2 6. Cell Cycle and Cell Cycle Control 6.1 Phases of Cell Cycle 6.2 Special Apparatus of Mitosis6.2.1 Chromatin/ChromosomeChromatin DNAPacking of ChromatinNucleosome, histone codes, epigenetic phenomena6.2.2 Spindle
3 6.3 Cell Cycle Control 6.3.1 Core set of cell cycle control system 6.3.2 Cell cycle phases are triggered sequentially6.3.3 Check points in cell cycle6.3.4 proto-oncogene and tumor suppressor gene
4 6.1 Phases of Cell Cycle 6.1.1 Cell cycle The cell cycle is process from the end of a cell division to the start of the next cell division. Cell cycle entails an ordered series of macromolecular events that lead to cell division and the production of two daughter cells each containing chromosomes identical to those of the parental cell.
5 6.1.2 Phases of cell cycleThe primary events of a mammalian cell cycle are replication of chromosomes and their segregation to daughter cells with extraordinarily high fidelity.According to this, cell cycle can be divided into INTERPHASE which includes G1, S, G2 phase and DIVISION which is equal to M phase.M phase includes MITOSIS and CYTOKINESISG0 phase: not divides, perform particular functions, can return to the cell cycle when proper be stimulated.
10 6.2 Special Apparatus of Mitosis 6.2.1 Chromatin/Chromosome Chromatin DNA p228There are three kinds of sequence elements in a chromatin DNA1 centromere2 telomereSeveral replication origins
11 replication originsat which DNA polymerases and other proteins initiate synthesis of DNA.centromereattach any chromosome that contains it to mitotic spindle during M phase and guarantees the proper separation of chromosomes.telomerespermit a linear chromosome to be completely replicated.
22 histone codes, epigenetic phenomena Modification of histone influence chromatin structure participate in the regulation of transcription.(1) acetylation and deacetylation Lys-NH2 the greater the acetylation, the less chromatin condensation(2) methylation Lys-NH2, Arg a process that pevents acetylation(3) phosphorylation Ser and Thr hydroxy introducing a negative chargeEpigenetic: not depend on DNA sequence
37 6.3 Cell Cycle Control 6.3.1 Core set of cell cycle control system cyclincyclin dependent kinases, CDKscyclin dependent kinases inhibitors, CKIsanaphase promoting complex, APC
38 cyclin dependent kinase cyclin A~HG1 phase cyclincyclin C,D,E are only synthesized at G1 phase and degraded at S phaseS phase cyclincyclin A are only synthesized at G1 phase and degraded at M phaseM phase cyclincyclin B synthesized at S phase and degraded at the end of M phasecyclin dependent kinase
39 cyclin dependent kinases, CDKs a kind of protein kinases who will not be fully activated unless they are binding with cyclins and phosphorylated at proper residues at the same time.CDKs are constantly synthesized in the whole cell cycle but are selectively activated by different cyclins and promote the shift of cell cycle phases.Table p322,maturation promoting factor, MPF =CDK1+cyclinB, G2/M and M phaseSTART kinase, CDK4/6+cyclinD, G0/G1
40 cyclin dependent kinase inhibitors, CKIs Selectively inhibit the kinase activity of CDKs by binding to complex of CDKs and cyclinsp21, p27, p16anaphase-promoting complex, APCis a complex of several proteins which is activated during mitosis to initiate anaphase.The APC is an E3 ubiquitin ligase that marks target proteins, e.g. cyclinB and cyclinA, for degradation by the 26S proteasome. The irreversibility of proteolysis is utilized by cells to give the cell cycle directionality.
58 6.3.3 Checkpoints in cell cycle Cell cycle checkpoints exist at specific points in the cell cycle in eukaryotic cells to prevent them from progressing to the next phase of the cell cycle in the event of DNA damage or another condition which would make cell division dangerous for the cell.
