Novel functions of thyroid hormone receptor mutants: Beyond nucleus-initiated transcription

Study of molecular actions of thyroid hormone receptor beta (TR beta) mutants in vivo has been facilitated by creation of a mouse model (TR beta PV mouse) that harbors a knockin mutant of T beta (denoted PV). PV, which was identified in a patient with resistance to thyroid hormone, has lost T3 binding activity and transcription capacity. The striking phenotype of thyroid cancer exhibited by TR beta(PV/PV) mice has allowed the elucidation of novel oncogenic activity of a TR beta mutant (PV) [PAS1] beyond nucleus-initiated transcription. PV was found to physically interact with the regulatory p85 alpha subunit of phosphatidylinositol 3-kinase (PI3K) in both the nuclear and cytoplasmic compartments. This protein-protein interaction activates the PI3K signaling by increasing phosphorylation of AKT, mammalian target of rapamycin (mTOR), and p70(S6K). PV, via interaction with p85 alpha, also activates the PI3K-integrin-linked kinase-matrix metalloproteinase-2 signaling pathway in the extra-nuclear compartment. The PV-mediated PI3K activation results in increased cell proliferation, motility migration, and metastasis. In addition to affecting these membrane-initiated signaling events, PV affects the stability of the pituitary tumor-transforming gene (PTTG) product. PTTG (also known as securin), a critical mitotic checkpoint protein, is physically associated with TR beta or PV in vivo. Concomitant with T3-induced degradation of TR beta, PTTG is degraded by the proteasome machinery, but no such degradation occurs when PTTG is associated with PV The degradation of PTTG/TR beta is activated by the direct interaction of the T3-bound TR beta with the steroid receptor coactivator-3 (SRC-3) that recruits a proteasome activator (PA28 gamma). PV that does not bind T3 cannot interact directly with SRC-3/PA28 gamma to activate proteasome degradation, and the absence of degradation results in an aberrant accumulation of PTTG. The PV-induced failure of timely degradation of PTTG results in mitotic abnormalities. PV, via novel protein-protein interaction and transcription regulation, acts to antagonize the functions of wild-type TRs and contributes to the oncogenic functions of this mutation. (c) 2006 Elsevier Inc. All rights reserved.