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Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002.

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Molecular Biology of the Cell. 4th edition.

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An Overview of Gene Control

The different cell types in a multicellular organism differ dramatically in both structure and function. If we compare a mammalian neuron with a lymphocyte, for example, the differences are so extreme that it is difficult to imagine that the two cells contain the same genome (Figure 7-1). For this reason, and because cell differentiation is often irreversible, biologists originally suspected that genes might be selectively lost when a cell differentiates. We now know, however, that cell differentiation generally depends on changes in gene expression rather than on any changes in the nucleotide sequence of the cell's genome.

Figure 7-1. A mammalian neuron and a lymphocyte.

Figure 7-1

A mammalian neuron and a lymphocyte. The long branches of this neuron from the retina enable it to receive electrical signals from many cells and carry those signals to many neighboring cells. The lymphocyte is a white blood cell involved in the immune (more...)

The Different Cell Types of a Multicellular Organism Contain the Same DNA

The cell types in a multicellular organism become different from one another because they synthesize and accumulate different sets of RNA and protein molecules. They generally do this without altering the sequence of their DNA. Evidence for the preservation of the genome during cell differentiation comes from a classic set of experiments in frogs. When the nucleus of a fully differentiated frog cell is injected into a frog egg whose nucleus has been removed, the injected donor nucleus is capable of directing the recipient egg to produce a normal tadpole (Figure 7-2A). Because the tadpole contains a full range of differentiated cells that derived their DNA sequences from the nucleus of the original donor cell, it follows that the differentiated donor cell cannot have lost any important DNA sequences. A similar conclusion has been reached in experiments performed with various plants. Here differentiated pieces of plant tissue are placed in culture and then dissociated into single cells. Often, one of these individual cells can regenerate an entire adult plant (Figure 7-2B). Finally, this same principle has been recently demonstrated in mammals, including sheep, cattle, pigs, goats, and mice by introducing nuclei from somatic cells into enucleated eggs; when placed into surrogate mothers, some of these eggs (called reconstructed zygotes) develop into healthy animals (Figure 7-2C).

Figure 7-2. Evidence that a differentiated cell contains all the genetic instructions necessary to direct the formation of a complete organism.

Figure 7-2

Evidence that a differentiated cell contains all the genetic instructions necessary to direct the formation of a complete organism. (A) The nucleus of a skin cell from an adult frog transplanted into an enucleated egg can give rise to an entire tadpole. (more...)

Further evidence that large blocks of DNA are not lost or rearranged during vertebrate development comes from comparing the detailed banding patterns detectable in condensed chromosomes at mitosis (see Figure 4-11). By this criterion the chromosome sets of all differentiated cells in the human body appear to be identical. Moreover, comparisons of the genomes of different cells based on recombinant DNA technology have shown, as a general rule, that the changes in gene expression that underlie the development of multicellular organisms are not accompanied by changes in the DNA sequences of the corresponding genes. There are, however, a few cases where DNA rearrangements of the genome take place during the development of an organism—most notably, in generating the diversity of the immune system of mammals (discussed in Chapter 24).

Different Cell Types Synthesize Different Sets of Proteins

As a first step in understanding cell differentiation, we would like to know how many differences there are between any one cell type and another. Although we still do not know the answer to this fundamental question, we can make certain general statements.

1.

Many processes are common to all cells, and any two cells in a single organism therefore have many proteins in common. These include the structural proteins of chromosomes, RNA polymerases, DNA repair enzymes, ribosomal proteins, enzymes involved in the central reactions of metabolism, and many of the proteins that form the cytoskeleton.

2.

Some proteins are abundant in the specialized cells in which they function and cannot be detected elsewhere, even by sensitive tests. Hemoglobin, for example, can be detected only in red blood cells.

3.

Studies of the number of different mRNAs suggest that, at any one time, a typical human cell expresses approximately 10,000–20,000 of its approximately 30,000 genes. When the patterns of mRNAs in a series of different human cell lines are compared, it is found that the level of expression of almost every active gene varies from one cell type to another. A few of these differences are striking, like that of hemoglobin noted above but most are much more subtle. The patterns of mRNA abundance (determined using DNA microarrays, discussed in Chapter 8) are so characteristic of cell type that they can be used to type human cancer cells of uncertain tissue origin (Figure 7-3).

4.

