Hormones tissue specificity

Hormone response elements (for steroids, T3, retinoic acid, peptides, etc) act as—or in conjunction with— enhancers or silencers (Chapter 43). Other processes that enhance or silence gene expression—such as the response to heat shock, heavy metals (Cd and Zn +), and some toxic chemicals (eg, dioxin)—are mediated through specific regulatory elements. Tissue-specific expression of genes (eg, the albumin gene in liver, the hemoglobin gene in reticulocytes) is also mediated by specific DNA sequences. 

The adenohypophysis is derived embryonically from glandular tissue, specifically, Rathke s pouch. This tissue originates from the oropharynx, or the roof of the mouth. It then migrates toward the embryonic nervous tissue destined to form the neurohypophysis. When these two tissues come into contact, Rathke s pouch loses its connection with the roof of the mouth and the pituitary gland is formed. Unlike the neurohypophysis, which releases hormones originally synthesized in the hypothalamus, the adenohypophysis synthesizes its own hormones in specialized groups of cells. Similar to the neurohypophysis, however, the release of these hormones into the blood is regulated by the hypothalamus. 

Gastrin is a hormone produced by gastric endocrine tissue — specifically, the G cells in the pyloric gland area. It is released into the blood and carried back to the stomach. The major function of gastrin is to enhance acid secretion by directly stimulating parietal cells (HC1) and chief cells (pepsinogen). Gastrin also stimulates the local release of histamine from enterochromaf-fin-like cells in the wall of the stomach. Histamine stimulates parietal cells to release HC1. 

Fujiwara, K., et al. Identification of thyroid hormone transporters in humans different molecules are involved in a tissue-specific manner. Endocrinology 2001, 342, 2005-2012. 

FIGURE 1 8-5 Tissue-specific processing of the pro-opiomelanocortin (POMC) precursor yields a wide array of bioactive peptide products. Processing of the POMC precursor varies in various tissues. In anterior pituitary, adrenocorticotropic hormone (ACTH (1-39)) and P-1 ipo tropin (P-LPH) are the primary products of post-translational processing. Arcuate neurons produce the potent opiate P-endorphin (P-endo (1-31)) as well as ACTIK1 -13) NIT,. Intermediate pituitary produces a-melanocyte-stimulating hormone (aMSH), acetylated P endof 1 31) and P-endo(l-27). NTS, nucleus tractus solitarius. 

FIGURE 18-7 Processing of the proopiomelanocortin (POMC) precursor proceeds in an ordered, stepwise fashion. Cleavage of the POMC precursor occurs at seven sites, with some of the reactions being tissue-specific. The circled numbers indicate the temporal order of cleavage in tissues where these proteolytic events occur. ACTH, adrenocorticotropic hormone CLIP, corticotropin-like intermediate lobe peptide JP, joining peptide LPH, lipotropin MSH, melanocyte-stimulating hormone PC, prohormone convertase. 

How do a wide variety of neurotransmitters and hormones produce tissue- and cell-specific biological responses, if many such responses are mediated by the same intracellular messengers, cAMP and cAMP-depen-dent protein kinase Specificity is achieved at two levels at the level of tissue-specific receptors for the neurotransmitter or hormone and at the level of tissue-specific substrate proteins for the protein kinase. Only tissues that possess specific receptors will respond to a certain neurotransmitter or hormone. Moreover, since all cells contain very similar catalytic subunits of protein kinase A (see Ch. 23), the nature of the proteins that are phosphor-ylated in a given tissue depends on the types and amounts of proteins expressed in that tissue and on their accessibility to the protein kinase. 

Ligand-bound corticosteroid receptors have been shown to interact to form heterodimers with other transcription factors, such as the jun protein. Such interactions are responsible for transactivation of the ds-regulatory sites known as AP-1 sites and for the glucocorticoid-mediated suppression of transcription, such as that seen in the pro-opiomelanocortin gene. A number of such specific protein interactions have been reported these interactions and their locations relative to other transcription factors transform a ubiquitous steroid hormone signal into a tissue-specific, graded cellular response. 

Yu, S., Yu, D., Lee, E., Eckhaus, M., et al. (1998) Variable and tissue-specific hormone resistance in heterotrimeric Gs protein alpha-subunit (Gsalpha) knockout mice is due to tissue-specific imprinting of the gsalpha gene. Proc. Natl. Acad. Sci. U. S. A. 95, 8715-8720. 

Many proteins are formed as inactive precursors and become activated by proteolysis. The inactive precursors are termed proenzymes, zymogens or - for hormones like e.g. insulin - prehormones. Processing to the active form occius in a cell- and tissue-specific way and usually requires a specific protease. Activation can also occur intramolecu-larly by autoproteolysis. In most cases, short sequences of the protease substrate serve as a recognition signal for the attack of the processing protease. Of the numerous examples of proteolytic processing of proteases only the digestive proteases will be discussed in more detail. 

An example of the importance of enzymatic modification of hormones for the tissue specificity of hormone action is the effect of the mineral corticoid aldosterone in the presence of a large excess of the glucocorticoid cortisol. Aldosterone regulates the Na -export and K -retention in the kidney by binding on the aldosterone receptor. 

Fig. 4.3. Example of a tissue-specific hormone inactivation. Cortisol is enzymatically converted to an keto compound at the Cll position. The modified cortisol compound can no longer bind and activate the aldosterone receptor. Aldosterone can not be turned over by 11-P-dehydroge-nase because the OH group at position 11 forms a half-acetal with the formyl group (C18).

Heterodimerization of receptor molecules is a mechanism that can increase and modulate the diversity and regulation of signal transduction pathways. Since the various members of a receptor family differ in the exact structure of the autophosphorylation sites and the other regulatory sequences, it is assumed that activity and regulation are different for the various combinations of receptor subtypes. Tissue-specific expression of receptor subtypes enables the organism to process growth hormone signals in a differential way. 

Kletzien, R.F., Harris, P.K., FoeUmi, L.A. (1994) Glucose 6-phosphate dehydrogenase a housekeeping enzyme subject to tissue-specific regulation by hormones, nutrients, and oxidant stress. FASEB J. 8, 174-181. 

Fujiwara K, Adachi H, Nishio T, Unno M, Tokui T, Okabe M, Onogawa T, Suzuki T, Asano N, Tanemoto M, Seki M, Shiiba K, Suzuki M, Rondo Y, Nunoki K, Shimose-gawa T, Iinuma K, Ito S, Matsuno S, Abe T (2001) Identification of thyroid hormone transporters in humans different molecules are involved in a tissue-specific manner. Endocrinology 142, 2005—2012. 

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