A truncated, activin-induced Smad3 isoform acts as a transcriptional repressor of FSHβ expression in mouse pituitary

Mol Cell Endocrinol. 2011 Aug 6;342(1-2):64-72. doi: 10.1016/j.mce.2011.05.036. Epub 2011 Jun 1.


The receptor-regulated protein Smad3 is key player in the signaling cascade stimulated by the binding of activin to its cell surface receptor. Upon phosphorylation, Smad3 forms a heterocomplex with Smad2 and Smad4, translocates to the nucleus and acts as a transcriptional co-activator. We have identified a unique isoform of Smad3 that is expressed in mature pituitary gonadotropes. 5' RACE revealed that this truncated Smad3 isoform is transcribed from an ATG site within exon 4 and consists of 7 exons encoding half of the linker region and the MH2 region. In pituitary cells, the truncated Smad3 isoform was phosphorylated upon activin treatment, in a manner that was temporally distinct from the phosphorylation of full-length Smad3. Activin-induced phosphorylation of Smad3 and the truncated Smad3 isoform was blocked by both follistatin and siRNA-mediated knockdown of Smad3. The truncated Smad3 isoform antagonized Smad3-mediated, activin-responsive promoter activity. We propose that the pituitary gonadotrope contains an ultra-short, activin-responsive feedback loop utilizing two different isoforms of Smad3, one which acts as an agonist (Smad3) and another that acts as an intracrine antagonist (truncated Smad3 isoform) to regulate FSHβ production.

Publication types

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

MeSH terms

  • Activins / genetics
  • Activins / metabolism*
  • Animals
  • Cell Line
  • Follicle Stimulating Hormone, beta Subunit / genetics
  • Follicle Stimulating Hormone, beta Subunit / metabolism*
  • Follistatin / pharmacology
  • Gonadotrophs / drug effects
  • Gonadotrophs / metabolism
  • Humans
  • Mice
  • Pituitary Gland / metabolism*
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Smad2 Protein / metabolism
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism*
  • Transcription, Genetic*


  • Follicle Stimulating Hormone, beta Subunit
  • Follistatin
  • RNA, Small Interfering
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • activin A
  • activin B
  • Activins