Molecular Biology of the Cell Textbook - Chapter 17: The Cell Cycle PDF

Molecular Biology of the Cell Sixth Edition Chapter 17 The Cell Cycle  OVERVIEW OF THE CELL CYCLE OVERVIEW THE CELL-CYCLE CONTROL SYSTEM S PHASE MITOSIS CYTOKINESIS MEIOSIS CONTROL OF CELL DIVISION AND CELL GROWTH  OVERVIEW OF THE CELL CYCLE Introduction – Chromosome...

Molecular Biology of the Cell Sixth Edition Chapter 17 The Cell Cycle  OVERVIEW OF THE CELL CYCLE OVERVIEW THE CELL-CYCLE CONTROL SYSTEM S PHASE MITOSIS CYTOKINESIS MEIOSIS CONTROL OF CELL DIVISION AND CELL GROWTH  OVERVIEW OF THE CELL CYCLE Introduction – Chromosome duplication occurs during S phase (S for DNA synthesis), which requires 10~12 hrs and occupies about half of the cell-cycle time – After S phase, chromosome segregation and cell division occur in M phase (M for mitosis), which requires much less time (less than a hour) – M phase comprises two major events: nuclear division, or mitosis, during which the copied chromosomes are distributed into a pair of daughter nuclei; and cytoplasmic division, or cytokinesis, when the cell itself divides in two (figure 2) Introduction The condensation begins in early M phase to serve at least two purposes - disentangle (풀다) sister chromatids to lie side by side so that they can easily separate - protect fragile DNA from being broken as they are pulled to separate (from Chapter 4) The Eukaryotic Cell Cycle Usually Consists of Four Phases Each DNA Molecule That Forms a Linear Chromosome Must Contain a Centromere, Two Telomeres, and Replication Origins  OVERVIEW OF THE CELL CYCLE The Eukaryotic Cell Cycle Consists of Four Phases – Most cells require much more time to grow and double proteins and organelles than duplicate their chromosomes and divide – To allow time for growth, most cell cycles have gap phases – a G1 phase between M and S phase and a G2 phase between S phase and mitosis (figure 4) – G1, S, and G2 together are called interphase – In a typical human cell, interphase might occupy 23 hours of a 24-hour cycle, with 1 hour of M phase – Cell growth occurs throughout the cell cycle, except during mitosis  OVERVIEW OF THE CELL CYCLE The Eukaryotic Cell Cycle Consists of Four Phases – The G1 phase is especially important in monitoring the internal and external environment before the cell commits itself to S phase – Facing unfavorable conditions, cells delay progress through G1 and enter a specialized resting state known as G0 – Many cells remain permanently in G0 until they or the organism dies  THE CELL-CYCLE CONTROL SYSTEM The Cell-Cycle Control System Triggers the Major Events of the Cell Cycle – In most eukaryotic cells, the cell-cycle control system governs cell-cycle progression at three major regulatory transitions – The first is Start (G1/S transition) where the cell commits to cell-cycle entry and chromosome duplication; the second is the G2/M transition where the control system triggers the mitotic events; the third is the metaphase-to-anaphase transition where sister-chromatid separation is stimulated, leading to the completion of mitosis and cytokinesis (figure 9) The Cell-Cycle Control System Triggers the Major Events of the Cell Cycle  THE CELL-CYCLE CONTROL SYSTEM The Cell-Cycle Control System Depends on Cyclically Activated Cyclin-Dependent Protein Kinases (Cdks) – Cdk activities rise and fall as the cell progresses through the cycle – Cyclical changes in Cdk activity are controlled primarily by cyclins and Cdk-activating kinases (CAKs) The Cell-Cycle Control System Depends on Cyclically Activated Cyclin-Dependent Protein Kinases (Cdks) I (form during Cinitiate methto G2 nhignaciea (2) anaphase > - trigger PNA rep. -trigger I mitosis and ↳ Cdk unc. Ko do (him cyclin doi (live graph) Tcyclin conc. through start trigger  THE CELL-CYCLE CONTROL SYSTEM The Cell-Cycle Control System Depends on Cyclically Activated Cyclin-Dependent Protein Kinases (Cdks) – G1/S-cyclins activate Cdks in late G1 and thereby help trigger progression through Start (figure 11) – S-cyclins bind Cdks soon after progression through Start and help stimulate chromosome duplication. S- cyclin remains elevated until mitosis contributing to