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Transcript
Chapter 15 Regulation of Cell Number Normal and Cancer Cells • The cell proliferation machinery • Programmed cell death (apoptosis) • Controlling cell proliferation and apoptosis • Cancer: genetics of aberrant cell control Apoptosis in Drosophila embryo A) Wild-type, bright spots indicate cells that undergo cell apoptosis B) Mutant which is defective for programmed cell death Various combinations (complexes) of cyclins and CDKs act through the cell cycle Cell proliferation Cyclins and cyclin-dependent protein kinases are important for cell cycle control Cyclins and Cyclin-Dependent Protein Kinases The 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-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 cell cycle-controlled transcription, in which the previously active cyclin-CDK 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 this cyclin's 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 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 phosphorylation of specific serine and threonine residues of specific target proteins. CDK targets How 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 factors. 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 and from biochemical studies of cultured mammalian cells. A wellunderstood example is the Rb-E2F pathway in mammalian cells. Rb is the target protein of a CDK-cyclin complex called Cdk2-cyclin A, and E2F is the transcription factor that Rb regulates. From late M phase through the middle of G1, the Rb and E2F proteins are combined in a protein complex that is inactive in promoting transcription. In late G1, the Cdk2-cyclin A complex is produced and phosphorylates the Rb protein. This phosphorylation produces a change in the shape of Rb such that it can no longer bind to the E2F protein. The free E2F protein is then able to promote transcription of certain genes that encode enzymes vital for DNA synthesis. This allows the next phase of the cell cycle (S phase) to proceed. Rb and E2F are in fact representatives of two families of related proteins. In mammals, different cyclin- CDK complexes are thought to selectively phosphorylate different proteins of the Rb family, each of which in turn releases the specific E2F family member to which it is bound. The different E2F transcription factors then promote the transcription of different genes that execute different aspects of the cell cycle. Message Sequential activation of different CDK-cyclin complexes ultimately controls progression of the cell cycle. Yeast as a model for the cell cycle The cell cycle of the budding yeast Saccharomyces cerevisiae. The scanning electron micrograph shows cells at different points in the cell cycle, as indicated by different bud sizes. The principal events in the cell cycle are shown. The Apoptosis Pathway In multicellular organisms, systems have evolved to eliminate damaged (and, hence, potentially harmful) cells through a self-destruct and disposal mechanism: programmed cell death, or apoptosis. This selfdestruct mechanism can be activated under many different circumstances. Regardless, the events in apoptosis seem to be the same. First, there is fragmentation of the DNA of the chromosomes, disruption of organelle structure, and loss of normal cell shape (apoptotic cells become spherical). Then, the cells break up into small cell fragments called apoptotic bodies that are phagocytosed (literally, eaten up) by motile scavenger cells. The role of caspases in apoptosis. A cascade of caspase activation leads to the activation of the executioner caspases. Cleavage of the zymogen (inactive precursor) form of the executioner caspase by another caspase takes place at several aspartate residues, producing several protein fragments. Two of these fragments, the large and small subunits, bind and form the enzymatically active caspase. Through cleavage of a series of target proteins (also by cleavage at aspartate residues in the target proteins), the various cellular breakdown events take place, leading to cell death and removal. Caenorhabiditis elegans as a model for programmed cell death Controlling cell proliferation and apoptosis The control can be exerted by intracellular and extracellular signals. Both positive and negative control loops exist. Intracellular signalling An example of negative control of cell cycle progression. In mammals, the transition from the G1 to S phase requires the phosphorylation of Rb protein by the CDK2-cyclin complex. In the presence of damaged DNA, p53 protein is induced, which in turn induces p21 protein.The elevated levels of p21 protein inhibit the protein kinase activity of the CDK2-cyclin complex. When the damaged DNA has been repaired, p53 levels drop. In turn, p21 levels decrease, and the inhibition of the CDK2-cyclin protein kinase activity is relieved, which allows Rb to be phosphorylated and E2F to become an active transcription factor, permitting the cell to enter S phase. Extracellular signals A cell in a multicellular organism continually assesses its own internal status regarding proliferation and survival. Nonetheless, the proliferative and survival abilities of a cell must be subservient to the needs of the population of cells of which it is a member (populations such as the entire early embryo, a tissue, or a body part such as a limb or an organ). For example, in many adult organs, stem cells divide to produce replacement cells only when there is a depletion of cell numbers. Without such homeostatic mechanisms, organs would not be proportioned appropriately for the size of a given individual organism. Mechanisms for cell-cell communication. Many kinds of signals need to be transmitted between cells to coordinate virtually all aspects of the development and physiology of complexmulticellular organisms. The major routes of cell-cell communication are briefly outlined here. All systems for intercellular communication have several components. A molecule called a ligand is produced by secretion from signaling cells. Some ligands, called hormones, are longrange endocrine signals that are transmitted throughout the body by being released from endocrine organs into the circulatory system. Hormones can act as master control switches for many different tissues, which can then respond in a coordinated fashion. Other secreted ligands act as paracrine signals; that