1. Chapter 12 & 13
The Cell Cycle

2. Overview: The Key Roles of Cell Division
The continuity of life
Is based upon the reproduction of cells, or cell division
Figure 12.1

3. Unicellular organisms often reproduce by mitotic cell division (asexual)
…but so do others
100 µm
An amoeba, a single-celled eukaryote, is dividing into two cells. Each new cell will be an individual organism.
Spores
Vegetative propagation
Animation of bacterial DNA replication = Binary fission.
budding

4. Multicellular organisms depend on cell division for
Development from a fertilized cell
Growth
Repair
20 µm
200 µm
(b) Growth and development This micrograph shows a sand dollar embryo shortly after the fertilized egg divided, forming two cells (LM).
(c) Tissue renewal. These dividing bone marrow cells (arrow) will give rise to new blood cells (LM).
Figure 12.2 B, C

5. CELL DIVISION Is an integral part of the cell cycle
MITOTIC cell division results in genetically identical daughter cells
Cells duplicate their genetic material
Before they divide, ensuring that each daughter cell receives an exact copy of the genetic material, DNA

6. Cellular Organization of the Genetic Material
A cell’s endowment of DNA, its genetic information
Is called its genome
The DNA molecules in a cell
Are packaged into chromosomes
50 µm

7. Eukaryotic chromosomes
Consist of chromatin, a complex of DNA and protein that condenses during cell division
In animals
Somatic cells have two sets of chromosomes
Diploid (2n)
Gametes have one set of chromosomes
Haploid (n)

8. Distribution of Chromosomes During Cell Division
In preparation for cell division
DNA is replicated and the chromosomes condense
0.5 µm
Chromosome duplication (including DNA synthesis)
Centromere
Separation of sister chromatids
Sister chromatids
Centromeres
A eukaryotic cell has multiple chromosomes, one of which is represented here. Before duplication, each chromosome has a single DNA molecule.
Once duplicated, a chromosome consists of two sister chromatids connected at the centromere. Each chromatid contains a copy of the DNA molecule.
Mechanical processes separate the sister chromatids into two chromosomes and distribute them to two daughter cells.
Figure 12.4
Each duplicated chromosome has two sister chromatids, which separate during cell division

9. Eukaryotic cell division consists of
Mitosis, the division of the nucleus
Cytokinesis, the division of the cytoplasm
In meiosis
Sex cells are produced after a reduction in chromosome number

10. Phases of the Cell Cycle
The cell cycle consists of
The mitotic phase
Interphase
Notice the time spent in interphase
INTERPHASE G1
S (DNA synthesis) G2
Cytokinesis Mitosis
MITOTIC (M) PHASE
Figure 12.5

11. What happens during Interphase?
Interphase can be divided into subphases
G1 phase
S phase
G2 phase
The G0 phase (referred to the G zero phase) or resting phase is a period in the cell cycle in which cells exist in a quiescent state. G0 phase is viewed as either an extended G1 phase, where the cell is neither dividing nor preparing to divide, or a distinct quiescent stage that occurs outside of the cell cycle. Some types of cells, such as nerve and heart muscle cells, become quiescent when they reach maturity.

12. MITOSIS
The mitotic phase
Is made up of mitosis and cytokinesis

13. Kinetochore microtubule
PMAT
Mitosis consists of four distinct phases
Prophase
G2 OF INTERPHASE
PROPHASE
PROMETAPHASE
Centrosomes (with centriole pairs)
Chromatin (duplicated)
Early mitotic spindle
Aster
Centromere
Fragments of nuclear envelope
Kinetochore
Nucleolus
Nuclear envelope
Plasma membrane
Chromosome, consisting of two sister chromatids
Kinetochore microtubule
Figure 12.6
Nonkinetochore microtubules

14. TELOPHASE AND CYTOKINESIS
Metaphase
Anaphase
Telophase
Centrosome at one spindle pole
Daughter chromosomes
METAPHASE
ANAPHASE
TELOPHASE AND CYTOKINESIS
Spindle
Metaphase plate
Nucleolus forming
Cleavage furrow
Nuclear envelope forming
Figure 12.6

15. The Mitotic Spindle: A Closer Look
Is an apparatus of microtubules that controls chromosome movement during mitosis
The spindle arises from the centrosomes
And includes spindle microtubules and asters