the control of some early mitotic events (figure 11) – M-cyclins activate Cdks that stimulate entry into mitosis at the G2/M transition (figure 11) – G1-cyclins (not shown in Figure 11) help govern the activities of the G1/S cyclins The Cell-Cycle Control System Depends on Cyclically Activated Cyclin-Dependent Protein Kinases (Cdks) The Cell-Cycle Control System Depends on Cyclically Activated Cyclin-Dependent Protein Kinases (Cdks) Cyclin D = G1-cyclin +CDK4/6 = G1-CDK Cyclin E = G1/S-cyclin Cyclin A +CDK2 = G1/S-CDK Cyclin B = M-cyclin + CDK 1 Cyclin A = S-cyclin +CDK2 = S-CDK  THE CELL-CYCLE CONTROL SYSTEM Cdk Activity Can Be Suppressed By Inhibitory Phosphorylation and Cdk Inhibitor Proteins (CKIs) (by CAK)  THE CELL-CYCLE CONTROL SYSTEM Cdk Activity Can Be Suppressed By Inhibitory Phosphorylation and Cdk Inhibitor Proteins (CKIs) bind to both cyclin + cdk - distort active ↳ site + insert into ATP-binding site  16 (ckIs in mammals) 21 * p27 , , G1-CDK G1/S-CDK CKIS S-CDK M-CDK  THE CELL-CYCLE CONTROL SYSTEM Regulated Proteolysis Triggers the Metaphase-to- Anaphase Transition – Unlike the Start and G2/M transitions, progression through the metaphase-to-anaphase transition is triggered not by phosphorylation but by destruction – Anaphase-promoting complex (APC/C) is the key regulator, whose main targets for destruction include Securin, whose destruction activates a protease that separates the sister chromatids (figure 38) S- and M-cyclins (figure 15A) The APC/C Triggers Sister-Chromatid Separation and the Completion of Mitosis Regulated Proteolysis Triggers the Metaphase-to-Anaphase Transition ① recognized - gar ubiquitin chain ↑ ~ The Cell-Cycle Control System Functions as a Network of Biochemical Switches  THE CELL-CYCLE CONTROL SYSTEM The Cell-Cycle Control System Functions as a Network of Biochemical Switches – Table 2 summarizes some of the major components of the cell-cycle control system – Summary of the cell-cycle control system (figure 16) The Cell-Cycle Control System Functions as a Network of Biochemical Switches Nuclear receptor RTK (MAPK) cyclin-independent regulation E2F S-Cdk Initiates DNA Replication Once Per Cycle S-Cdk activation also prevents assembly of new preRCs at any origin until the following G1-thereby ensuring that each origin is activated only once : this is why S-Cdk remains active until early M  S PHASE S-Cdk Initiates DNA Replication Once Per Cycle – Every nucleotide in the genome must be replicated only once to prevent the damaging effects of gene amplification – In early G1, DNA helicases are loaded onto the replication origin forming the pre-replicative complex (preRC) – In S phase, S-Cdk activation leads to the activation of the helicases and the two replication forks move out from each origin (figure 17) – At the end of mitosis, APC/C activation leads to the inactivation of S-Cdks, allowing preRC to be reassembled  MITOSIS M-Cdk Drives Entry Into Mitosis – One of the most remarkable features of cell cycle control is that a single protein, M-Cdk, brings about all of the diverse processes in the early stages of mitosis: assembly of the mitotic spindle, attachment of each sister chromatid to the spindle, chromosome condensation, breakdown of the nuclear envelope, etc. – M-Cdk is regulated by M-cyclin, CAK, Wee1, and Cdc25, forming positive feedback, quickly promoting the activation of all M-Cdk molecules in the cell (figure 20) (by CAK) Dephosphorylation Activates M-Cdk at the Onset of Mitosis (by CAK)  MITOSIS The Mitotic Spindle Is a Microtubule-Based Machine – Mitotic spindle, a bipolar array of microtubules, pulls sister chromatids apart – The plus ends of the microtubules project away from the spindle pole, while the minus ends are anchored at the spindle pole  MITOSIS The Mitotic Spindle Is a Microtubule-Based Machine – Mitotic spindle, a bipolar array of microtubules, pulls sister chromatids apart – The plus ends of the microtubules project away from the spindle pole, while the minus ends are anchored at the spindle pole – Kinetochore microtubules connect the spindle poles with the kinetochores of sister chromatids, while interpolar microtubules from the two poles