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Evidence that Igf2 down-regulation in postnatal tissues and up-regulation in malignancies is driven by transcription

Julian C Lui1, Jeffrey Baron

  • 1Section on Growth and Development, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. luichunk@mail.nih.gov

Proceedings of the National Academy of Sciences of the United States of America
|March 27, 2013
PubMed

Insights

E2F transcription factor 3 (E2F3) drives changes in Insulin-like growth factor 2 (IGF2) expression. Decreased E2F3 with age lowers IGF2 in normal tissues, while E2F3 overexpression in cancers elevates IGF2.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Cancer Biology

Background:

  • Insulin-like growth factor 2 (IGF2) is a crucial fetal growth factor.
  • IGF2 expression decreases significantly in postnatal tissues but is often elevated in cancers.
  • The regulatory mechanisms behind IGF2's changing expression patterns remain largely unknown.

Purpose of the Study:

  • To investigate the role of E2F transcription factor 3 (E2F3) in regulating IGF2 expression during postnatal development and in cancer.
  • To elucidate the mechanisms by which E2F3 influences IGF2 levels.
  • To establish a causal link between E2F3 and IGF2 expression changes.

Main Methods:

  • Analysis of E2f3 and Igf2 mRNA and protein expression in mouse organs across different ages.
  • Experimental manipulation of E2f3 expression in mouse hepatocytes and HEK293 cells.
  • Reporter assays using constructs containing the mouse Igf2 promoter P2.
  • Examination of human microarray data for age-related changes in E2F3 and IGF2.
  • Correlation analysis of E2F3 and IGF2 expression in human cancers.

Main Results:

  • E2f3 mRNA, protein levels, and promoter binding decreased with age in multiple mouse organs.
  • Restoring E2F3 expression in late juvenile hepatocytes reactivated Igf2 expression, confirming a causal link.
  • E2F3 activated reporter constructs linked to the Igf2 promoter P2 in cell-based assays.
  • Human data mirrored mouse findings, showing age-related declines in E2F3 and IGF2.
  • E2F3 overexpression correlated with increased IGF2 in human prostate and bladder cancers.

Conclusions:

  • Postnatal down-regulation of E2F3 contributes to the decline in IGF2 expression in normal tissues.
  • E2F3 overexpression is a key driver of IGF2 up-regulation in various human cancers.
  • E2F3 acts as a critical regulator of IGF2 expression throughout development and in oncogenesis.

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