is, they do not enter the circulatory system but act only locally, in some cases only on immediately adjacent cells. We shall have more to say about paracrine and endocrine signals in Chapter 16. Some ligands are proteins, whereas others are small molecules such as steroids or vitamin D. Most (but not all) endocrine signals are small molecules, such as the mammalian steroid hormones that are responsible for male (androgen) or female (estrogen) sex-specific phenotypes. In contrast, most paracrine signals are proteins. Here we focus on paracrine signaling through protein ligands. Modes of intercellular signaling. (a) Endocrine signals enter the circulatory system and can be received by distant target cells. (b) Paracrine signals act locally and are received by nearby target cells. Examples of transmembrane receptors. (a) A receptor that passes through the cell membrane seven times. (b) Receptor tyrosine kinase RTK), which has a single transmembrane domain. The extracellular domain binds to ligand. The active site of the tyrosine kinase is in the cytoplasmic domain. The consequences of ligand binding on RTK activity and the initiation of the signal transduction cascade. On dimerization of the RTK, autophosphorylation occurs. The ability of activated RTK to initiate signal transduction is through two different routes: (a) by the activated RTK serving as an anchor site for some signal transduction proteins and (b) by the activated RTK phosphorylating other proteins. An example of the G-protein activity cycle. Ras is a member of the G-protein family. When Ras binds GDP, it does not signal. Through direct interactions with Ras, another protein called Sos causes conformational changes in Ras so that it preferentially binds GTP. The Ras-GTP complex is able to interact in turn with a cytoplasmic serine/threonine kinase, activating its kinase activity, and thus transmits the signal to the next step in the signal transduction pathway. When Ras-GTP is released from Sos, it hydrolyzes GTP to GDP and reassumes the inactive Ras-GDP state. One pathway for RTK signaling. Raf, MEK, and MAP kinase are three cytoplasmic protein kinases that are sequentially activated in the signal transduction cascade. Positive extracellular control of apoptosis. A molecule such as Apaf is activated through binding of FasL (Fas ligand), anchored on the outside of an adjacent cell. FasL binds to the Fas transmembrane receptor on the cell that will undergo apoptosis. Apaf activation in turn causes proteolysis and activation of the initiator caspase. A series of caspases are then proteolysed and activated in turn, ultimately leading to apoptosis of the cell. The inputs into control of cell number Cancer: genetics of aberrant cell control Message Tumors arise through a series of sequential mutational events that lead to a state of uncontrolled proliferation. The Relations between Function of the Wild-Type Protein Product and the Types of Tumor-Promoting Mutations That Can Arise in the Genes Encoding Those Products Type of wild-type protein function Properties of tumor-promoting mutations Promotes cell cycle progression Oncogene (gain of function) Inhibits cell cycle progression mutierte Tumor-suppressor gene (loss of function) Promotes apoptosis mutierte Tumor-suppressor gene (loss of function) Inhibits apoptosis Oncogene (gain of function) Promotes DNA repair Tumor-suppressor gene (loss of function) Oncogenes and mutated Tumor-suppressor genes Two general kinds of mutations are associated with tumors: oncogene mutations and mutations in tumor-suppressor genes. Oncogenes are mutated alleles of proto-oncogenes. Proto-oncogenes are positive regulators of the cell cycle. Oncogenes are mutated in such a way that the proteins that they encode are activated in tumor cells; they usually represent dominant mutant alleles. A tumor cell will typically be heterozygous for an oncogene mutation and its normal allelic counterpart, the proto-oncogene. Mutated Tumor-suppressor genes are mutated alles of negative regulators (for example p53) of the cell cycle. They can represent dominant or recessive alleles. For recessive mutations, the tumor cell will lack any copy of the corresponding wild-type allele. The p53 tumor-suppressor gene a link between cell cycle and apoptosis A very important recessive tumor-promoting mutation has identified the p53 gene as a tumorsuppressor gene. Mutations in p53 are associated with many types of tumors, and estimates are that more than 50 % of human tumors lack a functional p53 gene. The active p53 protein is a transcriptional regulator that is activated in response to DNA damage. Activated wildtype p53 serves double duty, preventing progression of the cell cycle until the DNA damage is repaired and, under some circumstances, inducing apoptosis. In the absence of a functional p53 gene, the p53 apoptosis pathway does not become activated, and the cell cycle progresses even in the absence of DNA repair. This progression elevates the overall frequency of mutations, The Ras oncoprotein. (a) The ras oncogene differs from the wild type by a single base pair, producing a Ras oncoprotein that differs from the wild type in one amino acid, at position 12 in the ras open reading frame. (b) The effect of this missense mutation is to create a Ras oncoprotein that cannot hydrolyze GTP to GDP. Because of this defect, the Ras oncoprotein remains in the active Ras-GTP complex and continuously activates the down-stream serine/threonine kinase Messages Oncogenes encode oncoproteins‚ deregulated forms of proteins whose wild-type function is to participate in the positive control of the cell cycle or in the negative control of apoptosis. Dominant oncogenes contribute to the oncogenic state by causing a protein to be expressed in an activated form or in the wrong cells (ectopic expression). Retinoblastoma, a cancer of the retina. The mutational origin of retinal tumors in hereditary and sporadic retinoblastoma. Recessive rb alleles of the RB gene lead to tumor development. The major pathways that are mutated to contribute to cancer formation and progression. The main events that contribute to tumor formation are increased cell proliferation and cell survival (decreased apoptosis). The pathways in red are susceptible to gain-of-function oncogene mutation. The pathways in blue are susceptible to loss-of-function tumorsuppressor gene mutation.