Steroid hormone receptor Signaling pathway

The transcription factors AP-1 and NFkB are at the end of a signal cascade activated by growth factors (see chapters 9,10,11), The ability of steroid hormone receptors in certain situations to nullify the effect other transcription factors demonstrates that two different signaling pathways can converge at the level of transcription. 

In contrast to signal transduction by the steroid hormone receptors there are multiple pathways by which the ligands of this group are made available for receptor activation (fig. 4.11) ... 

Several studies have highlighted the importance of multidomain FKBPs in the control of signal transduction pathways. For example, hFKBP51 and hFKBP52 have been found in steroid hormone receptor complexes and are thought to play an important role in complex formation and translocation of receptor-ligand complexes from the cytosol into the nucleus [82,83], Notably, these multidomain FKBPs share structural characteristics as demonstrated by an N-terminal PPIase... 

The understanding of the mechanism by which retinoids modulate gene expression implies that retinoids activate a signal-transduction pathway in which nuclear-retinoid receptors, which are members of the steroid hormone-receptor superfamily, play a pivotal role (14,16,18-22). Like other members of this family, the retinoid receptors are ligand-activated, DNA-binding transacting, transcription-modulating proteins. Two types of receptor have been identified retinoic acid receptors (RARs) and retinoid X receptors (RXRs) each type includes three subtypes of RAR (a, p, and y) and of RXR (a, P, and y) with distinct ammo- and carboxy-terminal domains. RXR-RAR... 

Whether SI consumption leads to differential effects in EQU producers and nonproducers is less clear in relation to cancer risk. There was no difference in mammographic density following a 1-y SP intervention in PMW compared to a milk protein control and this was unaffected by EQU status (Verheus et al. 2008). However, changes in gene expression, some of which were involved in pathways that are related to cell differentiation, increased cAMP signaling and G-protein-coupled protein metabolism, and increased steroid hormone receptor activity, were more marked in the lymphocytes of EQU producers compared to EQU nonproducers (Niculescu et al. 2007). 

Lipophilic signaling substances include the steroid hormones, calcitriol, the iodothy-ronines (T3 and T4), and retinoic acid. These hormones mainly act in the nucleus of the target cells, where they regulate gene transcription in collaboration with their receptors and with the support of additional proteins (known as coactivators and mediators see p.244). There are several effects of steroid hormones that are not mediated by transcription control. These alternative pathways for steroid effects have not yet been fully explained. 

The hippocampus has innumerable afferent and efferent connections to other brain structures both within the limbic system and beyond. There are receptors for many different chemical signals ranging from the "classical neurotransmitters such as acetylcholine to steroid hormones and neurotrophic factors. Some of these receptors are located in the synapses that form the intrinsic hippocampal circuits and others are the targets of specific projection pathways from other brain areas. A comprehensive review of all neurotransmitter interactions relevant to function is not within the scope of this chapter. There are detailed reviews of modulation of neurochemical systems on place learning in the watermaze (McNamara and Skelton, 1993) or other limbic-system dependent tasks (Izquierdo and Medina, 1995) in animals. The effects of key neurochemical, other than NMDA channel-mediated, and environmental influences are discussed below. 

The receptors of steroid hormones were the first representatives of the family of nuclear receptors to be characterized. With the characterization of further receptors it became clear that the signaling pathway of the nuclear receptors differ significantly in detail. Based on the receptor activation mechanism the nuclear receptors can be divided into two basic groups ... 

Figure 17.5 Endocrine signaling pathway involving steroid hormone, sex hormone binding globulin (SHBG), and the SHBG receptor.

Figure 2 General steps in steroid hormone action and their assays. The basic model depicts steroid (S) binding to its receptor molecule (R) to form receptor-steroid complexes (RS), which attach to biologically active DNA binding sites (HRE) to eventually produce changes in the levels of specific proteins. Experimental techniques to follow R at various stages in this pathway are indicated at the first point that each method can detect a signal. Most methods can also be used to detect receptors at any step downstream of the one for which it is first used.

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