Nucleolar localization of a netrin-1 isoform enhances tumor cell proliferation

Sci Signal. 2012 Aug 7;5(236):ra57. doi: 10.1126/scisignal.2002456.


Netrin-1 displays proto-oncogenic activity in several cancers, which is thought to be due to the ability of this secreted cue to stimulate survival when bound to its receptors. We showed that in contrast to full-length, secreted netrin-1, some cancer cells produced a truncated intranuclear form of netrin-1 (ΔN-netrin-1) through an alternative internal promoter. Because of a nucleolar localization signal located in its carboxyl terminus, ΔN-netrin-1 was targeted to the nucleolus, where it interacted with nucleolar proteins, affected nucleolar ultrastructure, and interacted with the promoters of ribosomal genes. Moreover, ΔN-netrin-1 stimulated cell proliferation in vitro and tumor growth in vivo. Thus, some cancer cells produce not only a full-length, secreted form of netrin-1 that promotes cell survival but also a truncated netrin-1 that stimulates cell proliferation, potentially by enhancing ribosome biogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Cell Line, Tumor
  • Cell Nucleolus / metabolism*
  • Cell Nucleolus / ultrastructure
  • Cell Proliferation*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Chick Embryo
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Microscopy, Confocal
  • Microscopy, Electron
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism*
  • Netrin-1
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA Interference
  • Transplantation, Heterologous
  • Tumor Burden
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • NTN1 protein, human
  • Nerve Growth Factors
  • Protein Isoforms
  • Tumor Suppressor Proteins
  • Green Fluorescent Proteins
  • Netrin-1