aim in this study was to investigate whether downregulation or cytoplasmic expression of GLTSCR2 has any pathological significance in prostatic cancer development or progression. In this study we show that GLTSCR2 is suppressed in prostatic cancers and its expression is significantly associated with Gleason's scores. Furthermore, we investigated the pathogenetic mechanism of downregulation and cytoplasmic expression of GLTSCR2 in development or progression of prostatic cancers. Taken together, our results indicate that GLTSCR2 functions as a tumor suppressor in prostatic adenocarcinomas.
    Cancer letters 08/2013; 340(1). DOI:10.1016/j.canlet.2013.07.035 · 5.02 Impact Factor