16. Some spindle microtubules
Attach to the kinetochores of chromosomes and move the chromosomes to the metaphase plate
Centrosome
Aster
Sister chromatids
Metaphase Plate
Kinetochores
Overlapping nonkinetochore microtubules
Kinetochores microtubules
Chromosomes
Microtubules
0.5 µm
1 µm
Figure 12.7

17. In anaphase, sister chromatids separate
And move along the kinetochore microtubules toward opposite ends of the cell
EXPERIMENT
1 The microtubules of a cell in early anaphase were labeled with a fluorescent dye that glows in the microscope (yellow).
Spindle pole
Kinetochore
Figure 12.8

18. Nonkinetechore microtubules from opposite poles
Overlap and push against each other, elongating the cell
In telophase
Genetically identical daughter nuclei form at opposite ends of the cell

19. Cytokinesis: A Closer Look
In animal cells
Cytokinesis occurs by a process known as cleavage, forming a cleavage furrow
Cleavage furrow
Contractile ring of microfilaments
Daughter cells
100 µm
(a) Cleavage of an animal cell (SEM)
Figure 12.9 A

20. (b) Cell plate formation in a plant cell (SEM)
In plant cells, during cytokinesis
A cell plate forms
Daughter cells
1 µm
Vesicles forming cell plate
Wall of patent cell
Cell plate
New cell wall
(b) Cell plate formation in a plant cell (SEM)
Figure 12.9 B

21. Mitosis in a plant cell Nucleus Chromatine condensing Chromosome1
Prophase. The chromatin is condensing. The nucleolus is beginning to disappear. Although not yet visible in the micrograph, the mitotic spindle is staring to from.
Prometaphase. We now see discrete chromosomes; each consists of two identical sister chromatids. Later in prometaphase, the nuclear envelop 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 cell as their kinetochore microtubles shorten.
Telophase. Daughter nuclei are forming. Meanwhile, cytokinesis has started: The cell plate, which will divided the cytoplasm in two, is growing toward the perimeter of the parent cell. 2 3 4 5
Nucleus
Nucleolus
Chromosome
Chromatine condensing
Figure 12.10

22. Mitosis and cytokinesis narrated animation
How the Cell Cycle Works narrated animation

23. The Cell Cycle Control System
The sequential events of the cell cycle
Are directed by a distinct cell cycle control system, which is similar to a clock
Figure 12.14
Control system
G2 checkpoint
M checkpoint
G1 checkpoint G1 S G2 M

24. The clock has specific checkpoints
Where the cell cycle stops until a go-ahead signal is received
G1 checkpoint G1 G0
(a) If a cell receives a go-ahead signal at the G1 checkpoint, the cell continues      on in the cell cycle.
(b) If a cell does not receive a go-ahead signal at the G1checkpoint, the cell exits the cell cycle and goes into G0, a
nondividing state.
Figure A, B

25. Regulation of the Cell Cycle
The frequency of cell division
Varies with the type of cell
The cell cycle is regulated by a molecular control system
Molecules present in the cytoplasm
Regulate progress through the cell cycle
Two types of regulatory proteins are involved in cell cycle control
Cyclins
Cyclin-dependent kinases (Cdks)
Narrated animation “Control of the Cell Cycle”

26. Cell division is tightly controlled by complexes made of several specific proteins.
These complexes contain enzymes called cyclin-dependent kinases (CDKs), which turn on or off the various processes that take place in cell division.
CDK partners with a family of proteins called cyclins.
One such complex is mitosis-promoting factor (MPF), sometimes called maturation-promoting factor, which contains cyclin A or B and cyclin-dependent kinase (CDK). (See Figure 2a.)
CDK is activated when it is bound to cyclin, interacting with various other proteins that, in this case, allow the cell to proceed from G2 into mitosis.
The levels of cyclin change during the cell cycle (Figure 2b). In most cases, cytokinesis follows mitosis.
Narrated animation: Cell Proliferation Signaling Pathway

27. As shown in Figure 3, different CDKs are produced during the phases
As shown in Figure 3, different CDKs are produced during the phases. The cyclins determine which processes in cell division are turned on or off and in what order by CDK. As each cyclin is turned on or off, CDK causes the cell to move through the stages in the cell cycle.

