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Ch 12 The Cell Cycle
What is the cell cycle in eukaryotes?
Just as organisms have a life cycle(birth-->maturation-->reproduction->-death)
Each cell has an ordered sequence of activities.
Draw cell cycle on board.
Most cells spend 90 % of life span in interphase: growth & synthesis
Remaining ~10% in M phase: mitosis and cell division (aka cytokinesis)
LE 12-5
G1
G2
S(DNA synthesis)
INTERPHASE
Cytokin
esis
MITOTIC(M) PHASE
Mito
sis
Summary of Cell Cycle Phases
– Mitotic (M) phase: mitosis and cytokinesis
– Interphase• G1 phase (“1st gap”):mRNA & protein synthesis
• S phase: DNA synthesis aka DNA replication, DNA
doubling
• G2 phase (“2nd gap”):mRNA & protein synthesis
Regulation of cell cycle
Two families of proteins control when the cell moves to different phases
1. Cyclins: regulatory subunits
2. Cyclin-dependent kinases (Cdks): catalytic subunits What is a kinase?
One subunit of each complex together in a heterodimer
Example: Cdk1/ cyclin B aka M-phase promoting factor (MPF)
Cdk: cyclin-dependent kinase
LE 12-16b
Degradedcyclin
G2
checkpoint
S
M
G 2G 1
Cdk
Cyclin isdegraded
MPFCyclin
Cdk
Molecular mechanisms that help regulate the cell cycle
accum
ulatio
nC
yclin
LE 12-16a
MPF activity
G1 G2S MS MG2G1
M
Cyclin
Time
Fluctuation of MPF activity and cyclin concentrationduring the cell cycle
Rel
ativ
e co
nce
ntr
atio
n
Based on the data what correlates with the cell
Entering M- phase?
Exiting M-phase and entering interphase?
Cyclin is synthesized and complexed to Cdk1 to form active MPF --> M phase induced.
Exit from M-phase correlated to cyclin degradation andMPF inhibition.
• For unicellular organisms
- Division of one cell reproduces the entire organism
Focus on M phase and cell divisionPurpose of cell division
• For multicellular organisms - Embryonic and fetal growth - Growth
- Repair
LE 12-2
Reproduction
100 µm
Tissue renewalGrowth and development
20 µm200 µm
• In preparation• During S phase
cell duplicates genetic material (DNA)
M-phase• One DNA copy each moves to opposite ends of the cell
• Mother cell undergoes cytokinesis --> two genetically identical daughter cells.
Focus on M-phaseMitosis Cytokinesis
Cellular Organization of the Genetic Material
Genome– A cell’s endowment of DNA
All its genetic information
Chromosomes DNA packaged with associated proteins
LE 12-3
25 µm
Orange: DNA
Yellow/green:MT
Staining of all the chromosomes or the genome in a cell
LE 12-4
Chromosomeduplication(DNA synthesis)
0.5 µm
Centromere
Sisterchromatids
Separationof sister
chromatids
Centromeres Sister chromatids
Single chromosome
• All eukaryotic species– Characteristic number of chromosomes located
in nucleus
• Somatic cells- Nonreproductive e.g. muscle, epidermal cells- Two sets of chromosomes (diploid)- Undergo mitosis
• Germ cells or gametes– Reproductive e.g. sperm and eggs–Half as many chromosomes as somatic cells (haploid)–Undergo meiosis
• Mitosis is conventionally divided into five phases:– Prophase
– Prometaphase
– Metaphase
– Anaphase
– Telophase
• Cytokinesis is well underway by late telophase
[Animations and videos listed on slide following figure]
LE 12-6ca
G2 OF INTERPHASE PROPHASE PROMETAPHASE
Blue: ChromosomesYellow/green: MT
LE 12-6da
METAPHASE ANAPHASE TELOPHASE AND CYTOKINESIS
10
µm
Video: Animal Mitosis
Video: Sea Urchin (time lapse)
Animation: Mitosis (All Phases)
Animation: Mitosis Overview
Animation: Late Interphase
Animation: Prophase
Animation: Prometaphase
Animation: Metaphase
Animation: Anaphase
Animation: Telophase
The Mitotic Spindle: A Closer Look
• Consists of MT– control chromosome movement during mitosis
