Fig 8. (A) Schematic depiction of the human D2 promoter and difference in the GATA-RE sequences between the D2 gene and TSHβ gene. The promoter structure and the position of the TSS (+1) are based on the reviews by Bianco et al. [8] and Gereben et al. [16]; however, Dentice et al. [66] later reported that FoxO3 activates transcription from another downstream TSS (*). The DNA sequences of u- and d-GATA-REs are conserved among species except for zebra fish (Danio rerio). While one report (Accession AB307676) suggests d-GATA-RE is conserved in chicken (#), another does not (##) [16]. The Pit-1-biding sequence in the TSHβ gene was underlined. (B) Tethering model of T3-dependent negative regulation of the human D2 gene in thyrotrophs.

The Zn-finger domain of GATA2 associates with TRβ2-DBD via a protein–protein interaction. In the presence of T3, TRβ2 interferes with the transactivation function of GATA2. The current study predicts a similar molecular mechanism in the negative regulation of the D2 gene by T3 in cardiomyocytes. The inhibition by T3 is dominant over the synergism between GATA2 and PKA signaling via CREB. After pre-existing D2 enzyme converts T4 to T3, the influence of de novo generated T3 is blunted owing to the reduction of D2 expression by T3. Thus, the T3 produced by D2 in thyrotrophs may reflect the real-time level of T4, which is taken up by thyrotrophs from circulating blood.