| 19-Aug-2008 |
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Contents
Chapter 1: The Cell Cycle [PDF] 1-0 Overview: Cell Reproduction [Full Text] [PDF] -Cell reproduction is a fundamental feature of all living things -Cells reproduce in discrete steps -The ordering of cell-cycle events is governed by an independent control system 1-1 Events of the Eukaryotic Cell Cycle [Full Text] [PDF] -Chromosome duplication and segregation occur in distinct cell-cycle phases that are usually separated by gap phases -Cytoplasmic components are duplicated throughout the cell cycle -Cell growth is usually coordinated with cell division 1-2 Variations in Cell-Cycle Organization [Full Text] [PDF] -Cell-cycle structure varies in different cells and organisms -Multiple rounds of chromosome duplication or segregation can occur in the same cell cycle -The symmetry of cell division varies in different cell types 1-3 The Cell-Cycle Control System [Full Text] [PDF] -Cell-cycle events are governed by an independent control system -The cell-cycle control system is based on oscillations in the activities of cyclin-dependent protein kinases -Cell-cycle events are initiated at three regulatory checkpoints -Cell-cycle progression in most cells can be blocked at checkpoints Chapter 2: Model Organisms in Cell-Cycle Analysis [PDF] Back to top 2-0 Overview: Cell-Cycle Analysis in Diverse Eukaryotes [Full Text] [PDF] -Mechanisms of cell-cycle control are similar in all eukaryotes -Budding and fission yeasts provide powerful systems for the genetic analysis of eukaryotic cell-cycle control -Early animal embryos are useful for the biochemical characterization of simple cell cycles -Control of cell division in multicellular organisms can be dissected genetically in Drosophila -Cultured cell lines provide a means of analyzing cell-cycle control in mammals 2-1 Life Cycles of Budding and Fission Yeasts [Full Text] [PDF] -Budding yeast and fission yeast divide by different mechanisms -Yeast cells alternate between haploid and diploid states and undergo sporulation in response to starvation 2-2 Genetic Analysis of Cell-Cycle Control in Yeast [Full Text] [PDF] -Cell biological processes are readily dissected with yeast genetic methods -Conditional mutants are used to analyze essential cell-cycle processes -Homologous genes have different names in fission yeast and budding yeast 2-3 The Early Embryo of Xenopus laevis [Full Text] [PDF] -The early embryonic divisions of Xenopus provide a simplified system for cell-cycle analysis -Unfertilized eggs develop from diploid oocytes by meiosis -The early embryonic cell cycle can be reconstituted in a test tube 2-4 The Fruit Fly Drosophila melanogaster [Full Text] [PDF] -Drosophila allows genetic analysis of cell-cycle control in metazoans -Cells of the early Drosophila embryo divide by a simplified cell cycle -Gap phases are introduced in late embryogenesis -Adult fly structures develop from imaginal cells 2-5 Mammalian Cell-Cycle Analysis [Full Text] [PDF] -Mammalian cell-cycle control can be analyzed in cells growing in culture -Mutations lead to immortalization and transformation of mammalian cells -Specific gene disruption is the ideal approach for assessing protein function in mammalian cells 2-6 Methods in Cell-Cycle Analysis [Full Text] [PDF] -Cell-cycle position can be assessed by many approaches -Cell populations can be synchronized at specific cell-cycle stages -Complete understanding of cell-cycle control mechanisms requires the analysis of protein structure and enzymatic behavior Chapter 3: The Cell-Cycle Control System [PDF] Back to top 3-0 Overview:The Cell-Cycle Control System [Full Text] [PDF] -The cell-cycle control system is a complex assembly of oscillating protein kinase activities -Multiple regulatory mechanisms govern Cdk activity during the cell cycle -The cell-cycle control system generates robust, switch-like and adaptable changes in Cdk activity 3-1 Cyclin-Dependent Kinases [Full Text] [PDF] -The cyclin-dependent kinases are a small family of enzymes that require cyclin subunits for activity -The active site of cyclin-dependent