Center for Cancer and Stem Cell Biology, Alkek Institute of Biosciences and Technology, Texas A and M Health Science Center, Houston, TX 77030, USA.
Oncogene. 2011 Apr 7;30(14):1716-26. doi: 10.1038/onc.2010.550. Epub 2010 Dec 6.
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 specific p53 targets (that is, 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.
鸟嘌呤核苷酸结合蛋白样 3 样（GNL3L）是一种核仁蛋白，也是核干细胞蛋白（NS）的脊椎动物同源物。我们之前曾报道过，NS 的核质易位可稳定 MDM2（鼠双微体 2）。在这里，我们研究了 GNL3L 作为一种新型 MDM2 调节剂的作用。我们发现 GNL3L 在体内与 MDM2 结合，并具有与 NS 相同的功能，可稳定 MDM2 蛋白并防止其泛素化。GNL3L 与 MDM2 之间的相互作用也发生在核质中。然而，GNL3L 对 MDM2 的调节活性是组成型的，并且不像 NS 那样强烈依赖于核仁释放机制。GNL3L 耗竭会在 p53 野生型 HCT116 细胞中引发比 p53 缺失细胞中更严重的 G2/M 期阻滞，并上调特定的 p53 靶标（即 Bax、14-3-3σ 和 p21），而不影响 p53 蛋白的泛素化或稳定性。GNL3L 对 p53 介导的转录的抑制活性与 GNL3L 的表达增加以及 14-3-3σ 和 p21 的表达减少相关，这在人类胃肠道肿瘤中得到了证实。这项工作表明，与大多数负调控 MDM2 的核仁蛋白不同，GNL3L 和 NS 是仅有的两种分别在基础或诱导条件下设计用于稳定 MDM2 蛋白的蛋白，它们可能作为促进肿瘤生长的基因发挥作用。
