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

Hao Ying1, Fumihiko Furuya, Mark C Willingham

  • 1Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD 20892-4264, USA.

Molecular and Cellular Biology
|August 19, 2005
PubMed

Insights

Steroid hormone receptor coactivator 3 (SRC-3) influences resistance to thyroid hormone (RTH) by affecting pituitary-thyroid axis function and growth. Modulating SRC-3 impacts RTH severity, highlighting its dual role in hormone regulation and cell growth.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • Resistance to thyroid hormone (RTH) results from thyroid hormone receptor beta (TRbeta) gene mutations.
  • RTH presents with elevated thyroid hormones, non-suppressible TSH, and impaired growth.
  • The in vivo modulation of TRbeta mutant actions in RTH remains incompletely understood.

Purpose of the Study:

  • To investigate the role of steroid hormone receptor coactivator 3 (SRC-3) in modulating RTH.
  • To elucidate the mechanisms by which SRC-3 influences RTH manifestation using a mouse model.

Main Methods:

  • Utilized a TRbetaPV mouse model harboring a knockin mutation for RTH.
  • Assessed the impact of SRC-3 deficiency on pituitary-thyroid axis function, hypercholesterolemia, and growth in TRbetaPV mice.
  • Analyzed insulin-like growth factor 1 (IGF-1) signaling pathways, including PI3K/AKT/mTOR.

Main Results:

  • SRC-3 deficiency lessened pituitary-thyroid axis dysfunction and hypercholesterolemia in TRbetaPV mice.
  • Growth impairment was exacerbated in SRC-3 deficient TRbetaPV mice.
  • Reduced thyroid and pituitary growth contributed to lessened pituitary-thyroid axis dysfunction.
  • Serum IGF-1 levels were further reduced in SRC-3 deficient mice, impairing IGF-1/PI3K/AKT/mTOR signaling.

Conclusions:

  • SRC-3 acts as a modulator of RTH through distinct mechanisms.
  • SRC-3 functions as a receptor coregulator in RTH.
  • SRC-3 regulates growth in RTH via the IGF-1/PI3K/AKT/mTOR signaling pathway.

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