22 an introduction to genetic analysis.docx

1、22 an introduction to genetic analysisChapter 22Cancer as a Genetic DiseaseKey ConceptsNormal cell proliferation is modulated by cell cycle regulation.Apoptosis is a normal self-destruction mechanism that eliminates damaged and potentially harmful cells.Signaling systems permit proliferation and apo

2、ptosis to be coordinated within a population of cells.In cancer, cells proliferate out of control and avoid fail-safe destruction mechanisms through the accumulation of a series of special mutations in the same somatic cell.Many of the classes of genes that are mutated to cause cancers are important

3、 components of the cell that directly or indirectly contribute to growth control and differentiation.IntroductionIn Chapter 11, we learned about some ways in which a cell monitors its status relative to its environment and responds accordingly. For example, by utilizing certain metabolites as allost

4、eric effectors of transcriptional regulatory proteins, an E. coli cell can make decisions about which sugar metabolic pathways to implement at any given time. Metazoa (multitissued animals) use steroids and other low-molecular-weight hormones as allosteric effectors of transcriptional regulatory mol

5、ecules to coordinate appropriate responses of different organs to a particular physiological event.A major point to remember is that cells have evolved mechanisms that modulate the activity of key target proteins by relatively minor modificationsin the two preceding examples, by forming complexes wi

6、th allosteric effectors. Much of genetics, indeed much of the biology of a cell, depends on such modulations, in which key proteins are toggled between active and inactive states.In this chapter and the next one, we shall see this theme exploited in a variety of situations: control of cell numbers,

7、control of developmental pathways, and formation of complex biological patterns. In this chapter, we focus on how such modulations achieve proper control of cell number and how the systems can be overcome by certain classes of mutations to produce uncontrolled proliferationthe diseases that we call

8、cancers.Cancer and the control of cell number: an overviewCancer is now clearly understood as a genetic disease of somatic cells. In cancer, the fail-safe mechanisms that are in place to ensure that cell number remains balanced to the needs of the whole organism are subverted, and cancerous cells pr

9、oliferate out of control. To understand how cells can mutate to a cancerous state, we must first understand the basic mechanisms governing the control of normal cell numbers.Machinery of cell proliferationCertain aspects of proliferation control are general to all organisms. Universally, the cell di

10、vision process has numerous events that must take place sequentially to produce viable progeny cells. Moreover, the cell division cycle has evolved so that there are checks and balances to prevent a subsequent event from taking place before the prerequisite events have been achieved. For example, it

11、 would be a lethal event if mitosis occurred before DNA replication was completed. Mechanisms have evolved that prevent such cellular disasters. We shall explore the regulation of the eukaryotic cell cycle. Protein kinases, enzymes that specifically phosphorylate certain amino acid residues on targe

12、t proteins, and protein phosphatases, enzymes that specifically remove phosphate groups from such amino acid residues, modulate the activities of key proteins in the cell division cycle. These phosphorylationdephosphorylation pathways ultimately converge to determine which key proteins are active fo

13、r a fraction of the entire cell division cycle. Put another way, it is the cyclical variations in these key proteins that determine which parts of the cell cycle are currently being executed.Machinery of cell deathSome aspects of cell control appear to have evolved only in multicellular organisms. T

14、o develop and maintain themselves normally, multicellular organisms must properly balance the numbers of the cell types in their various tissues. Almost all of these cell types are somaticthat is, they do not contribute to the germ line. Loss of such somatic cells is not a problem for the organism f

15、rom the point of view of propagation of the species, as long as proliferation of the remaining cells of that type in a particular tissue compensates for the cells that are eliminated. Furthermore, abnormal cells have the potential to do considerable harm. Thus, mechanisms have evolved to eliminate c

16、ertain cellsthrough a process called programmed cell death or apoptosis. A cascade of enzymes called caspases kill by disrupting numerous structural and functional systems within the cell. Subsequently, the carcasses of the dead cells are removed by scavenger cells.Linking cell proliferation and dea

17、th to the environmentThe cell proliferation and cell death machinery must be interconnected so that each is activated only under the appropriate environmental circumstances. For example, in adult organs, maintenance of proper cell number requires proper balance between the birth of new cells and the

