Fig. 1
Nongenomic and Genomic actions of Thyroid hormone and thyroid hormone receptor. The diagram of nongenomic and transcriptional actions of thyroid hormone (TH) and thyroid hormone receptor (THR). a Nongenomic effects of THs are initiated from Integrin αvβ3 localized on the plasma membrane or occurs at cytoplasm. T3 interacts with S1 domain of Integrin αvβ3 to activate the PI3K signal pathway via Src kinase, leading to trafficking of THRA from the cytoplasm to nucleus and increases HIF-1α expression. THs, mainly T4, also interact with S2 domain of Integrin αvβ3 to activate ERK 1/2 signal, causing phosphorylation and nuclear localization of THRβ, estrogen receptor α (ERα) and STAT3. Activated ERK1/2 and cytosolic THRB increase the activity of the sodium pump (Na, K-ATPase). T3-liganded THRs in the cytoplasm interact with the PI3K regulatory subunit, p85α, to activate Akt, subsequently triggering mTOR/p70S6K and eNOS signals. b In the nucleus, THRs form heterodimers with the retinoid X receptor (RXR) at thyroid hormone response elements (TREs), within the regulatory regions of downstream genes. In the absence of T3, the co-repressor complex involving histone deacetylase (HDACs), NCoR1 and SMRT deacetylate histones in the regulatory regions. Consequently, trimethylation of histone H3 at lysine 9 and 27 along with DNA methylation causes a more closed conformation in chromatin and blocks the transcriptional machinery access to the DNA, causing suppression of downstream targets transcription. Binding of T3 induces conformational changes of THRs and recruitment of transcriptional coactivators (such as PCAF/P300 and SRC-1/p160) with histone acetyltransferase (HAT) activity to increase histone acetylation at specific promoter regions, facilitating generation of a permissive chromatin state and further recruitment of general transcriptional machinery. Typical TREs within promoter regions of downstream genes contain two half-site sequences (A/G)GGT(C/A/G)A in a palindromic, direct repeat or inverted repeat arrangement that are recognized by THR