Interplay between human nucleolar GNL1 and RPS20 is critical to modulate cell proliferation

Abstract

Human Guanine nucleotide binding protein like 1 (GNL1) belongs to HSR1_MMR1 subfamily of nucleolar GTPases. Here, we report for the first time that GNL1 promotes cell cycle and proliferation by inducing hyperphosphorylation of retinoblastoma protein. Using yeast two-hybrid screening, Ribosomal protein S20 (RPS20) was identified as a functional interacting partner of GNL1. Results from GST pull-down and co-immunoprecipitation assays confirmed that interaction between GNL1 and RPS20 was specific. Further, GNL1 induced cell proliferation was altered upon knockdown of RPS20 suggesting its critical role in GNL1 function. Interestingly, cell proliferation was significantly impaired upon expression of RPS20 interaction deficient GNL1 mutant suggest that GNL1 interaction with RPS20 is critical for cell growth. Finally, the inverse correlation of GNL1 and RPS20 expression in primary colon and gastric cancers with patient survival strengthen their critical importance during tumorigenesis. Collectively, our data provided evidence that cross-talk between GNL1 and RPS20 is critical to promote cell proliferation.

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

“…RPS20 encodes a ribosomal protein which is a part of the S40 subunit. RPS20 has been suggested to be involved in cell proliferation and regulation, and as a stabilizer of p53 (Nieminen et al, 2014) but recently Krishnan et al (2018) provided evidence of a critical interaction between RPS20 and GNL1 -a nucleolar ATPase also involved in cell cycle regulation -which regulates and promotes the G1/S phase, and thus provided documentation of a possible link to tumorigenesis. Several factors support that the c.98A>T variant is pathogenic: Strong segregation analysis in the family presented in our study, in silico splicing prediction and the fact that the variant has not previously been reported or cataloged in gnomAD.…”

GWAS for Meat and Carcass Traits Using Imputed Sequence Level Genotypes in Pooled F2-Designs in Pigs

“…Six additional variants in the QTL on SSC4 (min. p-value 2.44 × 10 −12 ) lie in an intergenic region 13,463 – 14,460 bp downstream of RPS20 , a gene which in interplay with GNL1 is critical for cell growth (Krishnan et al 2018). Another likely candidate SNP to influence ADG is an intron variant in the PLAG1 transcription factor (p-value 1.32 × 10 −11 ), which is a regulator of IGF2 expression (Zatkova et al 2004).…”

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“…Similarly, low ELL2 expression (Figure 3D), regulated by microRNA (miRNA)-mediated gene silencing, was reported to be a marker for poorer survival in GBM patients [65]. GNL1 (Figure 3D) was found in our analysis to be associated with LGG and has been identified as being related to cell proliferation, given its role in the phosphorylation of Rb [66]. We also found associations with the Opioid-signaling pathway and G alpha (i) signaling events [67], and the tyrosine kinase receptor pathway VEGFR (Vascular Endothelial Growth Factor Receptor) and downstream signaling pathway ERK (Figure 3C-D), largely involved with proliferation and angiogenesis [68].…”

“…Next, we aimed to evaluate the utility of the group-regularized deep learning approach for gliomas [63]; as have ELL2 (Figure 2d), which was known to be regulated by microRNA (miRNA)-mediated gene silencing, and low ELL2 expression was reported to be a marker for poorer survival in GBM patients [64]. In addition, GNL1 ( Figure 2d) was found in our analysis to be associated with LGG and has been identified as being related to cell proliferation, given its role in the phosphorylation of Rb [65]. We also found associations with the Opioid-signaling pathway and G alpha (i) signaling events [66], and the tyrosine kinase receptor pathway VEGFR ; each small node corresponds to a pathway; node and text size proportional to the number of overlapping genes after differential gene-level embedding analysis; edge between nodes corresponds to shared genes; large ellipses correspond to found clusters using Markov Chain clustering, three words extracted to annotate cluster using a word cloud algorithm; right-side plots: example output of differential embedding (limma) and pathway enrichment analyses (g:Profiler) on embeddings; top 5 genes and select pathways listed of the many uncovered in each analysis.…”