18、 loss of existing ones. Eukaryotic cells have evolved elaborate intercellular signaling pathways to serve as status indicators of the environment. Some signals stimulate proliferation, whereas others inhibit it. Furthermore, other signals can activate apoptosis, whereas still others block activation

19、. Intercellular signaling pathways typically consist of several components: the signals themselves, the receptors that receive the signals, and the signal transduction systems responsible for relaying the signal to various regions of the cell. Just as allosteric effectors regulate the activity of ma

20、ny DNA-binding proteins in bacteria, modifications to the various components of the intercellular signaling systemsprotein phosphorylation, allosteric interactions between proteins and small molecules, or interaction between protein subunitscontrol the activity of these pathways.Cell proliferation m

21、achineryCell cycleThere are four main parts to the cell cycle: M phase mitosisand the three parts that are components of interphase; G1, the gap period between the end of mitosis and the start of DNA replication; S, the period during which DNA synthesis occurs; and G2, the gap period following DNA r

22、eplication and preceding the initiation of the mitotic prophase. In mammals, where the cell cycle is particularly well studied, differences in the rate of cell division are largely due to differences in the length of time between entering and exiting G1. This variation is due to an optional G0 resti

23、ng phase into which G1-phase cells can shunt and remain for variable lengths of time, depending on the cell type and on environmental conditions. Conversely, S, G2, and M phases are normally quite fixed in duration. In this section, we consider the molecules that drive the cell cycle. In a later sec

24、tion, we shall consider how these molecules are integrated into the overall biology of the cell.Cyclins and cyclin-dependent protein kinasesThe engines that drive progression from one step of the cell cycle to the next are a series of protein complexes composed of two subunits: a cyclin and a cyclin

25、-dependent protein kinase (abbreviated CDK). In every eukaryote, there is a family of structurally and functionally related cyclin proteins. Cyclins are so named because each is found only during one or another segment of the cell cycle. The onset of the appearance of a specific cyclin is due to cel

26、l-cycle-controlled transcription, in which the previously active cyclinCDK complex leads to the activation of a transcription factor that activates the transcription of this new cyclin. The disappearance of a cyclin depends on three events: rapid inactivation of the activator of transcription of thi

27、s cyclins gene (so that no new mRNA is produced), a high degree of instability of the cyclin mRNA (so that the existing pool of mRNA is eliminated), and a high level of instability of the cyclin itself (so that the pool of cyclin protein is destroyed).Cyclin-dependent protein kinases also constitute

28、 a family of structurally and functionally related proteins. Kinases are enzymes that add phosphate groups to target substrates; for protein kinases such as CDKs, the substrates are proteins. CDKs are so named because their activities are regulated by cyclins and because they catalyze the phosphoryl

29、ation of specific serine and threonine residues of specific target proteins.The target proteins for CDK phosphorylation are determined by the associated cyclin. In other words, the cyclin tethers the target protein so that the CDK can phosphorylate it (Figure 22-1), thereby changing the activity of

30、each target protein. Because different cyclins are present at different phases of the cell cycle (Figure 22-2), different phases of the cell cycle are characterized by the phosphorylation of different target proteins. The phosphorylation events are transient and reversible. When the cyclinCDK comple

31、x disappears, the phosphorylated substrate proteins are rapidly dephosphorylated by protein phosphatases.CDK targetsHow does the phosphorylation of some target proteins control the cell cycle? Phosphorylation initiates a chain of events that culminates in the activation of certain transcription fact

32、ors. These transcription factors promote the transcription of certain genes whose products are required for the next stage of the cell cycle. Much of our knowledge of the cell cycle comes from both genetic studies in yeast (see next section) and from biochemical studies of cultured mammalian cells.

33、A well-understood example is the RbE2F pathway in mammalian cells. Rb is the target protein of a CDKcyclin complex called Cdk2cyclin A, and E2F is the transcription factor that Rb regulates (Figure 22-3). From late M phase through the middle of G1, the Rb and E2F proteins are combined in a protein complex that is inactive