59 There are 3 main checkpoints which control the cell cycle in eukaryotes. G1 checkpoint, Restriction pointG2 check pointM check pointG1 CheckpointThe first checkpoint is located at the end of the cell cycle's G1 phase, just before entry into S phase, making the key decision of whether the cell should divide, delay division, or enter a resting stage. Most cells stop at this stage and enter a resting state called G0. Liver cells for instance only enter mitosis around once or twice a year. The G1 checkpoint is where eukaryotes typically arrest the cell cycle if environmental conditions make cell division impossible or if the cell passes into G0 for an extended period. In animal cells, the G1 phase checkpoint is called the restriction point, and in yeast cells it is called the start point.G2 CheckpointThe second checkpoint is located at the end of G2 phase, triggering the start of the M phase (mitosis). In order for this checkpoint to be passed the cell has to check a number of factors to insure the cell is ready for mitosis. If this checkpoint is passed, the cell initiates the many molecular processes that signal the beginning of mitosis. The CDK's associated with this checkpoint are activated by the removal of an inactivating phosphate by the action of a "Maturation promoting factor" (MPF). The MPF activates the CDK in response to environmental conditions being right for the cell and allows the cell to begin DNA replication.Metaphase CheckpointThe third checkpoint is located during metaphase, triggering the exit from mitosis and cytokinesis and the beginning of cytokinesis. After the cell has split into its two daughter cells the cell enters G1.
63 tumor suppressor genes proto-oncogene 6.3.4 proto-oncogenes andtumor suppressor genesproto-oncogeneA normal gene which, when altered by mutation, becomes an oncogene that can contribute to cancer. Proto-oncogenes may play an important role in many essential physiological processes such as cell proliferation, cell death andWhat Are Oncogenes?Oncogenes are mutated forms of genes that cause normal cells to grow out of control and become cancer cells. They are mutations of certain normal genes of the cell called proto-oncogenes. Proto-oncogenes are the genes that normally control how often a cell divides and the degree to which it differentiates (or specializes). When a proto-oncogene mutates (changes) into an oncogene, it becomes permanently "turned on" or activated when it is not supposed to be. When this occurs, the cell divides too quickly, which can lead to cancer.It may be helpful to think of a cell as a car. For it to work properly, there need to be ways to control how fast it goes. A proto-oncogene normally functions in a way that is similar to a gas pedal -- it helps the cell grow and divide. An oncogene could be compared to a gas pedal that is stuck down, which causes the cell to divide out of control.The pathway for normal cell growth starts with growth factor, which locks onto a growth factor receptor. The signal from the receptor is sent through a signal transducer. A transcription factor is produced, which causes the cell to begin dividing. If any abnormality is detected, the cell is made to commit suicide by a programmed cell death regulator.More than 100 oncogenes are now recognized, and undoubtedly more will be discovered in the future. Scientists have divided oncogenes into the 5 different classes described below.Growth factors: These oncogenes produce factors that stimulate cells to grow. The best known of these is called sis. It leads to the overproduction of a protein called platelet-derived growth factor, which stimulates cells to grow.Growth factor receptors: These are normally turned "on" or "off" by growth factors. When they are "on," they stimulate the cell to grow. Certain mutations in the genes that produce these cause them to always be "on." In other cases, the genes are amplified. This means that instead of the usual 2 copies of the gene, there may be several extras, resulting in too many growth factor receptor molecules. As a result, the cells become overly sensitive to growth-promoting signals. The best known examples of growth factor receptor gene amplification are erb B and erb B-2. These are sometimes known as epidermal growth factor receptor and HER2/neu. HER2/neu gene amplification is an important abnormality seen in about one third of breast cancers. Both of these oncogenes are targets of newly developed anti-cancer treatments.Signal transducers: These are the intermediate pathways between the growth factor receptor and the cell nucleus where the signal is received. Like growth factor receptors, these can be turned on or off. When they are abnormal in cancer cells, they are turned on. Two well known signal transducers are abl and ras. Abl is activated in chronic myelocytic leukemia and is the target of the most successful drug for this disease, imatinib or Gleevec. Abnormalities of ras are found in many cancers.Transcription factors: These are the final molecules in the chain that tell the cell to divide. These molecules act on the DNA and control which genes are active in producing RNA and protein. The best known of these is called myc. In lung cancer, leukemia, lymphoma, and a number of other cancer types, myc is often overly activated and stimulates cell division.Programmed cell death regulators: These molecules prevent a cell from committing suicide when it becomes abnormal. When these genes are overactive they prevent the cell from going through the suicide process. This leads to an overgrowth of abnormal cells, which can then become cancerous. The most well described one is called bcl-2. It is often activated in lymphoma cells.As scientists learn more about oncogenes, they may be able to develop drugs that inhibit or stop them. Many agents that target oncogenes are currently in development as potential anticancer drugs, and some have already been approved by the US Food and Drug Administration (FDA) for clinical use, as we will discuss in more detail later on in this document.
