FHL2 interacts with and acts as a functional repressor of Id2 in human neuroblastoma cells

Nucleic Acids Res. 2009 Jul;37(12):3996-4009. doi: 10.1093/nar/gkp332. Epub 2009 May 5.


Inhibitor of differentiation 2 (Id2) is a natural inhibitor of the basic helix-loop-helix transcription factors. Although Id2 is well known to prevent differentiation and promote cell-cycle progression and tumorigenesis, the molecular events that regulate Id2 activity remain to be investigated. Here, we identified that Four-and-a-half LIM-only protein 2 (FHL2) is a novel functional repressor of Id2. Moreover, we demonstrated that FHL2 can directly interact with all members of the Id family (Id1-4) via an N-terminal loop-helix structure conserved in Id proteins. FHL2 antagonizes the inhibitory effect of Id proteins on basic helix-loop-helix protein E47-mediated transcription, which was abrogated by the deletion mutation of Ids that disrupted their interaction with FHL2. We also showed a competitive nature between FHL2 and E47 for binding Id2, whereby FHL2 prevents the formation of the Id2-E47 heterodimer, thus releasing E47 to DNA and restoring its transcriptional activity. FHL2 expression was remarkably up-regulated during retinoic acid-induced differentiation of neuroblastoma cells, during which the expression of Id2 was opposite to that. Ectopic FHL2 expression in neuroblastoma cells markedly reduces the transcriptional and cell-cycle promoting functions of Id2. Altogether, these results indicate that FHL2 is an important repressor of the oncogenic activity of Id2 in neuroblastoma cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Differentiation
  • Cell Line
  • Cell Line, Tumor
  • DNA / metabolism
  • E-Box Elements
  • Gene Expression Regulation, Neoplastic*
  • Helix-Loop-Helix Motifs
  • Homeodomain Proteins / chemistry
  • Homeodomain Proteins / metabolism*
  • Humans
  • Inhibitor of Differentiation Protein 2 / antagonists & inhibitors*
  • Inhibitor of Differentiation Protein 2 / metabolism
  • LIM-Homeodomain Proteins
  • Muscle Proteins / chemistry
  • Muscle Proteins / metabolism*
  • Neuroblastoma / genetics*
  • Neuroblastoma / metabolism
  • Repressor Proteins / metabolism*
  • TCF Transcription Factors / metabolism
  • Transcription Factor 7-Like 1 Protein
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism*
  • Two-Hybrid System Techniques
  • Up-Regulation


  • FHL2 protein, human
  • Homeodomain Proteins
  • ID2 protein, human
  • Inhibitor of Differentiation Protein 2
  • LIM-Homeodomain Proteins
  • Muscle Proteins
  • Repressor Proteins
  • TCF Transcription Factors
  • TCF7L1 protein, human
  • Transcription Factor 7-Like 1 Protein
  • Transcription Factors
  • DNA