Essential Cell Biology

Chapter 18The Cell-Division CycleEssentialCell BiologyFOURTH EDITIONCopyright Garland Science 2014

Alberts Bray Hopkin Johnson Lewis Raff Roberts Walter

Cycle of Cell ReproductionFig. 18-1

Reproduction Rates Varyearly Drosophila embryo nuclei (not cells yet) 6 minutes!

Phases of Cell CycleFig. 18-2

There are quality control checkpoints along the way.Fig. 18-3

Cyclin/Cdk Complexes Regulate ProgressionFig. 18-4

Cyclin Abundance Regulates Cdk ActivityCdks present at all times; cyclin levels cycle.Fig. 18-8

How We Know: Cyclin/M-Cdk was first discovered in fertilized frog and clam eggs.

Cytoplasm from M phase fertilized egg induces mitosis in G2-arrested oocyteFig. 18-7Cyclin/M-Cdk is the active agent.(called Maturation Promoting Factor (MPF)arrested in G2

Progesterone induces Cyclin/M-Cdk to promote maturation of oocytes during meiosis (Maturation Promoting Factor)Cyclin/M-Cdk

Cyclin/M-Cdk

Cyclin/Cdk Complexes Drive Progression of All Cell Cycle Stages Well just refer to them as S-Cyclin and M-Cyclin.

Cyclin Abundance Determines Cdk ActivityCyclin abundance regulated by transcription and by proteolysis.Fig. 18-8

Cyclin proteolysis triggered by ubiquitylation by APC allows exit from M phaseFig. 18-9

M-Cdk activity also regulated by phosphorylationFig. 18-10phosphorylation controls entry into M phasePactivatingphosphateand kinase (CAK)

Positive Feedback Loop from M-Cdk on Cdc25 Makes M phase Entry Signal More RobustFig. 18-17Wee1kinasephosphorylation by M-Cdk activates Cdc25

S-Cdk regulated by inhibitory proteinsInhibitory proteins control entry into S phaseFig. 18-11S-

p27inactive cyclin-CdkcomplexUBIQUITYLATION OF p27 BY SCF

p27 proteolysis triggered by ubiquitylation by SCF allows entry into S phase Fig. 18-9 modifiedDESTRUCTION OF p27 IN PROTEASOME

Replication complete?DNA damage?Chromosome attachmentto spindle?Environmental cues?There are quality control checkpoints along the way.Fig. 18-12

Environmental Cues Can Induce S Phase Entry Through Rb InactivationCyclins, etc.Fig. 18-14

Internal Signals Can Induce Temporary Delay in S Phase Entry through p53 ActivationFig. 18-15Checkpoint kinases (Chk)functions like p27

Fig. 18-10Pactivatingphosphateand kinase (CAK)If DNA damage is detected during G2 phase, Cdc25 inactivation prevents entry into M phase.

Replication Proteins Are Targets of Cyclin/S-CdkFig. 18-16Cdc6 and ORC can only form pre-RC when de-phosphorylatedORC, Cdc6, and MCM phosphorylated,inactivating ORC & Cdc6 but activating MCMensures pre-RC assembly once and only once/ cell cycle-PMCM

Cyclin/Cdk Complexes Regulate ProgressionFig. 18-4What regulates Cdk Activity?Cyclin activates (its level cycles)Cdk inhibitors (p27 & p21)Cdk phosphorylation-activating kinase: CAK-inhibiting kinase: Wee1

-activating phosphatse: Cdc25

Fig. 18-10

M-Cdk phosphorylation controls entry into M phasePactivatingphosphateand kinase (CAK)How will mutations in these phosphorylation sites affect the cell cycle?

POLAR CHARGED

POLAR UNCHARGED

Ser, Thr, or Tyrmutated to Ala:can no longer be phosphorylated

Ser, Thr, or Tyrmutated to Asp or Glu:mimics phosphorylationEffects of Mutating Phosphorylation Sites

phosphorylation

Fig. 18-10

M-Cdk phosphorylation controls entry into M phasePactivatingphosphateand kinase (CAK)mutating inhibitory PO4 site to Glumutating inhibitory PO4 site to Alamutating activating PO4 site to Glumutating activating PO4 site to Alaconstitutive entry into M phaseunable to enter M phaseunable to enter M phaseconstitutive entry into M phase Mutation phenotype Dom/Rec?DomRecRecDom