kinases is blocked in the absence of cyclin 3-2 Cyclins [Full Text] [PDF] -Cyclins are the key determinants of Cdk activity and can be classified in four groups -Cyclins contain a conserved helical core 3-3 Control of Cdk Activity by Phosphorylation [Full Text] [PDF] -Full Cdk activity requires phosphorylation by the Cdk-activating kinase -Cdk function is regulated by inhibitory phosphorylation by Wee1 and dephosphorylation by Cdc25 3-4 The Structural Basis of Cdk Activation [Full Text] [PDF] -The conformation of the Cdk active site is dramatically rearranged by cyclin binding and phosphorylation by CAK 3-5 Substrate Targeting by Cyclin–Cdk Complexes [Full Text] [PDF] -Cyclins are specialized for particular functions -Cyclins can interact directly with the substrates of the associated Cdk -Cyclins can direct the associated Cdk to specific subcellular locations -Cks1 may serve as an adaptor protein that targets Cdks to phosphoproteins 3-6 Cdk Regulation by Inhibitory Subunits [Full Text] [PDF] -Cdk inhibitors help suppress Cdk activity in G1 -Cip/Kip proteins bind both subunits of the cyclin–Cdk complex -G1–Cdks are activated by Cip/Kip proteins and inhibited by INK4 proteins 3-7 Biochemical Switches in Signaling Systems [Full Text] [PDF] -Components of the cell-cycle control system are assembled into biochemical switches -Switch-like behavior can be generated by various mechanisms -Bistability is required for an effective binary switch 3-8 Switch-Like Activation of Cdk1 [Full Text] [PDF] -Cdk1 activation at mitosis is based on positive feedback -Cdk switches are robust as a result of multiple partly redundant mechanisms 3-9 Protein Degradation in Cell-Cycle Control [Full Text] [PDF] -Many cell-cycle regulators are destroyed by ubiquitin-dependent proteolysis -SCF catalyzes ubiquitination of phosphorylated substrates using interchangeable substrate-targeting subunits 3-10 The Anaphase-Promoting Complex [Full Text] [PDF] -The APC initiates anaphase and mitotic exit -Cdc20 activates the APC in anaphase -APC activity is maintained in G1 by Cdh1 -APC targets contain specific recognition sequences 3-11 Assembling and Regulating a Cell-Cycle Oscillator [Full Text] [PDF] -Negative feedback can generate a repeating oscillator -Regulated braking mechanisms allow the Cdk oscillator to be paused in G1 3-12 Transcriptional Control of Cell-Cycle Regulators [Full Text] [PDF] -A sequential program of gene expression contributes to cell-cycle control -Expression of a large fraction of the genes in the yeast genome is regulated during the cell cycle -Key gene regulatory proteins in yeast are activated at the major cell-cycle transitions -The E2F family controls cell-cycle-dependent changes in gene expression in metazoans 3-13 Programming the Cell-Cycle Control System [Full Text] [PDF] -The order of cell-cycle events is determined by regulatory interactions between multiple oscillators -The cell-cycle control system is responsive to many external inputs Chapter 4: Chromosome Duplication [PDF] Back to top 4-0 Overview: Chromosome Duplication and its Control [Full Text] [PDF] -DNA synthesis begins at replication origins -The cell-cycle control system activates replication origins only once in each S phase -Chromosome duplication requires duplication of chromatin structure 4-1 Basic Mechanisms of DNA Synthesis [Full Text] [PDF] -The two strands of DNA are replicated by different mechanisms -DNA replication begins with origin unwinding and primer synthesis -Discontinuous DNA fragments are joined together by DNA ligase -Telomerase synthesizes DNA at chromosome ends 4-2 The Replication Origin [Full Text] [PDF] -Replication origins in budding yeast contain well defined DNA sequences -Replication origins in animal chromosomes are defined by several factors in addition to DNA sequence 4-3 Assembly of the Prereplicative Complex at the Replication Origin [Full Text] [PDF] -The replication origin interacts with a multisubunit protein complex -The ORC and accessory proteins load the Mcm helicase onto origins -Mcm loading involves ATP-dependent protein remodeling 4-4 Regulation of