Although the differences in mRNAs among specialized cell types are striking, they nonetheless underestimate the full range of differences in the pattern of protein production. As we shall see in this chapter, there are many steps after transcription at which gene expression can be regulated. In addition, alternative splicing can produce a whole family of proteins from a single gene. Finally, proteins can be covalently modified after they are synthesized. Therefore a better way of appreciating the radical differences in gene expression between cell types is through the use of two-dimensional gel electrophoresis, where protein levels are directly measured and some of the most common posttranslational modifications are displayed (Figure 7-4).

Figure 7-3. Differences in mRNA expression patterns among different types of human cancer cells.

Figure 7-3

Differences in mRNA expression patterns among different types of human cancer cells. This figure summarizes a very large set of measurements in which the mRNA levels of 1800 selected genes (arranged top to bottom) were determined for 142 different human (more...)

Figure 7-4. Differences in the proteins expressed by two human tissues.

Figure 7-4

Differences in the proteins expressed by two human tissues. In each panel, the proteins have been displayed using two-dimensional polyacrylamide gel electrophoresis (see pp. 485–487). The proteins have been separated by molecular weight (top to (more...)

A Cell Can Change the Expression of Its Genes in Response to External Signals

Most of the specialized cells in a multicellular organism are capable of altering their patterns of gene expression in response to extracellular cues. If a liver cell is exposed to a glucocorticoid hormone, for example, the production of several specific proteins is dramatically increased. Glucocorticoids are released in the body during periods of starvation or intense exercise and signal the liver to increase the production of glucose from amino acids and other small molecules; the set of proteins whose production is induced includes enzymes such as tyrosine aminotransferase, which helps to convert tyrosine to glucose. When the hormone is no longer present, the production of these proteins drops to its normal level.

Other cell types respond to glucocorticoids differently. In fat cells, for example, the production of tyrosine aminotransferase is reduced, while some other cell types do not respond to glucocorticoids at all. These examples illustrate a general feature of cell specialization: different cell types often respond in different ways to the same extracellular signal. Underlying such adjustments that occur in response to extracellular signals, there are features of the gene expression pattern that do not change and give each cell type its permanently distinctive character.

Gene Expression Can Be Regulated at Many of the Steps in the Pathway from DNA to RNA to Protein

If differences among the various cell types of an organism depend on the particular genes that the cells express, at what level is the control of gene expression exercised? As we saw in the last chapter, there are many steps in the pathway leading from DNA to protein, and all of them can in principle be regulated. Thus a cell can control the proteins it makes by (1) controlling when and how often a given gene is transcribed (transcriptional control), (2) controlling how the RNA transcript is spliced or otherwise processed (RNA processing control), (3) selecting which completed mRNAs in the cell nucleus are exported to the cytosol and determining where in the cytosol they are localized (RNA transport and localization control), (4) selecting which mRNAs in the cytoplasm are translated by ribosomes (translational control), (5) selectively destabilizing certain mRNA molecules in the cytoplasm (mRNA degradation control), or (6) selectively activating, inactivating, degrading, or compartmentalizing specific protein molecules after they have been made (protein activity control) (Figure 7-5).

Figure 7-5. Six steps at which eucaryotic gene expression can be controlled.

Figure 7-5

Six steps at which eucaryotic gene expression can be controlled. Controls that operate at steps 1 through 5 are discussed in this chapter. Step 6, the regulation of protein activity, includes reversible activation or inactivation by protein phosphorylation (more...)

For most genes transcriptional controls are paramount. This makes sense because, of all the possible control points illustrated in Figure 7-5, only transcriptional control ensures that the cell will not synthesize superfluous intermediates. In the following sections we discuss the DNA and protein components that perform this function by regulating the initiation of gene transcription. We shall return at the end of the chapter to the additional ways of regulating gene expression.

Summary

The genome of a cell contains in its DNA sequence the information to make many thousands of different protein and RNA molecules. A cell typically expresses only a fraction of its genes, and the different types of cells in multicellular organisms arise because different sets of genes are expressed. Moreover, cells can change the pattern of genes they express in response to changes in their environment, such as signals from other cells. Although all of the steps involved in expressing a gene can in principle be regulated, for most genes the initiation of RNA transcription is the most important point of control.

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By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2002, Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter; Copyright © 1983, 1989, 1994, Bruce Alberts, Dennis Bray, Julian Lewis, Martin Raff, Keith Roberts, and James D. Watson .
Bookshelf ID: NBK26885