Granulosa cell tumor mutant FOXL2C134W suppresses GDF-9 and activin A-induced follistatin transcription in primary granulosa cells

Mol Cell Endocrinol. 2013 Jun 15;372(1-2):57-64. doi: 10.1016/j.mce.2013.03.021. Epub 2013 Apr 6.


A single somatic FOXL2 mutation (FOXL2(C134W)) was identified in almost all granulosa cell tumor (GCT) patients. In the pituitary, FOXL2 and Smad3 coordinately regulate activin stimulation of follistatin transcription. We explored whether a similar regulation occurs in the ovary, and whether FOXL2(C134W) has altered activity. We show that in primary granulosa cells, GDF-9 and activin increase Smad3-mediated follistatin transcription. In contrast to findings in the pituitary, FOXL2 negatively regulates GDF-9 and activin-stimulated follistatin transcription in the ovary. Knockdown of endogenous FOXL2 confirmed this inhibitory role. FOXL2(C134W) displayed enhanced inhibitory activity, completely ablating GDF-9 and activin-induced follistatin transcription. GDF-9 and activin activity was lost when either the smad binding element or the forkhead binding element were mutated, indicating that both sites are required for Smad3 actions. This study highlights that FOXL2 negatively regulates follistatin expression within the ovary, and that the pathogenesis of FOXL2(C134W) may involve an altered interaction with Smad3.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Activins / physiology*
  • Animals
  • Cells, Cultured
  • Female
  • Follistatin / genetics*
  • Follistatin / metabolism
  • Forkhead Box Protein L2
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation
  • Granulosa Cell Tumor
  • Granulosa Cells / metabolism*
  • Growth Differentiation Factor 9 / metabolism*
  • Humans
  • Mutation, Missense
  • Primary Cell Culture
  • Promoter Regions, Genetic
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Smad3 Protein / metabolism
  • Transcription, Genetic*
  • Transcriptional Activation


  • FOXL2 protein, human
  • Follistatin
  • Forkhead Box Protein L2
  • Forkhead Transcription Factors
  • Gdf9 protein, rat
  • Growth Differentiation Factor 9
  • RNA, Messenger
  • Smad3 Protein
  • Smad3 protein, rat
  • activin A
  • Activins