interdigitate (깍지끼다, 맞물리다) at the spindle Fagintag equator. Astral microtubules radiate out from the poles into the cytoplasm (figure 23) nei The Mitotic Spindle Is a Microtubule-Based Machine Microtubule-Dependent Motor Proteins Govern Spindle Assembly and Function Kinesin-5 pushes the centrosomes apart ria cell ↑ Dyneins pull the spindle poles toward the cell cortex and away from each other : promote centrosome separation and increase spindle length (( · Kinesin-14 pulls the poles together : it is not clear how the cell regulates the balance of opposing forces Kinesin-4,10 pushes the attached chromosome away from the pole  MITOSIS Microtubule-Dependent Motor Proteins Govern Spindle Assembly and Function – The function of the microtubule depends on numerous microtubule-dependent motor proteins: kinesin-related proteins, which usually move O toward the plus end of microtubules O end dyneins, which move toward the minus – Four major types of motor proteins – kinesin-5, kinesin-14, kinesin-4/10, and dynein – are particularly important in spindle assembly and function (figure 25) – M-Cdk and other mitotic protein kinases are required for centrosome separation and maturation. M-Cdk and Aurora-A phosphorylate kinesin-5 and stimulate them to drive centrosome separation. Bi-orientation Is Achieved by Trial and Error  MITOSIS Bi-orientation Is Achieved by Trial and Error – The success of mitosis demands that sister chromatids in a pair attach to opposite poles of the mitotic spindle, so that they move to opposite ends of the cell – How is bi-orientation achieved? – Incorrect attachments are corrected by a system of trial and error. How does the kinetochore sense a I correct attachment? (figure 33) – The tension-sensing mechanism depends on the protein kinase Aurora-B (figure 34) Bi-orientation Is Achieved by Trial and Error figure 31 ↓ Phosphorylate binding > - unstable ↳ not phosphorylated 12microtubul - - entsite away from each other  MITOSIS The APC/C Triggers Sister-Chromatid Separation and the Completion of Mitosis – After M-Cdk has triggered the complex processes leading up to metaphase, the cell cycle reaches its climax with the separation of the sister chromatids at the metaphase-to-anaphase transition – Although M-Cdk activity sets the stage, the activated APC initiates the sister-chromatid separation by activating separase, which cleaves cohesins (figure 38, 19) The APC/C Triggers Sister-Chromatid Separation and the Completion of Mitosis carescos Cohesins Hold Sister Chromatids Together Cohesin -  MEIOSIS Meiosis Includes Two Rounds of Chromosome Segregation – figure 53 Meiosis Includes Two Rounds of Chromosome Segregation Haploid vs diploid Homolog Segregation Depends on Several Unique Features of Meiosis I ~ @ centromere: giunguyen As & farms : cleared (A1) ↑attachte from microtubule same I  MEIOSIS Homolog Segregation Depends on Several Unique Features of Meiosis I – Two sister kinetochores in one homolog must attach to the same spindle pole, which is normally avoided during mitosis (figure 58) – Crossover generates physical linkage between homologs, much like cohesin holding sister chromatids (figure 58) – Cohesin is removed in anaphase I only from chromosome arms and not from centromeres (figure 58). While APC/C-activated separase cleaves cohesins along the arms, cohesins near the Es centromeres are protected by a kinetochore- associated protein called shugoshin  MEIOSIS Crossing-Over Is Highly Regulated DSB : double-strand break – Crossing-over helps hold homologs together and contributes to genetic diversification – Crossing-over is highly regulated: the number and location of DSBs along each chromosome, as well as the likelihood that a break will be converted into a cross-over, is controlled – On average, the result of this regulation is that each pair of homologs is linked by about two or three crossovers I homologs pair – Although DSBs can occur almost anywhere along the chromosome, they are not distributed uniformly; they cluster at hot spots, where the DNA is accessible, and occur only rarely in cold spots, such as heterochromatin around centromeres and telomeres  CONTROL OF CELL DIVISION AND CELL GROWTH