Epidermal growth factor (EGF) inhibits stimulated thyroid hormone secretion in the mouse

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.

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Epidermal Growth Factor Decreases Thyroid Hormone Receptors and Attenuates Thyroid Hormone Responses in GH4C1Cells*

Endocrinology ◽

10.1210/endo-120-2-537 ◽

1987 ◽

Vol 120 (2) ◽

pp. 537-543 ◽

Cited By ~ 2

Author(s):

HIDESUKE KAJI ◽

PATRICIA M. HINKLE

Keyword(s):

Growth Factor ◽

Thyroid Hormone ◽

Epidermal Growth Factor ◽

Hormone Receptors ◽

Thyroid Hormone Receptors ◽

Epidermal Growth ◽

Hormone Responses

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Thyroid hormone promotes the phosphorylation of STAT3 and potentiates the action of epidermal growth factor in cultured cells

Biochemical Journal ◽

10.1042/bj3380427 ◽

1999 ◽

Vol 338 (2) ◽

pp. 427-432 ◽

Cited By ~ 36

Author(s):

Hung-Yun LIN ◽

Ai SHIH ◽

Faith B. DAVIS ◽

Paul J. DAVIS

Keyword(s):

Growth Factor ◽

Thyroid Hormone ◽

Protein Kinase ◽

Epidermal Growth Factor ◽

Nuclear Translocation ◽

Thyroid Hormone Receptor ◽

Mapk Pathway ◽

Nuclear Fraction ◽

Epidermal Growth ◽

Fos Expression

We have examined the effects of l-thyroxine (T4) on the activation of signal transducer and activator of transcription 3 (STAT3) and on the STAT3-dependent induction of c-Fos expression by epidermal growth factor (EGF). T4, at a physiological concentration of 100 nM, caused tyrosine phosphorylation and nuclear translocation (i.e. activation) of STAT3 in HeLa cells in as little as 10–20 min. Activation by T4 of STAT3 was maximal at 30 min (15±4-fold enhancement; mean±S.E.M.) in 18 experiments. This effect was reproduced by T4–agarose (100 nM) and blocked by CGP 41251, genistein, PD 98059 and geldanamycin, inhibitors of protein kinase C (PKC), protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK) kinase and Raf-1 respectively. Tyrosine-phosphorylated MAPK also appeared in nuclear fractions within 10 min of treatment with T4. In the nuclear fraction of T4-treated cells, MAPK immunoprecipitate also contained STAT3. The actions of T4 were similar in HeLa and CV-1 cells, which lack thyroid hormone receptor (TR), and in TR-replete skin fibroblasts (BG-9). T4 also potentiated the EGF-induced nuclear translocation of activated STAT1α and STAT3 and enhanced the EGF-stimulated expression of c-Fos. Hormone potentiation of EGF-induced signal transduction and c-Fos expression was inhibited by CGP 41251, geldanamycin and PD 98059. Therefore the non-genomically induced activation by T4 of STAT3, and the potentiation of EGF by T4, require activities of PKC, PTK and an intact MAPK pathway.

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Neonatal hyperthyroidism alters submandibular gland epidermal growth factor response to thyroxine in the adult mouse

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y85-188 ◽

1985 ◽

Vol 63 (9) ◽

pp. 1151-1154

Author(s):

Peter Walker

Keyword(s):

Gene Expression ◽

Growth Factor ◽

Thyroid Hormone ◽

Epidermal Growth Factor ◽

Thyroid Hormones ◽

Submandibular Gland ◽

Adult Mice ◽

Neonatal Hyperthyroidism ◽

Epidermal Growth ◽

And Control

Neonatal hyperthyroidism (NH) in the rat is associated with permanent reductions in serum thyroxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone (TSH) concentrations in the adult, changes suggestive of a hypothyroid state. In the adult NH rat, the thyrotroph appears to be more sensitive to the feedback effects of thyroid hormones. To determine whether thyroid hormone sensitive tissues retain their responsiveness to thyroid hormones, the long-term effects of NH on mouse submandibular gland (SMG) epidermal growth factor (EGF) content were examined. NH was induced in female mice by 20 daily subcultaneous injections of 0.4 μg of T4 per gram of body weight. Control female mice received daily injections of vehicle alone. At 21 days of age, NH and control mice were sacrificed and SMG EGF content was measured by specific radioimmunoassay. SMG EGF content and concentration in 21-day-old NH mice exceeded that of control mice by 2400- and 1500-fold, respectively (P < 0.001). SMG EGF content and concentration in adult (90-day-old) NH mice were slightly, but not significantly, lower than those of control mice. Mean SMG weight, however, was significantly decreased in adult NH mice (P < 0.01). Interestingly, SMG content and concentration of EGF in adult NH mice were lower than in 21-day-old NH mice. After 5 days T4 treatment (16 μg/d) of adult mice, SMG weight in NH mice increased significantly (P < 0.01) but was unchanged in control mice. SMG EGF content and concentration increased significantly in both adult NH and control mice (P < 0.01). However, the magnitude of the increase was markedly obtunded in adult NH mice. These observations indicate that thyroid hormones precociously and exponentially increase SMG EGF content and concentration in neonatal mice. The marked increases strongly suggest thyroid hormone mediated synthesis of EGF and acceleration of maturation of gene expression for EGF synthesis. In addition, NH appears to modify thyroid hormone regulation of gene expression for EGF synthesis in adult mice.

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