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Oncogene (2011) 30, 17161726
& 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 http://www.nature.com/onc
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ORIGINAL ARTICLE
GNL3L depletion destabilizes MDM2 and induces p53-dependent G2/M arrest
L Meng, JK Hsu and RYL Tsai
Center for Cancer and Stem Cell Biology, Alkek Institute of Biosciences and Technology, Texas A and M Health Science Center, Houston, TX, USA
Guanine nucleotide binding protein-like 3-like (GNL3L) is a nucleolar protein and the vertebrate paralogue of nucleostemin (NS). We previously reported that nucleoplasmic mobilization of NS stabilizes MDM2 (mouse double minute 2). Here, we investigated the role of GNL3L as a novel MDM2 regulator. We found that GNL3L binds MDM2 in vivo and displays the same function as NS in stabilizing MDM2 protein and preventing its ubiquitylation. The interaction between GNL3L and MDM2 also takes place in the nucleoplasm.However, the MDM2 regulatory activity of GNL3L occurs constitutively and does not so much depend on the nucleolar release mechanism as NS does. GNL3L depletion triggers G2/M arrest in the p53-wild-type HCT116 cells more than in the p53-null cells, and upregulates specic p53 targets (that is, Bax, 14-3-3r and p21) without affecting the ubiquitylation or stability of p53 proteins. The inhibitory activity of GNL3L on p53-mediated transcription correlates with the increased expression of GNL3L and reduced expression of 14-3-3r and p21 in human gastrointestinal tumors. This work shows that in contrast to most nucleolar proteins that negatively control MDM2, GNL3L and NS are the only two that are designed to stabilize MDM2 protein under basal or induced condition, respectively, and may act as tumor-promoting genes.
Oncogene (2011) 30, 17161726; doi:http://dx.doi.org/10.1038/onc.2010.550
Web End =10.1038/onc.2010.550 ; published online 6 December 2010
Keywords: colorectal carcinoma; G2/M arrest; GNL3L;
MDM2; nucleostemin; p53
Introduction
As proteins residing in the nucleolus are being cataloged systematically, so is the focus on this classic organelle turned from its ribosomal function to non-ribosomal role (Pederson and Tsai, 2009). Nucleostemin (NS) is one of the nucleolar proteins shown to be capable of
exercising non-ribosomal activities. It is preferentially expressed by undifferentiated stem/progenitor cells undergoing active proliferation, and has an essential role in early embryogenesis and self-renewal. The vertebrate NS family includes three membersNS, guanine nucleotide binding protein-like 3-like (GNL3L) and Ngp-1, all of which contain a unique MMR1_HSR1 domain...