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Alberts B, Bray D, Lewis J, et al. Molecular Biology of the Cell. 3rd edition. New York: Garland Science; 1994.

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Molecular Biology of the Cell. 3rd edition.

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An Overview of Gene Control

Introduction

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. For this reason, and because cell differentiation is usually 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 gene loss.

The Different Cell Types of a Multicellular Organism Contain the Same DNA 1

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. The best 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 programming the recipient egg to produce a normal tadpole. 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 done 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 9-1).

Figure 9-1. Regeneration of a whole plant from a single differentiated cell.

Figure 9-1

Regeneration of a whole plant from a single differentiated cell. In many types of plants, differentiated cells retain the ability to "dedifferentiate" so that a single cell can form a clone of progeny cells that can later give rise to an entire plant. (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 Figure8-32). 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 (for an important exception, however, see Figure23-27).

Different Cell Types Synthesize Different Sets of Proteins 2

As a first step in trying to understand cell differentiation, one 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, certain general statements can be made.

1.

Many processes are common to all cells, and any two cells in a single organism therefore have many proteins in common. These include some abundant proteins that are easy to analyze, such as the major structural proteins of the cytoskeleton and of chromosomes, some of the proteins essential to the endoplasmic reticulum and Golgi membranes, ribosomal proteins, and so on. Many nonabundant proteins, such as various enzymes involved in the central reactions of metabolism, are also the same in all cell types.

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.

If the 2000 or so most abundant proteins (those present in quantities of 50,000 or more copies per cell) are compared among different cell types of the same organism using two-dimensional polyacrylamide-gel electrophoresis, remarkably few differences are found. Whether the comparison is between two cell lines grown in culture (such as muscle and nerve cells lines) or between cells of two young rodent tissues (such as liver and lung), the great majority of the proteins detected are synthesized in both cell types and at rates that differ by less than a factor of five; only a few percent of the proteins are present in very different amounts in the two cell types.

Studies of the number of different mRNA sequences in a cell suggest that a typical higher eucaryotic cell synthesizes 10,000 to 20,000 different proteins. Most of these are too rare to be detected by two-dimensional gel electrophoresis of cell extracts. If these minor cell proteins differ among cells to the same extent as the more abundant proteins, as is commonly assumed, only a small number of protein differences (perhaps several hundred) suffice to create very large differences in cell morphology and behavior.

A Cell Can Change the Expression of Its Genes in Response to External Signals 3

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 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 amino-transferase, 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 in different ways. 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 this specialization are features that do not change, which give each cell type its permanently distinctive character. These features reflect the persistent expression of different sets of genes.

Gene Expression Can Be Regulated at Many of the Steps in the Pathway from DNA to RNA to Protein 4

If differences between 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? 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 primary RNA transcript is spliced or otherwise processed (RNA processing control), (3) selecting which completed mRNAs in the cell nucleus are exported to the cytoplasm (RNA transport 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, or compartmentalizing specific protein molecules after they have been made (protein activity control) (Figure 9-2).

Figure 9-2. Six steps at which eucaryote gene expression can be controlled.

Figure 9-2

Six steps at which eucaryote gene expression can be controlled. Only controls that operate at steps 1 through 5 are discussed in this chapter. The regulation of protein activity (step 6) is discussed in Chapter 5; this includes reversible activation or (more...)

For most genes transcriptional controls are paramount. This makes sense because, of all the possible control points illustrated in Figure9-2, only transcriptional control ensures that no superfluous intermediates are synthesized. In the following sections we discuss the DNA and protein components that regulate the initiation of gene transcription. We return at the end of the chapter to the other 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 © 1994, Bruce Alberts, Dennis Bray, Julian Lewis, Martin Raff, Keith Roberts, and James D Watson.
Bookshelf ID: NBK28440