the Prereplicative Complex [Full Text] [PDF] -Assembly of prereplicative complexes is restricted to G1 by multiple mechanisms -Prereplicative complex components are destroyed or inhibited in yeast as a result of Cdk activity -Pre-RC assembly is controlled in animals by both Cdks and the APC 4-5 Cyclins Required for Activation of Replication Origins in Yeast [Full Text] [PDF] -Cdks and Cdc7 trigger the initiation of DNA replication -In budding yeast, the cyclins Clb5 and Clb6 are key activators of replication origins -Yeast cells lacking S cyclins can replicate their DNA 4-6 Cyclins Required for Activation of Replication Origins in Metazoans [Full Text] [PDF] -Different cyclins control initiation of DNA replication in different stages of animal development -Cyclin A is a major regulator of replication initiation in cultured mammalian cells -DNA replication in frog embryos is triggered by cyclin E-Cdk2 -Cyclin E–Cdk2 is a major regulator of DNA replication in Drosophila 4-7 Control of Replication by the Protein Kinase Cdc7–Dbf4 [Full Text] [PDF] -Cdc7 triggers the activation of replication origins -Cdc7 is activated during S phase by the regulatory subunit Dbf4 -Dbf4 levels are regulated by multiple mechanisms 4-8 Activation of the Replication Origin [Full Text] [PDF] -Replication begins with DNA unwinding at the origin -Late-firing origins are regulated independently -Replication must be completed before chromosome segregation occurs 4-9 Basic Chromatin Structure [Full Text] [PDF] -Chromatin is complex and dynamic -The basic unit of chromatin structure is the nucleosome -Higher-order chromatin structure is also controlled by non-histone proteins, histone H1 and histone modifications 4-10 Histone Synthesis in S phase [Full Text] [PDF] -Histone synthesis rises sharply during S phase -Transcription of histone genes increases in S phase -Histone mRNA processing and stability increase in S phase -The level of free histones in the cell acts as a signal to link histone synthesis to DNA synthesis 4-11 Nucleosome Assembly on Nascent DNA [Full Text] [PDF] -Nucleosomes are distributed to both new DNA strands behind the replication fork -Nucleosome assembly factors load histones on nascent DNA 4-12 Heterochromatin at Telomeres and Centromeres [Full Text] [PDF] -Heterochromatin is inherited by epigenetic mechanisms -Telomeres are packaged in a heritable heterochromatin structure -The centromere nucleates a heritable and poorly understood form of heterochromatin 4-13 Molecular Mechanisms of Heterochromatin Duplication [Full Text] [PDF] -Duplication of heterochromatin structure involves proteins that recognize and promote localized histone modification -The Sir proteins form a heritable polymer at telomeres in budding yeast -HP1 may nucleate heritable chromatin structure at the centromere and other regions -Sister-chromatid cohesion in S phase prepares the cell for mitosis Chapter 5: Early Mitosis: Preparing the Chromosomes for Segregation [PDF] Back to top 5-0 Overview: The Events of Mitosis [Full Text] [PDF] -The central events of mitosis are sister-chromatid separation and segregation -The events of early mitosis set the stage for sister-chromatid segregation -The completion of mitosis begins with sister-chromatid segregation 5-1 Overview: Principles of Mitotic Regulation [Full Text] [PDF] -Phosphorylation and proteolysis control progression through mitosis -Mitotic events must go to completion -Mitotic entry and exit are major regulatory transitions with differing importance in different species 5-2 Cyclins that Promote Mitotic Entry in Yeast [Full Text] [PDF] -cyclin–Cdk complexes trigger mitotic entry in all eukaryotes -Fission yeast cells trigger mitosis with a single mitotic cyclin -Two pairs of mitotic cyclins control budding yeast mitosis 5-3 Cyclins that Promote Mitotic Entry in Metazoans [Full Text] [PDF] -Mitosis in metazoans is governed by cyclins A and B -Vertebrate mitosis is driven by multiple forms of cyclins A and B -The active cyclin B1–Cdk1 complex moves from cytoplasm to nucleus in late prophase -Vertebrate cyclins A and B drive different mitotic