64 tumor suppressor genes Tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, and tell cells when to die (a process known as apoptosis or programmed cell death). When tumor suppressor genes don't work properly, cells can grow out of control, which can lead to cancer.What Are Tumor Suppressor Genes?Tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, and tell cells when to die (a process known as apoptosis or programmed cell death). When tumor suppressor genes don抰 work properly, cells can grow out of control, which can lead to cancer. About 30 tumor suppressor genes have been identified, including p53, BRCA1, BRCA2, APC, and RB1. Some of these will be described in more detail later on.A tumor suppressor gene is like the brake pedal on a car – it normally keeps the cell from dividing too quickly just as a brake keeps a car from going too fast. When something goes wrong with the gene, such as a mutation, cell division can get out of control.An important difference between oncogenes and tumor suppressor genes is that oncogenes result from the activation (turning on) of proto-oncogenes, but tumor suppressor genes cause cancer when they are inactivated (turned off). Another major difference is that while the overwhelming majority of oncogenes develop from mutations in normal genes (proto-oncogenes) during the life of the individual (acquired mutations), abnormalities of tumor suppressor genes can be inherited as well as acquired.Types of Tumor Suppressor GenesGenes that control cell division: Some tumor suppressor genes help control cell growth and reproduction. The RB1 (retinoblastoma) gene is an example of such a gene. Abnormalities of the RB1 gene can lead to a type of eye cancer (retinoblastoma) in infants, as well as to other cancers. Because all our chromosomes are paired, there are always 2 copies of each gene. But the inherited RB1 mutation only affects one of the gene pairs. In this situation there is no cancer. The person has one good gene and one mutated one and is therefore said to be heterozygous for the trait coded into that gene pair. Then during the infant抯 development, a random mutation can occur in the normal copy of the RB1 gene. Scientists call this process loss of heterozygosity (LOH), and it applies to most abnormalities in tumor suppressor genes. As long as one copy of the gene is normal, no cancer develops. But when the other copy mutates, even in one cell, then cancer can start to develop. Evidently, these mutations occur often, but we are protected as long as one of the pair in the cell is normal.Genes that repair DNA: A second group of tumor suppressor genes is responsible for repairing DNA damage. Every time a cell prepares to divide into 2 new cells, it must duplicate its DNA. This process is not perfect, and copying errors sometimes occur. Fortunately, cells have DNA repair genes, which make proteins that proofread DNA. But if the genes responsible for the repair are faulty, then the DNA can develop abnormalities that may lead to cancer. When DNA repair genes don抰 work, mutations can slip by, allowing oncogenes and abnormal tumor suppressor genes to be produced. The genes responsible for HNPCC (hereditary nonpolyposis colon cancer) are examples of DNA repair gene defects. When these genes do not repair the errors in DNA, HNPCC can result. HNPCC accounts for up to 5% of all colon cancers and some endometrial cancers.Cell "suicide" genes: If there is too much damage to a cell抯 DNA to be fixed by the DNA repair genes, the p53 tumor suppressor gene is responsible for destroying the cell by a process sometimes described as "cell suicide." Other names for this process are programmed cell death or apoptosis. If the p53 gene is not working properly, cells with DNA damage that has not been repaired continue to grow and can eventually become cancerous. Abnormalities of the p53 gene are sometimes inherited, such as in the Li-Fraumeni syndrome (LFS). People with LFS have a higher risk for developing a number of cancers, including soft-tissue and bone sarcomas, brain tumors, breast cancer, adrenal gland cancer, and leukemia. Many sporadic (not inherited) cancers such as lung cancers, colon cancers, breast cancers as well as others often have mutated p53 genes within the tumor.