• Assembly of spindle MT– at centrosome, the microtubule organizing
center (MTOC)
• Centrosome replicates (late G2)– migrate to opposite ends poles, as spindle
microtubules grow out from them
• Aster (a radial array of short microtubules) extends from each centrosome
• Spindle• includes the centrosomes, spindle MT, asters
• Some MT• attach to the kinetochores of chromosomes and
move chromosomes to metaphase plate
LE 12-7
Microtubules Chromosomes
Sisterchromatids
AsterCentrosome
Metaphaseplate
Kineto-chores
Kinetochoremicrotubules
0.5 µm
Overlappingnonkinetochoremicrotubules
1 µmCentrosome
LE 12-8b
Chromosomemovement
Microtubule Motorprotein
Chromosome
Kinetochore
Tubulinsubunits
Movement of xhromosomes toward poles
MT shortens--> drags chromosome toward pole
• In anaphase– sister chromatids separate– move along the kinetochore microtubules toward
opposite ends of the cell
• MTs shorten by depolymerization of their kinetochore ends
• Nonkinetochore MT– overlap and push against each other from
opposite poles– Cause cellular elongation
–In telophase– nuclear envelopes reform around each chromosome set copy
–genetically identical daughter nuclei form at opposite ends of the cell
–Chromosomes decondense
–MT depolymerize
Cytokinesis: A Closer Look
• In animal cells– cleavage furrow forms by action of contractile ring (actinomyosin)
• In plant cells– cell plate forms by fusion and elongation of vesicles between daughter
cells
Animation: Cytokinesis
LE 12-9a
Cleavage furrow100 µm
Contractile ring ofmicrofilaments
Daughter cells
Cleavage of an animal cell (SEM)
LE 12-9b
1 µm
Daughter cells
Cell plate formation in a plant cell (TEM)
New cell wallCell plate
Wall ofparent cell
Vesiclesformingcell plate
LE 12-10
NucleusCell plateChromosomesNucleolus
Chromatincondensing 10 µm
Prophase. The chromatin is condensing.The nucleolus is beginning to disappear.Although not yet visible in the micrograph, the mitotic spindle is starting to form.
Prometaphase. Wenow see discrete chromosomes; each consists of two identical sister chromatids. Laterin prometaphase, the nuclear envelope will fragment.
Metaphase. The spindle is complete, and the chromosomes, attached to microtubules at their kinetochores, are all at the metaphase plate.
Anaphase. The chromatids of each chromosome have separated, and the daughter chromosomes are moving to the ends of the cell as their kinetochore micro- tubules shorten.
Telophase. Daughter nuclei are forming. Meanwhile, cytokinesis has started: The cell plate, which will divide the cytoplasm in two, is growing toward the perimeter of the parent cell.
Description of each mitotic phase
Prokaryotic Cell Division
• Binary fission– Usually one circular chromosome attached to
plasma membrane via origin of replication (ori)
– chromosome replicates
– Daughter chromosomes move apart as cell elongates
– Cell division
– Mechanism distinct from mitosis.
LE 12-11_1
Origin ofreplication
Cell wall
Plasmamembrane
Bacterialchromosome
E. coli cell
Two copiesof origin
Chromosome replication begins. Soon thereafter, one copy of the origin moves rapidly toward the other end of the cell.
LE 12-11_2
Origin ofreplication
Cell wall
Plasmamembrane
Bacterialchromosome
E. coli cell
Two copiesof origin
Chromosome replication begins. Soon thereafter, one copy of the origin moves rapidly toward the other end of the cell.
Replication continues. One copy of the origin is now at each end of the cell.
Origin Origin
LE 12-11_3
Origin ofreplication
Cell wall
Plasmamembrane
Bacterialchromosome
E. coli cell
Two copiesof origin
Chromosome replication begins. Soon thereafter, one copy of the origin moves rapidly toward the other end of the cell.