Introduction – Organ and body size (cell number and size) are determined by three processes: cell growth, cell division, and cell survival – Mitogens stimulate cell division primarily by triggering G1-Cdk and G1/S-Cdk activity – Growth factors stimulate cell growth (an increase in cell mass) by promoting protein synthesis (e.g. mTOR complex 1) – Survival factors promote cell survival by suppressing apoptosis (e.g. mTOR complex 2) – Misuse of ‘cell growth’ (cell growth + cell division) and ‘growth factor’ (growth factor + mitogen) The PI-3-Kinase–Akt Signaling Pathway Stimulates Animal Cells to Survive and Grow The PI-3-Kinase–Akt Signaling Pathway Stimulates Animal Cells to Survive and Grow  CONTROL OF CELL DIVISION AND CELL GROWTH Cells Can Enter a Specialized Nondividing State – In the absence of mitogenic signal to proliferate, progression into a new cell cycle is blocked. In some cases, cells withdraw from the cycle to a specialized nondividing state called G0 – Neurons and skeletal muscle cells are in a terminally differentiated G0 state, in which their cell-cycle pha huis control system is completely dismantled: the expression of the genes encoding various Cdks and cyclins is permanently turned off – Liver cells (regeneration), fibroblasts (would healing), and some lymphocytes (immune reaction) withdraw from the cell cycle only transiently and retain the ability to reassemble the cell-cycle control system quickly and re-enter the cycle  CONTROL OF CELL DIVISION AND CELL GROWTH Mitogens Stimulate G1-Cdk and G1/S-Cdk Activities – Mitogens trigger signal transduction pathways in which mitogen-activated protein kinase (MAPK) is involved, leading to mitosis. including..? The Cell-Cycle Control System Depends on Cyclically Activated Cyclin-Dependent Protein Kinases (Cdks) ???? Myc Cyclin D = G1-cyclin +CDK4/6 = G1-CDK Cyclin E = G1/S-cyclin Cyclin A +CDK2 = G1/S-CDK Cyclin A = S-cyclin +CDK2 = S-CDK  CONTROL OF CELL DIVISION AND CELL GROWTH Mitogens Stimulate G1-Cdk and G1/S-Cdk Activities G1-cyclin (cyclin D) positive feedback ↓ loop ↑ ↑ including..?  CONTROL OF CELL DIVISION AND CELL GROWTH DNA Damage Blocks Cell Division: The DNA Damage Response  CONTROL OF CELL DIVISION AND - CELL GROWTH Many Human Cells Have a Built-In Limitation on the Number of Times They Can Divide – Many human cells divide a limited number of times before they stop and undergo a permanent cell- cycle arrest (e.g. 25-50 doublings for fibroblasts in culture) – Toward the end of this time, proliferation slows down and finally halts, and the cells enter a nondividing state from which they never recover (replicative cell senescence – 노쇠/노화) – How? - Without telomerase activity, telomeres become shorter and the exposed chromosome ends are sensed as DNA damage, which activates p53- dependent cell-cycle arrest Abnormal Proliferation Signals Cause Cell-Cycle Arrest or Apoptosis, Except in Cancer Cells  CONTROL OF CELL DIVISION AND CELL GROWTH Abnormal Proliferation Signals Cause Cell-Cycle Arrest or Apoptosis, Except in Cancer Cells – Many of the components of mitogenic signaling pathways are encoded by genes that were originally identified as cancer-promoting genes, because mutations in these genes contribute to cancer development (e.g. Ras, Myc) – Hyperactivated Ras or Myc, however, causes permanent cell-cycle arrest or apoptosis … how? – Normal cells seem able to detect abnormal mitogenic stimulation (figure 63) – How do cancer cells arise, then?  CONTROL OF CELL DIVISION AND CELL GROWTH Cell Proliferation is Accompanied by Cell Growth – If cells proliferated without growing, they would get progressively smaller and there would be no net increase in total cell mass – Like mitogens, the growth factors that stimulate cell growth bind to cell-surface receptors – These pathways stimulate the accumulation of proteins and other macromolecules Cell Proliferation is Accompanied by Cell Growth > - ↑ Myc - inhibita degradation inhibit  CONTROL OF CELL DIVISION AND CELL GROWTH Cell Proliferation is Accompanied by Cell Growth – Mitogen -> Ras -> MAPK -> Myc/E2F -> Cyclins – Growth factor -> PI3K -> Akt -> mTOR1 – Survival factor -> PI3K -> Akt -> Bad