events 5-4 Regulation of Mitotic Cdks by Wee1 and Cdc25 [Full Text] [PDF] -Cyclin B–Cdk1 complexes are activated rapidly in early M phase by dephosphorylation -Multiple Wee1-related kinases and Cdc25-related phosphatases govern Cdk1 activity in animal cells 5-5 Switch-like Activation of Cyclin B–Cdk1 at Mitosis [Full Text] [PDF] -Mitotic Cdk1 activation involves multiple positive feedback loops -Cdc25B and cyclin A–Cdk help trigger cyclin B–Cdk1 activation 5-6 Subcellular Localization of Mitotic Regulators [Full Text] [PDF] -Cyclin B1–Cdk1 is regulated by changes in its subcellular localization -Cyclin B1–Cdk1 location is controlled by phosphorylation of cyclin B1 -Cdc25C localization is regulated by phosphorylation -Cyclin B1–Cdk1 activation and nuclear accumulation are partly interdependent 5-7 Protein Kinases of the Polo and Aurora Families [Full Text] [PDF] -Polo-like kinases (Plks) help control spindle assembly and mitotic exit -Spindle function and sister-chromatid segregation are controlled in part by aurora kinases 5-8 Preparations for Mitosis: Sister-Chromatid Cohesion [Full Text] [PDF] -Sister chromatids are held together by two mechanisms -Cohesin is a key mediator of sister-chromatid cohesion -Cohesion is established during DNA replication -DNA decatenation prepares sister chromatids for separation 5-9 Entry into Mitosis: Sister-Chromatid Condensation and Resolution [Full Text] [PDF] -Chromosomes are dramatically reorganized in mitosis -Condensin complexes drive chromosome condensation and resolution 5-10 Regulation of Chromosome Condensation and Resolution [Full Text] [PDF] -Mitotic Cdks act on condensin to govern the timing of chromosome condensation -Sister-chromatid resolution is governed by Plk and aurora B in animal cells Chapter 6: Assembly of the Mitotic Spindle [PDF] Back to top 6-0 Overview: The Mitotic Spindle [Full Text] [PDF] -Chromosome segregation depends on the mitotic spindle -The mitotic spindle must be bipolar -Multiple mechanisms drive spindle assembly 6-1 Microtubule Structure and Behavior [Full Text] [PDF] -Microtubules are polymers of tubulin subunits -Microtubules exhibit dynamic instability 6-2 Microtubule Nucleation, Stability and Motility [Full Text] [PDF] -Cellular microtubules originate on preformed protein complexes that are usually concentrated in a microtubule-organizing center -Microtubule dynamics are governed by a variety of stabilizing and destabilizing proteins -Motor proteins move along microtubules 6-3 The Centrosome and the Spindle Pole Body [Full Text] [PDF] -The centrosome cycle resembles the chromosome cycle -Centrosome behavior is determined by the centrioles -The yeast spindle pole body is embedded in the nuclear envelope 6-4 Control of Centrosome Duplication [Full Text] [PDF] -Duplication of the centrosome and spindle pole body is initiated in late G1 by G1/S–Cdks -Centrosome duplication normally occurs once per cell cycle 6-5 The Kinetochore [Full Text] [PDF] -The kinetochore is the major site of microtubule–chromosome attachment -The kinetochore provides a stable attachment to a dynamic microtubule plus end 6-6 Early Steps in Spindle Assembly [Full Text] [PDF] -Spindle assembly begins in prophase -Mitotic microtubules are highly dynamic -Centrosome separation initiates spindle assembly -Centrosome maturation increases microtubule nucleation in mitosis 6-7 Nuclear Envelope Breakdown [Full Text] [PDF] -The nuclear envelope is composed of two membranes on an underlying protein support -Nuclear envelope breakdown begins at nuclear pores -The endoplasmic reticulum and Golgi apparatus are reorganized in mitosis 6-8 Mitotic Chromosome Function in Spindle Assembly [Full Text] [PDF] -Spindles self-organize around chromosomes -Microtubules can be stabilized by a gradient of Ran–GTP around chromosomes 6-9 Attachment of Sister Chromatids to the Spindle [Full Text] [PDF] -Centrosomes search for and capture kinetochores in prometaphase -Some kinetochore microtubules originate at the kinetochore -Chromosome attachment results in tension between sister kinetochores 6-10 Bi-Orientation of Sister Chromatids [Full