28. Both internal and external signals Control the cell cycle checkpoints
There are three checkpoints a cell must pass through: the G1 checkpoint, G2 checkpoint, and the M-spindle checkpoint (Figure 4).
At each of the checkpoints, the cell checks that it has completed all of the tasks needed and is ready to proceed to the next step in its cycle.
Cells pass the G1 checkpoint when they are stimulated by appropriate external growth factors; for example, platelet-derived growth factor (PDGF) stimulates cells near a wound to divide so that they can repair the injury.
The G2 checkpoint checks for damage after DNA is replicated, and if there is damage, it prevents the cell from going into mitosis.
The M-spindle (metaphase) checkpoint assures that the mitotic spindles or microtubules are properly attached to the kinetochores (anchor sites on the chromosomes). If the spindles are not anchored properly, the cell does not continue on through mitosis.
The cell cycle is regulated very precisely.
Mutations in cell cycle genes that interfere with proper cell cycle control are found very often in cancer cells.

29. Growth Factor proteins
Growth factors
Stimulate other cells to divide
EXPERIMENT
A sample of connective tissue was cut up into small pieces.
Enzymes were used to digest the extracellular matrix, resulting in a suspension of free fibroblast cells.
Cells were transferred to sterile culture vessels containing a basic growth medium consisting of glucose, amino acids, salts, and antibiotics (as a precaution against bacterial growth). PDGF was added to half the vessels. The culture vessels were incubated at 37°C. 3 2 1
Petri plate
Without PDGF
With PDGF
Scalpels
Figure 12.17

30. Environmental effects on cell cycling
In density-dependent inhibition
Crowded cells stop dividing
Most animal cells exhibit anchorage dependence
In which they must be attached to a substratum to divide
Cells anchor to dish surface and
divide (anchorage dependence).
When cells have formed a complete single layer, they stop dividing (density-dependent inhibition).
If some cells are scraped away, the remaining cells divide to fill the gap and then stop (density-dependent inhibition).
Normal mammalian cells. The availability of nutrients, growth factors, and a substratum for attachment limits cell density to a single layer.
(a)
25 µm
Figure A

31. Cancer cells
Exhibit neither density-dependent inhibition nor anchorage dependence
25 µm
Cancer cells do not exhibit anchorage dependence or density-dependent inhibition.
Cancer cells. Cancer cells usually continue to divide well beyond a single layer, forming a clump of overlapping cells.
(b)
Most oncogenes are mutations of certain normal genes called proto-oncogenes.
Proto-oncogenes are the "good" genes that normally control what kind of cell it is and how often it divides.
When a proto-oncogene mutates (changes) into an oncogene, it becomes a "bad" gene that can become permanently turned on or activated when it is not supposed to be. When this happens, the cell grows out of control, which can lead to cancer.

32. Loss of cell cycle control
How cell division (and thus tissue growth) is controlled is very complex. The following terms are some of the features that are important in regulation, and places where errors can lead to cancer.
Cancer is a disease where regulation of the cell cycle goes awry and normal cell growth and behavior is lost.
Cdk (cyclin dependent kinase, adds phosphate to a protein), along with cyclins, are major control switches for the cell cycle, causing the cell to move from G1 to S or G2 to M.
MPF (Maturation Promoting Factor) includes the CdK and cyclins that triggers progression through the cell cycle.
p53 is a protein that functions to block the cell cycle if the DNA is damaged. If the damage is severe this protein can cause apoptosis (cell death).
p53 levels are increased in damaged cells. This allows time to repair DNA by blocking the cell cycle.
A p53 mutation is the most frequent mutation leading to cancer. An extreme case of this is Li Fraumeni syndrome, where a genetic a defect in p53 leads to a high frequency of cancer in affected individuals.
p27 is a protein that binds to cyclin and cdk blocking entry into S phase. Recent research (Nature Medicine 3, 152 (1997)) suggests that breast cancer prognosis is determined by p27 levels. Reduced levels of p27 predict a poor outcome for breast cancer patients.

