Activation of Thyroid Hormone Is Transcriptionally Regulated by Epidermal Growth Factor in Human Placenta-Derived JEG3 Cells

Abstract

Human type II deiodinase is a master regulator of thyroid hormone activation in several tissues. In placenta, type II deiodinase mRNA levels and enzymatic activity are elevated only during the first trimester of pregnancy and then progressively decline. During this early stage, mitogens such as epidermal growth factor (EGF) have been shown to promote the proliferation of the trophoblast by acting through multiple mechanisms. Here we show that EGF modulates transcription of human type II deiodinase gene (Dio2) through distinct signaling pathways, leading to the assembly of a heterogeneous transcription factor complex. Gene expression and deiodination assays have shown that EGF promptly induces a short-lived Dio2 mRNA and enzymatic activity. The induction is mediated by ERK and p38 kinases, as demonstrated by selective inhibition or overexpression of different mitogen-activated kinases. Reporter assays of mutant constructs indicate that EGF-induced transcriptional activity on Dio2 promoter is mediated by the cAMP response element (CRE) and does not involve the activating protein 1 site. With functional and biochemical approaches, we have demonstrated that the EGF stimulation culminates with the assembly and recruitment over the Dio2 CRE of a composite complex, which consists of c-Jun, c-Fos, and CRE-binding protein. These results further support the hypothesis that placental iodothyronine metabolism is critical during early pregnancy.

Genetic analysis of genes causing hypertension and stroke in spontaneously hypertensive rats: Gene expression profiles in the kidneys

“…In order to identify further interactions between SHR-specific G-1 and G-2 genes, we applied the IPA path explorer tool, suggested the presence of one gene that assisted in these interactions, and found such a condition when we proposed the Jun proto-oncogene ( Jun ) ( 41 ), which interacts directly with specific target DNA sequences to regulate gene expression. The presence of Jun has been shown to facilitate interactions between 3 G-1 genes: Bcl6 ( 13 ), Sox2 ( 15 ) and ankyrin repeat domain 35 ( Ankrd35 ) ( 42 ), and 8 G-2 genes: Spib ( 43 ), Ephx2 ( 44 ), Tp73 ( 45 ), Dio2 ( 46 ), cytochrome P450, family 8, subfamily b, polypeptide 1 ( Cyp8b1 ) ( 47 ), Mylpf ( 48 ), glial cell derived neurotrophic factor ( Gdnf ) ( 49 ) and neurofilament, heavy polypeptide ( Nefh ) ( 50 ) ( Fig. 2 ).…”

Involvement of SIK2/TORC2 signaling cascade in the regulation of insulin-induced PGC-1α and UCP-1 gene expression in brown adipocytes

“…Expression of the Dio2 gene is upregulated by multiple stimuli, including cAMP, and a CRE in the proximal promoter is important for the regulation of the Dio2 gene (3). In addition to CREB, the complex of c-Jun/c-fos is also recruited on the Dio2 CRE to exert epidermal growth factor-dependent transcriptional activity (7). Recently, TORC1 was found to activate c-Jun/c-fos, which is independent of CREB (6).…”

miRNAs as common regulators of the transforming growth factor (TGF)-β pathway in the preeclamptic placenta and cadmium-treated trophoblasts: Links between the environment, the epigenome and preeclampsia

“…This cell line maintains characteristics of first trimester trophoblast cells (Matsuo and Strauss 1994) and has been used to assess biological effects of exposures to environmental toxicants (Bergemann et al 2003; Canettieri et al 2008; Ding et al 2011; Koc et al 2003; Matscheski et al 2006; Adebambo et al 2015; Guan et al 2013; Kummu et al 2012; Alvarez and Chakraborty 2011). Cells were grown in Dulbecco’s Eagle Minimum Essential Media with 10% FBS, sodium pyruvate, and penicillin/streptomycin at 37°C with 5% CO 2 .…”