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Modern Genetic Analysis Chapter 14. Regulation of Gene Transcription
Regulation of Transcription Factors

Some transcription factors are synthesized only in specific tissues. The activities of the factors themselves are also regulated in different cell types.

Steroid Hormones: Linking Enhancers to the Physiology of the Organism

Just as it was crucial in prokaryotes to wed the activity of transcriptional regulatory proteins to the physiological state of the bacterium, the tie between transcriptional regulation and physiology is crucial in eukaryotes as well. In Chapter 16, we shall see examples of how pathways of differentiation and pattern development provide the physiological context for activation of specific transcription factors. Sometimes, the regulatory signal that activates eukaryotic transcription factors comes from a very distant source in the body. For instance, hormones released into the circulatory system by an organ that is part of the endocrine system (Figure 14-30) can travel through the circulation to essentially all parts of the body. The endocrine system can thus serve as a master regulator to coordinate changes in transcription in cells of many different tissues. This mechanism underlies sex determination in mammals, which will be discussed in Chapter 16.

Some hormones are small molecules that, because of their lipid-solubility properties, can directly pass through the plasma membrane of the cellexamples are various steroid hormones, such as glucocorticoid, testosterone, and estrogen. Once in the cell, steroid hormones bind to and regulate specific transcription factors in the nucleus. In this respect, we can think of steroids as being analogous to allosteric effectors regulating some bacterial operons.

One example is the female sex hormone estrogen. In chicken oviducts, the egg white protein ovalbumin is specifically synthesized in response to estrogen, which causes increased transcription of the ovalbumin gene. The estrogen molecule activates transcription by binding to a protein receptor molecule that first recognizes the estrogen molecule in the cytoplasm and transports it to the nucleus. The receptor molecule is a transcription factor that then binds to the DNA at an enhancer site called an HRE (hormone-response element). The general process of steroid-receptor activation is depicted in Figure 14-31.

MESSAGE
Just as in prokaryotes, eukaryotic transcriptional regulatory proteins must contain domains that interact with molecular signals of the physiological state of the cell.

Structure of Regulatory Proteins

Throughout this chapter, we have seen that proteins such as Lac repressor, CAP, or TATA-binding protein are crucial to gene regulation. Such sequence-specific DNA-binding proteins are vital to transcriptional regulation in all organisms. We need to consider how DNA sequence-specific binding takes place.

Protein sequence analyses and structural comparisons indicate that DNA-binding regulatory proteins have important features in common. Many consist of a DNA-binding domain, located at one end of the protein, that protrudes from the main "core" of the protein. In certain cases, the core protein contains the allosteric effector site. This arrangement holds for the Lac repressor (Figure 14-32) and CAP, as well as for many other regulatory proteins such as the steroid receptors. For such proteins, certain protruding a helices fit into the major groove of the DNA. This fit has been visualized by solving the three-dimensional structures of various proteinDNA complexes, such as the Lac repressoroperator complex (Figure 14-33). Here two a helices from the repressor protein interact with the two consecutive major grooves of the DNA of the operator site. The helices are connected by a turn in the protein secondary structure. This helix-turn-helix motif (Figure 14-34) is common to many regulatory proteins. However, many other DNA-binding motifs abound as well. As just one example, Figure 14-35 shows the structure of a part of a zinc-finger protein, in which a zinc atom is conjugated to four amino acids of a small part of a polypeptide chain [two cysteines (C) and two histidines (H)]. Zinc-finger proteins generally have several such zinc fingers. Each zinc finger appears to be able to interact with a specific DNA sequence.

MESSAGE
The structures of DNA-binding proteins help us understand how they contact specific DNA sequences through polypeptide domains that fit into the major groove of the DNA double helix.

© 1999 by W. H. Freeman and Company. All rights reserved.