Replication continues. One copy of the origin is now at each end of the cell.
Origin Origin
Replication finishes. The plasma membrane grows inward, and new cell wall is deposited.
Two daughtercells result.
My genome hurts!
It’s time to ask some questions.
Regulation of Eukaryotic Cell Cycle
Checkpoint controls
LE 12-14
G1 checkpoint
G1
S
M
M checkpoint
G2 checkpoint
G2
Controlsystem
(pauses if DNA is damaged or incompletely replicated)
(pauses if DNA is damaged)
(pauses if any kinetochoresare not attached to MT)
(aka spindle checkpoint)
• For many cells• G1 checkpoint most important one
• Go-ahead signal (no damaged DNA) at the G1 checkpoint -->• cell completes the S, G2, and M phases and divides
• e.g. skin cells, cells of gut lining and mouth
•No go-ahead signal
•Cells exits G1 and enters quiescent state of G0
•No cell division•e.g. nerve cells
LE 12-15
G1
G1 checkpoint
G1
G0
If a cell receives a go-ahead signal at the G1 checkpoint, the cell continues on in the cell cycle.
If a cell does not receive a go-ahead signal at the G1 checkpoint, the cell exits the cell cycle and goes into G0, a nondividing state.
Internal and External Signals at the Checkpoints Examples:
• Internal – Attachment of spindle to kinetochore (spindle checkpoint)
– What happens if no attachment occurs?
Arrest in metaphase; cell delays anaphase
• External–Growth factors secreted by neighboring cells–e.g. platelet-derived growth factor (PDGF) stimulates the division of human fibroblast cells in culture
LE 12-17
Petriplate
Scalpels
Without PDGF
With PDGF
Without PDGF
With PDGF
10 mm
Day 0
Day 4
Dissociate tissue into cells
What did PDGF induce?
• Other examples of external signals– Density-dependent inhibition (or contact inhibition):
-crowded cells stop dividing
–Anchorage dependence: -cells must be attached to a substratum in order to divide
LE 12-18a
Cells anchor to dish surface anddivide (anchorage dependence).
When cells have formed a completesingle layer, they stop dividing(density-dependent inhibition).
If some cells are scraped away, theremaining cells divide to fill the gap andthen stop (density-dependent inhibition).
25 µmNormal mammalian cells
Note: each cell is anchoredto plastic substratum.
• Cancer cells are NOT:– Density or anchorage dependent
LE 12-18b
Cancer cells do not exhibitanchorage dependenceor density-dependent inhibition.
Cancer cells25 µm
Loss of Cell Cycle Controls in Cancer Cells
• Do not respond normally to the body’s control mechanisms
• Form tumors, masses of abnormal cells within otherwise normal tissue
- Benign if stay at original site
- Malignant if migrate into other parts of body (metastisis)
LE 12-19
Cancer cell
Bloodvessel
LymphvesselTumor
Glandulartissue
Metastatictumor
A tumor grows from asingle cancer cell.
Cancer cells invadeneighboring tissue.
Cancer cells spreadthrough lymph andblood vessels toother parts of thebody.
A small percentageof cancer cells maysurvive and establisha new tumor in anotherpart of the body.
What triggers cancerous growth?
Chemicals e.g. in smoke and soot, ionizing radiation, certainRNA- and DNA containing viruses e.g. HIV, hepatitis B, papilloma virus; normal metabolic damage
Common property:Mutagenic: induce changes in the genome
that cause:
- over-expression of oncogenes, which encode proteins that push cell cycle forward
- under-expression of tumor-suppressor genes, which encode proteins that normally slow cell cycle down
-Chemotherapy
-Radiation
-Surgery
-Inhibitors of oncogenes
-Gene therapy
-Immunotherapy
-Anti-angiogenesis therapy (block blood supply to tumor)
How do these treatments stop cancer? Can they have negative side-effects,too?
Tumor Treatments:
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