Mitosis: The Most Visibly Dramatic Part of Cell Cycle

prophasemetaphaseanaphasetelophase

Panel 18.1chromosomes condensemitotic spindle formskinetochore formsnuclear envelope disperseschromosomes alignedchromosomes separatechromosomes decondensenuclear envelope reformsDNA replication

Chromosome Proteins Are Targets of Cyclin/M-Cdk in ProphaseFig. 18-18

-Cohesin and Condensin are structurally related ring-forming proteins. -Cohesin holds sister chromatids together during metaphase. -Condensin condenses chromosomes into visible bodies. target of Cyclin/M-Cdk phosphorylation

Mitosis requires assembly of two transient cytoskeletal structuresFig. 18-19mitosis cytokinesis

M phase

Prophase: MT reorganization

Prometaphase: chromosomes attach

Metaphase: chromosomes align & separateMitotic spindle assemblybegins with centrioleduplication during S phaseFig. 18-21

Microtubule Associated Proteins (MAPs) are targets of Cyclin/M-Cdk during prophasedynamic instability increasedinteractions between MTs from opposite poles stabilizeMT + endsmotorscross-linkinterpolar MTsFig. 18-22

Sister chromatids bind kinetochore MTs from opposite poles during prometaphase, allowing separation during anaphase.kinetochore proteinFig. 18-24

Sister chromatids bind kinetochore MTs from opposite poles and separate during anaphase.

Fig. 18-27metaphase anaphase

Degradation of Securin and cleavage of Cohesin allow separation.Fig. 18-28

kinesin motorsdynein motorsdynein motorskinesin:

dynein:MT disassemblyfrom + endsTwo processes at play during sister chromatid segregationFig. 18-29pushes poles apart

pulls poles apart

Kinetochore proteins bind microtubule sides, instead of ends, allowing assembly/disassembly at + endAlberts MBOC

Nuclear Envelope Assembly/Reassembly During MitosisFig. 18-30targets ofCyclin/M-Cdkphosphatase

Nuclear division is followed by cytokinesis. Fig. 18-32

Cells lose adhesion to their substratum and change shape during cytokinesis. Fig. 18-33

Programmed cell death (apoptosis) is another mechanism for controlling cell numbers.apoptotic cells Fig. 18-35Apoptosis needed for digit formation during embryonic development.

Apoptosis needed for tail lossduring frog metamorphosis tadpole adult frog

Fig. 18-36

Apoptosis also needed for neuron pruning during neural development Fig. 18-41

Necrosis Apoptosis Apoptosis in Animal

Fig. 18-37Necrosis is messy; apoptosis is neat.

Caspase enzymes mediate apoptosis. Fig. 18-38cleave targetproteinsto kill cellallowing nuclease access to DNA

External signaling molecules can induce apoptosis in a developmental program.Fig. 18-40eliminates self-recognizing T cells from immune system

Intrinsic signals can also induce apoptosis in response to DNA damage.Balance of pro-apoptotic and anti-apoptotic Bcl2 proteins determines outcome Fig. 18-39pro-apoptoticDNA damage activates pro-apoptotic Bcl2 proteins

Survival factors increase expression of anti-apoptotic Bcl2 proteinsFig. 18-42

Growth Factors Control Cell Size (Growth) by Regulating Protein Synthesis & Degradation Fig. 18-43Insulin is growth factor(Lab 4B)Cells remain in G1 or G0

Extracellular signal proteins can control cell growth, division and/or survival.

Muscle cells: control of both cell division and growthNeurons: primarily growthLiver cells: primarily divisionChapter 19Sexual Reproduction and the Power of GeneticsEssentialCell BiologyFOURTH EDITIONCopyright Garland Science 2014

Alberts Bray Hopkin Johnson Lewis Raff Roberts Walter

Fig. 19-4Most multicellular organisms reproduce sexually.fertilization of egg by sperm

After fertilization,the diploid zygote then undergoes rounds of mitosisto generate a new multicellular adult.Fig. 19-5

Meiosis differs from mitosis in also having a reductive division.Fig. 19-6reductivedivisionnon-reductivedivisionnon-reductivedivision

Physical Basis of reductive division: separation of chromosome homologuesFig. 19-7

Physical Basis of reductive division: separation of chromosome homologuesFig. 19-8

Fig. 19-9Paired chromosome homologues after duplication (one from each parent)Synaptonemal Complex holds homologues togetherCohesin holds sister chromatids together