GNL3L depletion destabilizes MDM2 and induces p53-dependent G2/M arrest

Abstract

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 up-regulates specific p53 targets (i.e. Bax, 14-3-3σ, 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 14-3-3σ 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.

Leucine Zipper Down-regulated in Cancer-1 (LDOC1) interacts with Guanine nucleotide binding protein-like 3-like (GNL3L) to modulate Nuclear Factor-kappa B (NF-κB) signaling during cell proliferation

“…29 The nucleolar localization of GNL3L was also found to be critical for the progression of 'G2/M' phase of the cell cycle. 3,4 Depletion of intracellular GTP pool and mutations in the conserved residues within G-domains has also been reported to alter the nucleolar localization of GNL3L.…”

“…4 GNL3L competes with steroid receptor co-activators (SRCs) for binding to estrogen-related receptor (ERR) and blocks SRC-mediated co-activation of ERR.…”

Distinct genome protective vs. ribosome synthetic functions of the paralogous nucleolar proteins nucleostemin and GNL3L

“…The subsequent identification of GNL3L, the mammalian paralog of nucleostemin, broadened the landscape of possible functions of these two nucleolar GTP-binding proteins. Subsequent work on both nucleostemin and GNL3L (Lin et al, 2010;Ma and Pederson, 2007;Meng et al, 2011a;Meng et al, 2011b;Meng et al, 2008;Zhu et al, 2009;Zhu et al, 2006) drew attention to the involvement of both proteins in cell proliferation, although the direct roles of the proteins were not rigorously proven. At the same time, evidence appeared in Drosophila linking the invertebrate protein, GNL3, to ribosome biosynthesis (Rosby et al, 2009), and another report implicated mammalian nucleostemin in ribosome biosynthesis (Romanova et al, 2009a).…”

Nucleolar GTP-binding Protein-1 (NGP-1) Promotes G1 to S Phase Transition by Activating Cyclin-dependent Kinase Inhibitor p21Cip1/Waf1

“…1, A-C, panel i). Interestingly, other members of the HSR1-MMR1 family, NS and GNL3L, have been shown to modulate p53 to regulate the cell cycle (3,8). Because p53 is an important regulator of the cell cycle, we determined the status of p53 and its targets upon NGP-1 expression.…”

“…Certain nucleolar proteins such as guanine nucleotide-binding proteinlike 3-like (GNL3L), nucleostemin (NS), 2 nucleolin, and nucleophosmin modulate ribosomal as well as nonribosomal pathways (3)(4)(5)(6)(7)(8)(9)(10). GNL3L and NS belong to the HSR1-MMR1 family of GTPases and are up-regulated in various cancers (8,(11)(12)(13)(14). Another member of the same family, guanine nucleotide-binding protein-like 2 (GNL2) also known as nucleolar GTP-binding protein-1 (NGP-1), is observed to be overexpressed in breast, colon, and colorectal cancers and is a breast cancer autoantigen (15).…”