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

Cell Cycle. 2016 Dec;15(23):3251-3267. doi: 10.1080/15384101.2016.1242534. Epub 2016 Oct 20.

Abstract

Guanine nucleotide binding protein-like 3-like (GNL3L) is an evolutionarily conserved putative nucleolar GTPase belonging to the HSR1-MMR1 family. In the present study, using protein-protein interaction assays, we show that Leucine Zipper Down-regulated in Cancer-1 (LDOC1) is a novel interacting partner of GNL3L. Furthermore, our results reveal that ectopic expression of LDOC1 destabilizes endogenous GNL3L levels and down modulates GNL3L-induced cell proliferation, in contrast, the knockdown of LDOC1 potentiates cell proliferation upon GNL3L expression. Interestingly, GNL3L upregulates NF-κB dependent transcriptional activity by modulating the expression of NF-κB subunit p65, which is reversed upon co-expression of LDOC1 with GNL3L. GNL3L also potentiates TNF-α mediated NF-κB activity. In addition, anti-apoptotic function of GNL3L is impaired upon p65 knockdown, suggesting its critical role in GNL3L mediated cell proliferation/survival. An inverse correlation of GNL3L and LDOC1 expression profiles in various tumor tissues from BioXpress database indicate their critical role in cancer. Collectively, our data provides evidence that GNL3L-LDOC1 interplay regulates cell proliferation through the modulation of NF-κB pathway during tumorigenesis.

Keywords: Apoptosis; GNL3L; LDOC1; NF-κB transcription factor; cell signaling; proliferation; protein-protein interaction.

MeSH terms

  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Proliferation
  • Down-Regulation
  • GTP-Binding Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Models, Biological
  • NF-kappa B / metabolism*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Stability
  • Signal Transduction*
  • Transcription Factor RelA / metabolism
  • Transcription, Genetic
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / metabolism*

Substances

  • GNL3L protein, human
  • LDOC1 protein, human
  • NF-kappa B
  • Nuclear Proteins
  • Transcription Factor RelA
  • Tumor Suppressor Proteins
  • GTP-Binding Proteins