NIRF constitutes a nodal point in the cell cycle network and is a candidate tumor suppressor

Cell Cycle. 2011 Oct 1;10(19):3284-99. doi: 10.4161/cc.10.19.17176. Epub 2011 Oct 1.

Abstract

In biological networks, a small number of "hub" proteins play critical roles in the network integrity and functions. The cell cycle network orchestrates versatile cellular functions through interactions between many signaling modules, whose defects impair diverse cellular processes, often leading to cancer. However, the network architecture and molecular basis that ensure proper coordination between distinct modules are unclear. Here, we show that the ubiquitin ligase NIRF (also known as UHRF2), which induces G1 arrest, interacts with multiple cell cycle proteins including cyclins (A2, B1, D1 and E1), p53 and pRB, and ubiquitinates cyclins D1 and E1. Consistent with its versatility, a bioinformatic network analysis demonstrated that NIRF is an intermodular hub protein that is responsible for the coordination of multiple network modules. Notably, intermodular hubs are frequently associated with oncogenesis. Indeed, we detected loss of heterozygosity of the NIRF gene in several kinds of tumors. When a cancer outlier profile analysis was applied to the Oncomine database, loss of the NIRF gene was found at statistically significant levels in diverse tumors. Importantly, a recurrent microdeletion targeting NIRF was observed in non-small cell lung carcinoma. Furthermore, NIRF is immediately adjacent to the single nucleotide polymorphism rs719725, which is reportedly associated with the risk of colorectal cancer. These observations suggest that NIRF occupies a prominent position within the cell cycle network, and is a strong candidate for a tumor suppressor whose aberration contributes to the pathogenesis of diverse malignancies.

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Chromosomes, Human, Pair 9
  • Cyclin A2 / metabolism
  • Cyclin B1 / metabolism
  • Cyclin D1 / metabolism
  • Cyclin E / metabolism
  • G1 Phase Cell Cycle Checkpoints
  • Gene Deletion
  • Humans
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Retinoblastoma Protein / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Cell Cycle Proteins
  • Cyclin A2
  • Cyclin B1
  • Cyclin E
  • Recombinant Fusion Proteins
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53
  • Cyclin D1
  • UHRF2 protein, human
  • Ubiquitin-Protein Ligases