1. Chapter 12
The Cell Cycle

2. Cell Division: Key Roles
Reproduction
Growth and Development
Tissue Renewal

3. The Cell Cycle
From origin until split in two

4. Genome: cell’s genetic information
Somatic (body cells) cells
Gametes (reproductive cells): sperm and egg cells
Chromosomes: DNA molecules
Diploid (2n): 2 sets of chromosomes
Haploid (1n): 1 set of chromosomes

5. Chromatin: DNA-protein complex
Chromatids: replicated strands of a chromosome
Centromere: narrowing “waist” of sister chromatids
Mitosis: nuclear division
Cytokinesis: cytoplasm division
Meiosis: (reduction division) gamete cell division

6. The Mitotic Cell Cycle Interphase (90% of cycle) G1 phase-growth
S phase- synthesis of DNA
G2 phase- preparation for cell division

7. The Cell Cycle Mitotic phase Mitosis- nuclear division
Cytokinesis- cytoplasm division

8. Mitosis
Prophase
Prometaphase
Metaphase
Anaphase
Telophase

9. Prophase Chromosomes visible Nucleoli disappear Sister chromatids
Mitotic spindle forms
Centrosomes move

10. Prometaphase Nuclear membrane fragments
Spindle interaction with chromosomes
Kinetochore develops

11. Metaphase Centrosomes at opposite poles Centromeres are aligned
Kinetochores of sister chromatids attached to microtubules (spindle)

12. Anaphase Paired centromeres separate; sister chromatids liberated
Chromosomes move to opposite poles
Each pole now has a complete set of chromosomes

13. Telophase Daughter nuclei form Nuclear envelopes arise
Chromatin becomes less coiled
Two new nuclei complete mitosis

14. Cytokinesis
Cytoplasmic division
Animals- cleavage furrow

15. Plants- cell plate formation -vessicles from Golgi coalesce
Plants- cell plate formation -vessicles from Golgi coalesce. form cell membrane. Then Cell Wall forms

16. Cell Cycle Regulation Growth factors Density-dependent inhibition
Anchorage dependence

17. Mitosis in eukaryotes may have evolved from binary fission in bacteria
Prokaryotes reproduce by binary fission.
Most bacterial genes are located on a single bacterial chromosome which consists of a circular DNA molecule
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18. These copied regions begin to move to opposite ends of the cell.
In binary fission, chromosome replication begins at one point in the circular chromosome, the origin of replication site.
These copied regions begin to move to opposite ends of the cell.
Fig
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19. continues to grow until it reaches twice its original size.
inward growth of the plasma membrane,
dividing the parent cell into two daughter cells
Fig
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20. Cell Cycle Regulation Growth factors Density-dependent inhibition
Anchorage dependence