Text] [PDF] -Kinetochore–microtubule attachment is stabilized by tension -Aurora B is required for the correction of syntelic attachments -Merotelic attachments are processed by multiple mechanisms 6-11 Forces Driving Chromosome Movement [Full Text] [PDF] -Multiple forces act on chromosomes in the spindle -The kinetochore is a major source of poleward force -Microtubule flux generates poleward force -A polar ejection force is generated by chromosome arms 6-12 Chromosome Congression [Full Text] [PDF] -Chromosome oscillations in prometaphase are generated by changes in the state of kinetochores -Microtubule flux may promote chromosome congression Chapter 7: The Completion of Mitosis [PDF] Back to top 7-0 Overview: The Completion of Mitosis [Full Text] [PDF] -The final events of mitosis occur in anaphase and telophase -The metaphase-to-anaphase transition is initiated by ubiquitination and destruction of regulatory proteins -Dephosphorylation of Cdk targets drives the events of late M phase -APCCdc20 initiates Cdk inactivation 7-1 Initiation of Anaphase: Activation of the APC [Full Text] [PDF] -APCCdc20 activation in early mitosis is essential for anaphase to occur -Phosphorylation promotes APCCdc20 activation in early mitosis 7-2 Initiation of Anaphase: The Spindle Checkpoint [Full Text] [PDF] -Unattached kinetochores generate a signal that prevents anaphase -The spindle checkpoint monitors defects in microtubule attachment and kinetochore tension 7-3 Inhibition of APC(Cdc20) by the Spindle Checkpoint [Full Text] [PDF] -Unattached kinetochores catalyze the formation of inhibitory signaling complexes -The spindle checkpoint signal is rapidly turned off once kinetochores are attached 7-4 Control of Sister-Chromatid Separation [Full Text] [PDF] -Separase is inhibited before anaphase by securin -In vertebrate cells Cdk1 inhibits separase by phosphorylation 7-5 Control of Late Mitosis in Budding Yeast [Full Text] [PDF] -Cdk inactivation in mitosis in budding yeast is not due to APCCdc20 alone -The protein phosphatase Cdc14 is required to complete mitosis in budding yeast 7-6 Control of Anaphase Events [Full Text] [PDF] -The anaphase spindle segregates the chromosomes -Dephosphorylation of Cdk targets governs anaphase spindle behavior 7-7 Control of Telophase [Full Text] [PDF] -Dephosphorylation of Cdk substrates drives the final steps of mitosis -Spindle disassembly is the central event of telophase -Nuclear envelope assembly begins around individual chromosomes Chapter 8: Cytokinesis [PDF] Back to top 8-0 Overview: Cytokinesis [Full Text] [PDF] -Cytokinesis distributes daughter nuclei into separate cells -Cytokinesis depends on a contractile ring and membrane deposition -The cleavage plane is positioned between the daughter nuclei -The timing of cytokinesis is coordinated with the completion of mitosis 8-1 The Actin–Myosin Ring [Full Text] [PDF] -Bundles of actin assemble at the site of division -Force is generated in the contractile ring by non-muscle myosin II -Actin filament formation depends on formins 8-2 Assembly and Contraction of the Actin–Myosin Ring [Full Text] [PDF] -Contractile ring function depends on accessory factors whose importance varies in different species -Contraction of the actin–myosin ring is regulated by activation of myosin II -The GTPase Rho controls actin and myosin behavior at the cleavage site 8-3 Membrane and Cell Wall Deposition at the Division Site [Full Text] [PDF] -Membrane deposition is required during cytokinesis -Membrane addition occurs in parallel with actin–myosin contraction 8-4 The Positioning and Timing of Cytokinesis in Yeast [Full Text] [PDF] -Preparations for cytokinesis in budding yeast begin in late G1 -Fission yeast uses the nucleus to mark the division site in early mitosis 8-5 The Positioning and Timing of Cytokinesis in Animal Cells [Full Text] [PDF] -Signals from the mitotic spindle determine the site of cleavage in animal cells -Multiple regulatory components at the central spindle help control cytokinesis -Cytokinesis is coordinated with mitosis by the spindle and Cdk1 inactivation 8-6 Specialization of