**Part 3**

**The Thyroid Gland** 

98 Contemporary Aspects of Endocrinology

Zhu T, Goh EL, Graichen R, Ling L, Lobie PE. 2001 Signal transduction via the growth

Zhu T, Ling L, Lobie PE. 2002 Identification of a JAK2-independent pathway regulating

growth hormone (GH)-stimulated p44/42 mitogen-activated protein kinase activity. GH activation of Ral and phospholipase D is Src-dependent. *J Biol Chem*.

hormone receptor. *Cell Signal.* 13: 599–16.

277(47): 45592-603.

**5** 

*Japan* 

**Negative Regulation of the Thyrotropin** 

Shigekazu Sasaki, Akio Matsushita and Hirotoshi Nakamura

Thyroid hormone (T3 and T4) is secreted from the thyroid gland, and is known to reduce the level of serum thyrotropin (thyroid-stimulating hormone, TSH) in the pituitary gland (Sarapura et al., 2002; Shupnik et al., 1989) (Fig. 1A). This is a typical example of negative feedback between the pituitary and endocrine organs, and is a key component of thyroid hormone homeostasis. TSH is one of the peptide hormones generated in the anterior pituitary, and is a heterodimer composed of an α chain (α-glycoprotein subunit, αGSU) and a β chain (TSHβ) (Shupnik et al., 1989). While αGSU is common to follicle stimulating hormone (FSH), luteinizing hormone (LH) and chorionic gonadotropin (CG), TSHβ is specific to TSH alone. Although the concentration of serum T4 is much higher than that of T3, T4 is converted to T3 by deiodinase (Dio) in the TSH-producing cells (thyrotrophs) of the pituitary (Christoffolete et al., 2006), and T3 exhibits biological activity as a thyroid hormone (Gereben et al., 2008). T3 inhibits expression of both *TSHβ* and *αGSU* at the transcriptional level (Shupnik et al., 1989). The magnitude of T3-induced repression of the *TSHβ* gene is greater than that of *αGSU*. Here, we provide an overview of the molecular mechanisms involved in T3-induced negative regulation of the *TSHβ* gene and its related

T3 receptor (TR) belongs to the nuclear hormone receptor (NHR) superfamily, and is a ligand-dependent transcription factor (Cheng et al., 2010). TR is encoded by two separate alleles; *TRα* and *TRβ*. Through alternative splicing, the *TRα* gene generates TRα1 and TRα2, while the *TRβ* gene generates TRβ1 and TRβ2 (Fig. 2). While TRα1, TRβ1 and TRβ2 have T3-binding capacity, TRα2 does not bind T3. Hence, TRα1, TRβ1 and TRβ2 are thought to be the functional TRs. TRβ2 is expressed in limited organs including pituitary, hypothalamus and retina, while TRα1 and TRβ1 are ubiquitously expressed (Cheng et al., 2010). As in the case of other NHRs, TR consists of an N-terminal region (NTD), a central DNA binding domain (DBD), a hinge region and a C-terminal ligand binding domain

**1. Introduction** 

genes.

(LBD) (Fig. 2).

**2. Structure of T3 receptors (TRs)** 

 **Gene by Thyroid Hormone** 

*Second Division of Internal Medicine Hamamatsu University School of Medicine* 
