Transcript Cell Cycle
CELL DIVISION CYCLE Kanokporn Boonsirichai TWO TYPES OF CELL DIVISION Mitosis Chromosome number is preserved. Meiosis Chromosome number is reduced by half. MITOSIS MEIOSIS Meiosis does two things 1) Meiosis takes a cell with two copies of every chromosome (diploid) and makes cells with a single copy of every chromosome Crossing over (haploid). 2) Meiosis scrambles the specific forms of each gene that each sex cell (egg or sperm) receives. Independent assortment Crossing over CONTROL OF CELL CYCLE Figure 18-1 Essential Cell Biology (© Garland Science 2010) Prokaryote: Escherichia coli ~ 20 minutes PHASES OF THE CELL CYCLE Figure 18-2 Essential Cell Biology (© Garland Science 2010) CELL CYCLE CONTROL SYSTEM A timer/clock: when and how long A play list: ordering of event Preventions of repeats On/off switches Backup mechanisms Adaptibility/sensors CELL CYCLE CHECKPOINTS Cause the cell to become arrested at a specific point in the cell cycle, if previous events have not been completed Utilize negative signals What do you think might be the nature of the cell cycle control system? CYCLIN-CDK COMPLEXES Cdk (cyclin-dependent kinase): cyclically activated protein kinase Cyclin: switches Cdk on and off Figure 18-5 Essential Cell Biology (© Garland Science 2010) CYCLINCDK ACTIVITY AND CELL CYCLE wikipedia FOUR CLASSES OF CYCLINS G1 cyclins promote the cell through “Start” or restriction point in late G1 G1/S-cyclins bind Cdks at the end of G1 and commit the cell to DNA replication S-cyclins bind Cdks during S phase and are required for initiation of DNA replication M-cyclins promote the events of mitosis MAJOR CYCLINS AND CDKS CyclinCdk complex G1-Cdk Vertbrate Cyclin cyclin D Cdk Budding yeast Cyclin Cdk Cdk4, 6 Cln3 Cdk1 G1/S-Cdk cyclin E Cdk2 Cln1, 2 Cdk1 S-Cdk cyclin A Cdk2 Cln5, 6 Cdk1 M-Cdk cyclin B Cdk1 Cln1, 2, 3, 4 Cdk1 Figure 18-10 Essential Cell Biology (© Garland Science 2010) ACTIVATION OF CDKS Binding to cyclins Phosphorylation by Cdk-activating kinase (CAK) near the entrance of the active site Figure 18-9 Essential Cell Biology (© Garland Science 2010) INHIBITION OF CDK ACTIVITY Binding of cyclin-Cdk complexes by Cdk inhibitor proteins (CKI) Proteolysis of cyclin CELL CYCLE CHECKPOINTS At G1 checkpoint, cell decides whether to commit to another cell cycle. At each checkpoint, cell may be arrested if conditions are not favorable. Figure 18-12 Essential Cell Biology (© Garland Science 2010) THE S PHASE Active S-Cdk Initiation of DNA replication Prevention of rereplication INITIATION OF DNA REPLICATION REGULATION AT THE ORIGIN OF DNA REPLICATION S-Cdk allows DNA replication to initiate. PREVENTION OF RE-REPLICATION Cdc6 Mcm S-Cdk M-Cdk S-Cdk M-Cdk Cdc6 Mcm Ubiquityl ation by SCF Export from the nucleus THE M PHASE Chromosome separation Figure 18-17 Essential Cell Biology (© Garland Science 2010) ROLES OF M-CDK IN MITOSIS Induces the assembly of the mitotic spindle Ensures that replicated chromosomes are attached to the spindle Triggers chromosome condensation, nuclear envelope breakdown, actin rearrangement, reorganization of Golgi apparatus and ER POSITIVE FEEDBACK LOOP Figure 18-18 Essential Cell Biology (© Garland Science 2010) Positive feedback loop allows for commitment to a cell cycle event. SPINDLE-ATTACHMENT CHECKPOINT Ensures that all chromosomes are properly attached to the mitotic spindle before sisterchromatid separation occurs Unattached kinetochores send out a negative signal that blocks activation of Cdc20-APC complex Binding of Mad2 to unattached kinetochore, leading to inhibition of Cdc20-APC and securin degradation Exit from Mitosis Figure 18-29 Essential Cell Biology (© Garland Science 2010) CREATION OF G1 PHASE Destruction of M-cyclin at the end of mitosis leads to: inactivation