Regulation of the Cell Cycle Chapter 12 Pg. 228 245 Functional Limitations Various factors determine whether and when a cell divides. Two functional limitations for cell size limit growth or influence the start of a new cell division based on Surface-to-volume ratio (S/V) Genome-to-volume ratio (G/V) Surface-to-Volume Ratio (S/V) When a cell grows, the volume of a cell increases faster than the surface area of the plasma membrane enclosing it. This is because volume increases by the cube of the radius, whereas the surface area increases only by the square of the radius. When S/V is large, the surface area is large relative to the volume. Under these conditions, the cell can efficiently react with the outside environment. For example, adequate amounts of oxygen for respiration can diffuse into the cell, and waste products can be rapidly eliminated. When S/V is small, the surface area is small compared to the volume. When this occurs, the surface area might be unable to exchange enough substances with the outside environment to service the large volume of the cell. At this point, cell growth stops or cell division begins. Genome-to-Volume Ratio (G/V) The genetic material (chromosomes) in the nucleus, collectively called its genome, controls the cell by producing substances that make enzymes and other biosynthetic substances. These substances, in turn, regulate cellular activities. The capacity of the genome to do this is limited by its finite amount of genetic material. As the cell grows, its volume increases, but its genome size remains constant. As the G/V decreases, the cell s size exceeds the ability of its genome to produce sufficient amounts of materials for regulating cellular activities. Internal Regulation At the molecular level, the cell cycle is strictly controlled by various signal molecules within the cell. These signals respond to internal factors, insuring that the necessary steps in the cell cycle have been accurately completed before going on to the next step in the cell Methods of internal regulation include Checkpoints Cyclin-dependent kinases (Cdks) 1
Checkpoints At specific points during the cell cycle, the cell evaluates internal and external conditions to determine whether or not to continue through the cell The three checkpoints are: G 1 checkpoint G 2 checkpoint M checkpoint G 1 Checkpoint Occurs near the end of the G 1 phase. Also called the restriction point (R) the most important checkpoint in mammals. The quality of DNA is evaluated: If DNA damage is detected, DNA repair is attempted. If that fails, apoptosis (program for selfdestruction) ensues. If nutrients or growth factors are absent, the cell proceeds no further through the cell cycle, remaining in an extended G 1 phase until conditions are appropriate. Some cells, like nerve or muscle cells, are genetically programmed not to divide, and remain in a G 0 phase, rarely dividing after they have matured. Liver cells, on the other hand, can leave the G 0 phase and return to dividing if they need to replace injured liver tissue. G 2 Checkpoint Occurs at the end of the G 2 phase of the cell cycle Evaluates the accuracy of DNA replication and signals whether or not to begin mitosis If DNA damage is detected, DNA repair is attempted. If repair is unsuccessful, apoptosis ensues. M Checkpoint Occurs during metaphase Ensures microtubules are properly attached to all kinetochores at the metaphase plate before division continues with anaphase Cyclin-Dependent Kinases (Cdks) Cdks are proteins responsible for advancing the cell past the checkpoints and through the cell They have the following attributes: Cdks are kinases, which are enzymes that phosphorylate other proteins. Once phosphorylated, the protein is energized and ready to act. Proteins can be inactivated by dephosphorylation or by destruction by other enzymes. 2
Cdks are activated by cyclins, which are proteins that attach to Cdks, altering their conformation and readying them for activation. Complete activation requires phosphorylation. Without a cyclin attached, a Cdk is inactive (that s why it s described as cyclin-dependent). Mitosis-promoting factor (or maturation-promoting factor) (MPF) is a cyclin-cdk complex that advances the cell cycle through the G 2 checkpoint. Each checkpoint has its own combination of a specific Cdk and a specific cyclin that advances the cell cycle through the checkpoint. How Cdks Work Concentrations of different cyclins vary ( cycle ) during the cell cycle with a regular pattern. As the cell cycle approaches each checkpoint, a specific cyclin combines with a specific Cdk. The conformation change that results unblocks an active site on the Cdk, readying it for activation. If checkpoint conditions are met, the Cdk is activated, often by phosphorylation, and the