33. Loss of Cell Cycle Controls in Cancer Cells
Do not respond normally to the body’s control mechanisms
Form tumors
P53 is a tumor suppressor protein that in humans is encoded by the TP53 gene
Ras proteins also play a role in cell growth and division. Overactive Ras signaling can ultimately lead to cancer
(rat sarcoma)
BRCA1 and BRCA 2 are tumor-suppressor genes expressed in the cells of breast and other tissue, where it helps repair damaged DNA, or destroy cells if DNA cannot be repaired. If BRCA itself is damaged, damaged DNA is not repaired properly and this increases risks for cancers

34. Malignant tumors invade surrounding tissues and can metastasize
Exporting cancer cells to other parts of the body where they may form secondary tumors
Tumor
Glandular
tissue
Cancer cell
Blood vessel
Lymph vessel
Metastatic Tumor
A tumor grows from a single cancer cell. 1
Cancer cells invade neighboring tissue. 2
Cancer cells spread through lymph and blood vessels to
other parts of the body. 3
A small percentage of cancer cells may survive and establish a new tumor in another part of the body. 4
Figure 12.19

35. Meiosis
Concept 13.3: Meiosis reduces the number of chromosome sets from diploid to haploid
Meiosis takes place in two sets of divisions, meiosis I and meiosis II
Animated comparison between mitosis and meiosis

36. Overview
Meiosis I
Replicates the diploid number of chromosomes and recombines them randomly
Meiosis II
Reduces the number of chromosomes from diploid to haploid
Narrated animation of the stages of meiosis

37. Interphase and meiosis I
Centrosomes
(with centriole pairs)
Sister
chromatids
Chiasmata
Spindle
Tetrad
Nuclear
envelope
Chromatin
Centromere
(with kinetochore)
Microtubule
attached to
kinetochore
Tertads line up
Metaphase
plate
Homologous
chromosomes
separate
Sister chromatids
remain attached
Pairs of homologous
chromosomes split up
Chromosomes duplicate
Homologous chromosomes
(red and blue) pair and exchange
segments; 2n = 6 in this example
INTERPHASE
MEIOSIS I: Separates homologous chromosomes
PROPHASE I
METAPHASE I
ANAPHASE I
Figure 13.8

38. Telophase I, cytokinesis, and meiosis II
TELOPHASE I AND
CYTOKINESIS
PROPHASE II
METAPHASE II
ANAPHASE II
TELOPHASE II AND
MEIOSIS II: Separates sister chromatids
Cleavage
furrow
Sister chromatids
separate
Haploid daughter cells
forming
During another round of cell division, the sister chromatids finally separate;
four haploid daughter cells result, containing single chromosomes
Two haploid cells
form; chromosomes
are still double
Figure 13.8

39. A Comparison of Mitosis and Meiosis
Meiosis and mitosis can be distinguished from mitosis by three events in Meiosis l
Synapsis and crossing over
Homologous chromosomes physically connect and exchange genetic information
Tetrads on the metaphase plate
At metaphase I of meiosis, paired homologous chromosomes (tetrads) are positioned on the metaphase plates
Separation of homologues
At anaphase I of meiosis, homologous pairs move toward opposite poles of the cell
In anaphase II of meiosis, the sister chromatids separate
Flash animation of these events

40. Daughter cells of meiosis II
A comparison of mitosis and meiosis
Figure 13.9
MITOSIS
MEIOSIS
Prophase
Duplicated chromosome
(two sister chromatids)
Chromosome
replication
Parent cell
(before chromosome replication)
Chiasma (site of
crossing over)
MEIOSIS I
Prophase I
Tetrad formed by
synapsis of homologous
chromosomes
Metaphase
Chromosomes
positioned at the
metaphase plate
Tetrads
Metaphase I
Anaphase I
Telophase I
Haploid
n = 3
MEIOSIS II
Daughter
cells of
meiosis I
Homologues
separate
during
anaphase I;
sister
chromatids
remain together
Daughter cells of meiosis II n
Sister chromatids separate during anaphase II
Anaphase
Telophase
Sister chromatids
separate during
anaphase 2n
Daughter cells
of mitosis
2n = 6

41. Meiosis leads to greater genetic variation in offspring
Concept 13.4: Genetic variation produced in sexual life cycles contributes to evolution
Reshuffling of genetic material in meiosis (crossing over) animation
Produces genetic variation