Dual functions of the steroid hormone receptor coactivator 3 in modulating resistance to thyroid hormone

Mol Cell Biol. 2005 Sep;25(17):7687-95. doi: 10.1128/MCB.25.17.7687-7695.2005.


Mutations of the thyroid hormone receptor beta (TRbeta) gene cause resistance to thyroid hormone (RTH). RTH is characterized by increased serum thyroid hormone associated with nonsuppressible thyroid-stimulating hormone (TSH) and impaired growth. It is unclear how the actions of TRbeta mutants are modulated in vivo to affect the manifestation of RTH. Using a mouse model of RTH that harbors a knockin mutation of the TRbeta gene (TRbetaPV mouse), we investigated the effect of the steroid hormone receptor coactivator 3 (SRC-3) on RTH. In TRbetaPV mice deficient in SRC-3, dysfunction of the pituitary-thyroid axis and hypercholesterolemia was lessened, but growth impairment of RTH was worsened. The lessened dysfunction of the pituitary-thyroid axis was attributed to a significant decrease in growth of the thyroid and pituitary. Serum insulin-like growth factor 1 (IGF-1) was further reduced in TRbetaPV mice deficient in SRC-3. This effect led to reduced signaling of the IGF-1/phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway that is known to mediate cell growth and proliferation. Thus, SRC-3 modulates RTH by at least two mechanisms, one via its role as a receptor coregulator and the other via its growth regulatory role through the IGF-1/PI3K/AKT/mTOR signaling.

MeSH terms

  • Body Weight
  • Cholesterol / blood
  • Drug Resistance*
  • Histone Acetyltransferases
  • Liver / metabolism
  • Nuclear Receptor Coactivator 3
  • Organ Size
  • RNA, Messenger / genetics
  • Signal Transduction
  • Thyroid Gland / metabolism
  • Thyroid Hormone Receptors beta / genetics
  • Thyroid Hormone Receptors beta / metabolism
  • Thyroid Hormones / pharmacology*
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*


  • RNA, Messenger
  • Thyroid Hormone Receptors beta
  • Thyroid Hormones
  • Trans-Activators
  • Cholesterol
  • Histone Acetyltransferases
  • Ncoa3 protein, mouse
  • Nuclear Receptor Coactivator 3