activated cyclin-cdk complex initiates activity that advances the cell cycle through the checkpoint. Once through the cycle phase, the cyclins are destroyed and new cyclins, specific for the next checkpoint, begin to accumulate. External Regulation Various external factors also influence the cell cycle: Growth factors. The plasma membranes of cells have receptors for growth factors that stimulate a cell to divide. For example, when platelets encounter damaged tissue, they release platelet-derived growth factor (PDGF), which binds to the plasma membrane of fibroblasts (a connective tissue) and stimulates its cell division. The new fibroblasts contribute to the healing of damaged tissue. More than 50 different growth factors are known. Density-dependent inhibition. Many cells stop dividing when the surrounding cell density reaches a certain maximum. Anchorage dependence. Most cells only divide when they are attached to an external surface, such as the flat surface of a neighboring cell (or the side of a culture dish). Apoptosis Cells that are infected, damaged, or simply have come to the end of their life span die by apoptosis, a genetically programmed series of events that result in cell death. During this process, the DNA, organelles, and other cytoplasmic components are chopped up. The parts are packaged in vesicles that are engulfed by special scavenger cells. 3
Why Apoptosis? Embryonic development when cells are no longer needed, they die and are engulfed. Think about the tail of a tadpole! Genetic damage the cell sacrifices itself to prevent the spread of mutated DNA/cells (cancer). This is common for epithelial cells exposed to extensive solar radiation (sunburn). Defense against infection in plants fungus and bacterial infections will result in apoptosis to prevent their spread. Caspase pathways in mammals, enzymes called caspases cause apoptosis. The trigger may be from a neighboring cell, inside the cell itself (if it is damaged), or from the endoplasmic reticulum where excessive protein misfolding has occurred. Cancer Characterized by uncontrolled cell growth and division. Transformed cells, cells that have become cancerous, proliferate without regard to cell cycle checkpoints, density-dependent inhibition, anchorage dependence, and other regulatory mechanisms. Thus, cancer is a disease of the cell Transformation Transformation is the process that converts a normal cell to a cancer cell. A tumor is a mass of abnormal cells within otherwise normal tissues. If the abnormal cells remain at the original site, the lump is called a benign tumor. A malignant tumor becomes invasive enough to impair the functions of one or more organs. An individual with a malignant tumor is said to have cancer. Metastasis occurs when cells separate from a malignant tumor and enter blood or lymph vessels and travel to other parts of the body. Cancer and Genes Oncogenes are cancer-causing genes. Proto-oncogenes are genes that code for proteins that are responsible for normal cell growth. They become oncogenes when a mutation occurs that causes an increase in the product of the protooncogene, or an increase in the activity of each protein molecule produced by the gene. Cancer can also be caused by a mutation in a gene whose products normally inhibit cell division. These genes are called tumorsuppressor genes. An important tumor suppressor gene is the p53 gene. The product of this gene is a protein that suppresses cancer in four ways. 4
p53 The p53 protein can activate the p21 gene, whose product halts the cell cycle by binding to cyclin-dependent kinases. This allows time for DNA to be repaired before the resumption of cell division. The p53 protein activates a group of mirnas (micro RNA), which inhibit the cell The p53 protein turns on genes directly involved in DNA repair. When DNA damage is too great to repair, the p53 protein activates suicide genes whose products cause cell death, a process termed apoptosis. More on Cancer The multistep model of cancer development is based on the idea that cancer results from the accumulation of mutations that occur throughout life. The longer we live, the more mutations that are accumulated and the more likely that cancer might develop. Embryonic development represents what happens when gene regulation proceeds correctly; cancer shows what can happen when gene regulation goes awry. Treating Cancer Surgery: removes tumors and cancerous cells Chemotherapy: targets rapidly dividing cells with chemical compounds that have a number of functions Stop DNA replication Stops mitosis and cytokinesis Stops blood vessel growth High-energy radiation: kills rapidly dividing cells How does it still manage to come back sometimes? All it takes is a single cancerous cell left over to cause a recurrence of the disease. 5