Cytokinesis in Animal Development [Full Text] [PDF] -Cytokinesis can be blocked or incomplete in some stages of development -Cellularization is a specialized form of cytokinesis 8-7 Asymmetric Cell Division [Full Text] [PDF] -Asymmetric spindle positioning leads to daughter cells of unequal sizes -Unequal forces on the poles underlie asymmetric spindle positioning -The orientation of cell division is controlled by the mitotic spindle Chapter 9: Meiosis [PDF] Back to top 9-0 Overview: Meiosis [Full Text] [PDF] -Sexual reproduction is based on the fusion of haploid cells -The meiotic program involves two rounds of chromosome segregation -Homologous recombination is an important feature of meiosis -Defects in meiosis lead to aneuploidy 9-1 Regulation of Early Meiotic Events in Yeast [Full Text] [PDF] -The meiotic program is controlled at multiple checkpoints -The transcription factor Ime1 initiates the budding yeast meiotic program -Entry into the meiotic program is driven by the protein kinase Ime2 9-2 Homologous Recombination in Meiosis [Full Text] [PDF] -Homologous recombination is a central feature of meiotic prophase 9-3 Homolog Pairing in Meiotic Prophase [Full Text] [PDF] -Stages of meiotic prophase are defined by cytological landmarks -Homolog pairing occurs in two successive stages 9-4 Chiasma Formation in Late Meiotic Prophase [Full Text] [PDF] -A small number of recombination sites are selected for crossover formation in zygotene -Crossover sites nucleate the synaptonemal complex in some species -Chiasmata appear in diplotene 9-5 Controlling Entry into the First Meiotic Division [Full Text] [PDF] -Meiosis I is initiated by M–Cdk activity -Entry into the first meiotic division of animal cells is controlled in diplotene -Ndt80 and Cdk1 promote entry into the meiotic divisions of budding yeast -Recombination defects block entry into meiosis I 9-6 Chromosome Attachment in Meiosis I [Full Text] [PDF] -Homolog pairs are bi-oriented on the first meiotic spindle -Homolog bi-orientation depends on cohesion of sister-chromatid arms -Homolog linkage does not involve chiasmata in some species 9-7 Chromosome Segregation in Meiosis I [Full Text] [PDF] -Loss of sister-chromatid arm cohesion initiates anaphase I -The spindle checkpoint system helps control anaphase I -Centromeric cohesin is protected from cleavage in meiosis I 9-8 Finishing Meiosis [Full Text] [PDF] -Meiosis I is followed by meiosis II -Partial Cdk1 inactivation occurs after meiosis I -The meiotic program is coordinated with gametogenesis Chapter 10: Control of Cell Proliferation and Growth [PDF] Back to top 10-0 Overview: Control of Cell Proliferation and Growth [Full Text] [PDF] -Cell proliferation is controlled at a checkpoint in late G1 -Progression through Start depends on an irreversible wave of Cdk activity -Progression through Start requires changes in gene expression -Cell division is often coordinated with cell growth 10-1 Activation of Gene Expression at Start in Budding Yeast [Full Text] [PDF] -The gene regulatory proteins SBF and MBF drive expression of Start-specific genes in yeast -SBF and MBF are activated by Cln3–Cdk1 at Start -Small changes in the amount of Cln3 help trigger cell-cycle entry -SBF and MBF are inactivated in S phase by Clb–Cdk1 complexes 10-2 Activation of S–Cdks in Budding Yeast [Full Text] [PDF] -G1/S–Cdks promote activation of S–Cdks -Multisite phosphorylation of Sic1 generates switch-like S–Cdk activation -G1/S– and S–Cdks collaborate to inactivate APCCdh1 after Start 10-3 Extracellular Control of Start in Yeast: Mating Factor Signaling [Full Text] [PDF] -Yeast mating factors induce cell-cycle arrest in G1 -Far1 has multiple functions in proliferating and arrested cells -Far1 phosphorylation is triggered by a G-protein signaling pathway 10-4 Activation of Gene Expression at Start in Animals [Full Text] [PDF] -E2F transcription factors help control G1/S gene expression in animals -Stimulation of G1/S gene expression results from a combination of increased gene activation and decreased gene repression -E2F function is regulated by pRB proteins 10-5 Regulation