title: Dual functions of the steroid hormone receptor coactivator 3 in modulating resistance to thyroid hormone.
abstract: 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.
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD 20892-4264, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Ying
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Furuya
authors.forename: Mark C
authors.initials: MC
authors.lastname: Willingham
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: Sheue-Yann
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D004351:Drug Resistance; D051548:Histone Acetyltransferases; D008099:Liver / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D013961:Thyroid Gland / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism; D013963:Thyroid Hormones / Q000494:pharmacology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D015534:Trans-Activators; D002784:Cholesterol; D051548:Histone Acetyltransferases; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3