of Cdc20-APC activation of Hct1-APC activation of Sic1 CKI decrease in the transcription of M cyclin gene TRANSITION THROUGH START Extracellular signals cause an accumulation of G1 cyclin (not sensitive to Hct1-APC and Sic1) G1-Cdk stimulates transcription of G1/S cyclin gene G1/S-Cdk stimulates transcription of S-cyclin gene CONTROL OF S-PHASE INITIATION CELL GROWTH AND CELL CYCLE PROGRESSIO N MONITORING OF CELL CYCLE PROGRESSION Cln3, the budding yeast G1 cyclin, is synthesized in parallel to cell growth Cells may inherit a fixed amount of inhibitor that binds Cln3 DNA DAMAGE CHECKPOINTS Checkpoint in late G1 prevents entry into S phase Checkpoint in late G2 prevents entry into mitosis G1 CHECKPOINT DNA damage leads to the activation of p53, a gene regulatory protein p53 stimulates expression of many genes including a CKI called p21, which binds G1/S-Cdk and S-Cdk G2 CHECKPOINT Damaged DNA sends signals to inactivate Cdc25. X Figure 18-17 Essential Cell Biology (© Garland Science 2010) X CONTROL OF THE CELL CYCLE PROGRAMMED CELL DEATH FUNCTION OF APOPTOSIS To eliminate damaged cells Is an essential part of development in multicellular organisms Balances cell division to regulate tissue/organ size Necrotic cells Apoptotic cells CASPASE CASCADE Caspase is a class of proteases Contain cysteine at their active site Cleave at specific aspartic acid residue EXTRACELLULAR CONTROL OF CELL DIVISION EXTRACELLULAR SIGNALS Mitogens: stimulates cell division by relieving intracellular negative control Growth factors: stimulates cell growth by promoting synthesis of proteins and other macromolecules and inhibiting their degradation Survival factors: promotes cell survival by suppressing apoptosis PDGF: PLATELET-DERIVED GROWTH FACTOR Functions as a mitogen Secreted by platelet cells to stimulate cell division during wound healing Can act on multiple cell types: fibroblasts, neuroglial cells, smooth muscle cells MITOGEN SIGNALING PATHWAY (THROUGH GTPASE RAS AND MAP KINASES) OVERACTIVE MITOGENIC SIGNAL RESULTS IN CELL CYCLE ARREST OR APOPTOSIS REPLICATIVE CELL SENESCENCE Fibroblasts from normal human tissues can only go through 25-50 population doubling when cultured in standard mitogenic medium GROWTH FACTOR SIGNALING PATHWAY PI 3-kinase phosphorylates inositol phospholipid in the membrane activating S6 kinase which activates components of translational machinery NERVE CELLS GROWTH AND APOPTOSIS Nerve growth factor (NGF) Survial factors are produced in limited amount SURVIVAL FACTOR SIGNALING PATHWAY ANCHORAGE-DEPENDENT CELL DIVISION Cells are growth over non-adhesive substratum with or without a patch of adhesive palladium, fed with 3H-thymidine and autoradiographed. Integrins (cell surface matrix receptors) interact with laminin and/or fibronectin (extracellular matrix molecules, leading to activation of FAK (focal adhesion kinase) and signaling pathways that promote cell survival, growth and division Actin is labeled in green and proteins with phosphotyrosines are labeled in red EXTRACELLULAR NEGATIVE SIGNAL PROTEINS TGF-b signal proteins inhibit the proliferation of many cell types (blocking progression through G1 or stimulating apoptosis) BMP (bone morphogenetic protein) triggers apoptosis of cells between developing digits of a mouse paw EXTRACELLULAR NEGATIVE SIGNAL PROTEINS Myostatin inhibits proliferation of myoblasts that fuse to form muscle cells Mutations in myostatin gene can cause an increase in muscle cell size and number Through the control of total cell mass Salamanders of CONTROL OF BODY SIZE different ploidy levels hindbrain are of the same body size But their cell size and cell number are different Haploid Kidney tubules Tetraploid QUESTION Describe a mechanism by which Cdk is activated during the cell cycle.