of E2F–pRB Complexes [Full Text] [PDF] -G1/S gene expression at Start involves the replacement of repressor E2Fs with activator E2Fs -Phosphorylation of pRB proteins releases E2F -Multiple mechanisms of E2F activation provide robust regulation of Start 10-6 Mitogenic Signaling in Animal Cells [Full Text] [PDF] -Extracellular mitogens control the rate of cell division in animals -Activated mitogen receptors recruit signaling complexes to the cell membrane -Ras and Myc are components of many mitogenic signaling pathways -Activation of PI3 kinase helps promote mitogenesis 10-7 Activation of G1–Cdks by Mitogens [Full Text] [PDF] -Mitogenic signaling pathways lead to activation of cyclin D–Cdk complexes -Mitogens control cyclin D–Cdk localization and destruction -Mitogens and anti-mitogens control the concentrations of Cdk inhibitor proteins 10-8 Activation of G1/S– and S–Cdk Complexes in Animal Cells [Full Text] [PDF] -G1/S–Cdk activation at Start depends on removal of the inhibitor p27 -Cyclin A–Cdk2 activation is promoted in part by APC inhibition 10-9 Developmental Control of Cell Proliferation [Full Text] [PDF] -Developmental signals limit cell division to specific embryonic regions -Embryonic divisions are limited by depletion of key cell-cycle regulators 10-10 Overview: Coordination of Cell Division and Cell Growth [Full Text] [PDF] -Cell division and cell growth are separate processes -Cell growth is regulated by extracellular nutrients and growth factors -Cell growth and division are coordinated by multiple mechanisms -The size of a cell depends on its genomic content 10-11 Control of Cell Growth [Full Text] [PDF] -Cell growth rate is determined primarily by the rate of protein synthesis -Extracellular nutrients and growth factors stimulate cell growth by activating the protein kinase TOR -TOR affects cell growth mainly by stimulating protein synthesis -Growth factors stimulate protein synthesis through the activation of PI3 kinase 10-12 Coordination of Cell Growth and Division in Yeast [Full Text] [PDF] -Yeast cell growth and division are tightly coupled -Yeast cells monitor translation rates as an indirect indicator of cell size -Growth thresholds are rapidly adjustable 10-13 Coordination of Growth and Division in Animal Cells [Full Text] [PDF] -Growth and division are coordinated by multiple mechanisms in animal cells -Division depends on growth in many animal cell types -Animal cell growth and division are sometimes controlled independently 10-14 Control of Cell Death [Full Text] [PDF] -Animal cell numbers are determined by a balance of cell birth and death -Survival factors suppress the mitochondrial pathway of apoptosis -DNA damage and other stresses can trigger apoptosis Updates – 2007-2008 Back to top Stem cells U10-1 Stem-Cell Proliferation [Full Text] [PDF] -The maintenance of many adult tissues depends on stem cells -Two main mechanisms guide asymmetric stem-cell division U10-2 Control of Asymmetric Stem-Cell Division [Full Text] [PDF] -The stem-cell niche generates signals that promote stem-cell renewal -Mitotic spindle position orients stem-cell division Chapter 11: The DNA Damage Response [PDF] Back to top 11-0 Overview: The DNA Damage Response [Full Text] [PDF] -The DNA damage response helps maintain the genome -ATR and ATM are conserved protein kinases at the heart of the DNA damage response -Replication defects trigger a DNA damage response 11-1 Detection and Repair of DNA Damage [Full Text] [PDF] -DNA can be damaged in many ways -Base and nucleotide excision repair systems repair nucleotide damage -Double-strand breaks are repaired by two main mechanisms 11-2 The DNA Damage Response: Recruitment of ATR and ATM [Full Text] [PDF] -ATR is required for the response to multiple forms of damage -ATM is specialized for the response to unprocessed double-strand breaks 11-3 The DNA Damage Response: Adaptors and Chk1 and Chk2 [Full Text] [PDF] -Protein complexes assemble at DNA damage sites to coordinate DNA repair and the damage response -A PCNA-like complex is required for the ATR-mediated damage response -Adaptor proteins link DNA damage