BIOCHEMISTRY - L. Stryer - 1984

VOLUME 3

PART V. MOLECULAR PHYSIOLOGY

CHAPTER 35. HORMONE ACTION

35.17. Steroid Hormones Activate Specific Genes

The primary effect of Steroid Hormones, particularly estradiol, progesterone, and cortisone, is to influence Gene Expression rather than directly affect enzyme activity or transport processes. Unlike adrenaline, these steroid hormones exert their effects only after penetrating the target Cell. Furthermore, their primary Site of Action is not The Plasma Membrane, but the Cell Nucleus. The full expression of the BIOLOGICAL EFFECTS OF steroid hormones requires hours rather than minutes, as it depends on the synthesis of new Proteins. Actinomycin D inhibits the action of these Steroids, implying that it is linked to the synthesis of new mRNA.

17β-estradiol stimulates uterine growth. The first step in this action is the binding of the hormone to a specific receptor in the Cytoplasm of uterine Cells. This binding is characterized by high affinity (K = 10^-9M). The resulting hormone-receptor complex then migrates into The Cell nucleus. As a result of the receptor binding to estradiol, the affinity of the receptor for DNA increases significantly. In addition, the estradiol-bound receptor acquires a second subunit. The latter is reflected in an increase in the sedimentation coefficient from 4S to 5S. It remains unknown what determines the Specificity of the DNA segments that bind the estradiol receptor: whether it is The base sequence or chromosomal proteins. The interaction of the hormone-receptor complex with DNA is highly specific. Furthermore, receptor activation via hormone binding is also strictly specific. Estrone can bind to the estradiol receptor, but this complex does not interact with DNA. The inability of the estrone-receptor complex to bind DNA is fully consistent with the fact that estrone does not stimulate uterine growth.

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Apparently, The Mechanism of hormonal effect described is characteristic not only of estradiol, but generally of all steroid hormones. Thus, in experiments with hepatoma tissue culture, it was shown that the glucocorticoid steroid hormone dexamethasone also binds to a specific cytoplasmic receptor; the hormone-bound receptor undergoes conformational changes and then migrates into the cell nucleus, where it forms a complex with specific regions of DNA. The number of DNA sites binding this receptor has been determined to be 1 per 10⁶ Base Pairs. This number is consistent with the evidence that dexamethasone affects the METABOLISM/31.html">Transcription of only a small number of genes. The mechanism underlying this high selectivity in Transcriptional Regulation by steroid hormones remains an intriguing puzzle.

Fig. 35.22. Space-filling models of 17β-estradiol (A) and testosterone (B)

35.18. Protein Growth Factors Such as NGF and EGF Stimulate Target Cell Proliferation

How is Introduction/5.html">Eukaryotic Cell growth regulated? The recent isolation of protein growth factors capable of specifically stimulating target cells has made a substantial contribution to solving this interesting and important question. Rita Levi-Montalcini discovered that nerve growth factor (NGF) plays a crucial role in The Development of sympathetic Neurons and certain sensory neurons in vertebrates. Under The Influence of NGF, these cells undergo division and differentiation. A sensitive assay for the presence of nerve growth factor is the outgrowth of axons from cultured ganglia (Fig. 35.23). The biologically active NGF molecule consists of two identical polypeptide chains, each with a mass of 13 kDa. This dimer (referred to as the β subunit) accumulates at its site of synthesis—the Pancreas—as a complex with a subunit Structure of α₂γ₂β and a mass of 130 kDa. The γ subunit is a proteolytic enzyme, and the α subunit is an inhibitor of this proteinase. NGF is synthesized as a prohormone consisting of α and β subunits, which is subsequently cleaved by the γ proteinase. In its Amino Acid Sequence, NGF resembles Insulin. Notably, insulin not only strongly activates anabolic processes in Muscle, Liver, and adipose tissue, but also exerts a stimulatory effect on the growth of most cells. It can be hypothesized that the genes for NGF and insulin evolved from a common precursor.

Fig. 35.23. Nerve growth factor (NGF) induces axon outgrowth from cultured Nerve Cells. A - without NGF; B - in the presence of NGF

Epidermal growth factor (EGF) has also been isolated and studied. It is a 6 kDa polypeptide (Fig. 35.24) capable of stimulating the growth of epidermal and epithelial cells. EGF binds tightly to the plasma membrane of target cells. The dissociation constant of the EGF-receptor complex is approximately 10^-10 M. A few minutes after EGF binding at the membrane, clusters of EGF-receptor complexes enter the cell via endocytosis. The sites of endocytosis are the so-called coated pits (membrane invaginations) containing clathrin (sec. 29.32). Subsequently, vesicles containing EGF fuse with Lysosomes. NGF-receptor complexes enter cells in a similar manner (Fig. 35.25). It remains unknown to what extent the actual process of penetration of these complexes into the cell is necessary for the transmission of the stimulatory signal to the cell nucleus.

Fig. 35.24. Amino acid sequence of epidermal growth factor (EGF)

Fig. 35.25. Internalization of the NGF-receptor complex into the cell