to activation of Chk1 and Chk2 11-4 Activation of p53 by DNA Damage [Full Text] [PDF] -p53 is responsible for long-term inhibition of cell proliferation in animal cells -The major regulators of p53 include Mdm2, p300 and ARF -Damage-response kinases phosphorylate p53 and Mdm2 11-5 Effects of DNA Damage on Progression through Start [Full Text] [PDF] -DNA damage blocks cell-cycle progression at multiple points -DNA damage has minor effects on progression through Start in budding yeast -DNA damage in vertebrate cells triggers a robust G1 arrest -p53 has different effects in different cell types 11-6 Effects of DNA Damage at Replication Forks [Full Text] [PDF] -A DNA damage response is initiated at replication forks during S phase -ATR is the key initiator of the response to stalled replication forks -The DNA damage response stabilizes the replication fork 11-7 Effects of DNA Damage on DNA Synthesis and Mitosis [Full Text] [PDF] -DNA damage in S phase blocks replication origin firing -DNA damage blocks mitotic entry in most eukaryotes -DNA damage blocks anaphase in budding yeast 11-8 Responses to Mitogenic and Telomere Stress [Full Text] [PDF] -Hyperproliferative signals trigger the activation of p53 -Imbalances in mitogenic stimuli promote replicative senescence in mouse cells -Telomere degeneration promotes cell-cycle arrest in human cells Chapter 12: The Cell Cycle in Cancer [PDF] Back to top 12-0 Overview: Cell-Cycle Defects in Cancer [Full Text] [PDF] -Cancer cells break the communal rules of tissues -Cancer progression is an evolutionary process driven by gene mutation -Genetic instability accelerates cancer progression 12-1 Gene Mutations that Drive Cancer [Full Text] [PDF] -Mutations in oncogenes and tumor suppressors stimulate tumor progression -Oncogenes can be activated by many different mechanisms -Multiple mutations are required to cripple tumor suppressor genes -Cancer can be initiated by mechanisms other than gene mutation 12-2 Tissue Specificity in Cancer [Full Text] [PDF] -Cancers are a complex group of diseases -The molecular basis of tumorigenesis can vary in different tissues 12-3 Stimulation of Cell-Cycle Entry in Cancer Cells [Full Text] [PDF] -Tumor cells are independent of mitogens and resistant to anti-mitogens -G1/S gene regulation is defective in most cancers -Multiple mitogenic defects are required for tumor formation 12-4 Cell Growth and Survival in Tumors [Full Text] [PDF] -Cell growth is stimulated in tumors -Tumor cells are less dependent than normal cells on survival factors -Differentiation is often inhibited in tumor cells -Tumor cells are resistant to the hyperproliferation stress response 12-5 Genetic Instability in Cancer [Full Text] [PDF] -Most cancer cells have unstable genomes -Defects in the DNA damage response promote genetic instability in cancer -Genetic instability sometimes results from an increased rate of point mutation -Chromosomal instability is the major form of genetic instability 12-6 Telomeres and the Structural Instability of Chromosomes [Full Text] [PDF] -Defective DNA damage responses can lead to chromosomal instability -Degenerating telomeres can lead to chromosomal instability 12-7 Instability in Chromosome Number [Full Text] [PDF] -Cancer cells often become aneuploid through a tetraploid intermediate -Cancer cells often contain excessive numbers of centrosomes -Mutations in mitotic spindle components contribute to chromosomal instability 12-8 Cancer Progression [Full Text] [PDF] -There are many genetic routes to a malignant cancer -Colon cancer progression usually begins with mutations in the gene APC -Two forms of genetic instability drive colorectal cancer progression 12-9 Stopping Cancer [Full Text] [PDF] -Reducing cancer mortality begins with prevention and early diagnosis -Therapies must kill cancer cells but leave healthy cells intact -A detailed understanding of the molecular basis of cancer may lead to rational and more specific cancer therapies Updated References [Full Text] [PDF]  | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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