21. Introduction
The timing and rates of cell division in different parts of an animal or plant are crucial for normal growth, development, and maintenance.
The frequency of cell division varies with cell type.
Some human cells divide frequently throughout life (skin cells), others have the ability to divide, but keep it in reserve (liver cells), and mature nerve and muscle cells do not appear to divide at all after maturity.
Investigation of the molecular mechanisms regulating these differences provide important insights into how normal cells operate, but also how cancer cells escape controls.
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22. 1. A molecular control system drives the cell cycle
The cell cycle appears to be driven by specific chemical signals in the cytoplasm.
Example: Fusion of an S phase and a G1 phase cell, induces the G1 nucleus to start S phase.
Example: Fusion of a cell in mitosis with one in interphase induces the second cell to enter mitosis.
Fig
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23. The distinct events of the cell cycle are directed by a distinct cell cycle control system.
These molecules trigger and coordinate key events in the cell cycle.
The control cycle has a built-in clock, but it is also regulated by external adjustments and internal controls.
Fig
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24. Three major checkpoints are found in the G1, G2, and M phases.
A checkpoint in the cell cycle is a critical control point where stop and go signals regulate the cycle.
Three major checkpoints are found in the G1, G2, and M phases.
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25. The G1 checkpoint, the restriction point in mammalian cells, is often most important.
If the cells receives a go-ahead signal, it usually completes the cell cycle and divides.
If it does not receive a go-ahead signal, the cell exits the cycle and switches to a nondividing state, the G0 phase.
Most human cells are in this phase.
Liver cells can be “called back” to the cell cycle by external cues (growth factors), but highly specialized nerve and muscle cells never divide.
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26. Rhythmic fluctuations in the abundance and activity of control molecules pace the cell cycle.
Some molecules are protein kinases that activate or deactivate other proteins by phosphorylating them.
The levels of these kinases are present in constant amounts, but these kinases require a second protein (a cyclin) to become activated.
Level of cyclin proteins fluctuate cyclically.
The complex of kinases and cyclin forms cyclin-dependent kinases (Cdks).
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27. Cyclin levels rise sharply throughout interphase, then fall abruptly during mitosis.
Peaks in the activity of one cyclin-Cdk complex, MPF, correspond to peaks in cyclin concentration.
Fig a
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28. MPF (“maturation-promoting factor” or “M-phase-promoting-factor”) triggers the cell’s passage past the G2 checkpoint to the M phase.
1. MPF promotes mitosis by phosphorylating a variety of other protein kinases.
2. MPF stimulates fragmentation of the nuclear envelope.
3. It also triggers the breakdown of cyclin, dropping cyclin and MPF levels during mitosis and inactivating MPF.
Fig b
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29. The key G1 checkpoint is regulated by at least three Cdk proteins and several cyclins.
Similar mechanisms are also involved in driving the cell cycle past the M phase checkpoint.
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30. 2. Internal and external cues help regulate the cell cycle
Some signals originate inside the cell, others outside.
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31. A variety of external chemical and physical factors can influence cell division.
Particularly important for mammalian cells are growth factors, proteins released by one group of cells that stimulate other cells to divide.
For example, platelet-derived growth factors (PDGF), produced by platelet blood cells, bind to tyrosine-kinase receptors of fibroblasts, a type of connective tissue cell.
This triggers a signal-transduction pathway that leads to cell division.
Each cell type probably responds specifically to a certain growth factor or combination of factors.
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32. The role of PDGF is easily seen in cell culture.
Fibroblasts in culture will only divide in the presence of medium that also contains PDGF.
Fig
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33. In a living organism, platelets release PDGF in the vicinity of an injury.
The resulting proliferation of fibroblasts help heal the wound.

34. Growth factors appear to be a key in density-dependent inhibition of cell division.
Cultured cells normally divide until they form a single layer on the inner surface of the culture container.
If a gap is created, the cells will grow to fill the gap.
At high densities, the amount of growth factors and nutrients is insuffi- cient to allow continued cell growth.
Fig a
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35. Most animal cells also exhibit anchorage dependence for cell division.
To divide they must be anchored to a substratum, typically the extracellular matrix of a tissue.
Control appears to be mediated by connections between the extracellular matrix and plasma membrane proteins and cytoskeletal elements.
Cancer cells are free of both density-dependent inhibition and anchorage dependence.
Fig b
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36. 3. Cancer cells have escaped from cell cycle controls
Cancer cells divide excessively and invade other tissues because they are free of the body’s control mechanisms.
Cancer cells do not stop dividing when growth factors are depleted either because they manufacture their own, have an abnormality in the signaling pathway, or have a problem in the cell cycle control system.
If and when cancer cells stop dividing, they do so at random points, not at the normal checkpoints in the cell cycle.
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37. Cancer cell may divide indefinitely if they have a continual supply of nutrients.
In contrast, nearly all mammalian cells divide 20 to 50 times under culture conditions before they stop, age, and die.
Cancer cells may be “immortal”
HeLa cells from a tumor removed from a woman (Henrietta Lacks) in 1951 are still reproducing in cultures around the world today.
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38. The abnormal behavior of cancer cells begins when a single cell in a tissue undergoes a transformation that converts it from a normal cell to a cancer cell.
Normally, the immune system recognizes and destroys transformed cells.
However, cells that evade destruction proliferate to form a tumor - a mass of abnormal cells.
If the abnormal cells remain at the originating site, the lump is called a benign tumor.
Most do not cause serious problems and can be removed by surgery.
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39. Cell Cycle Controls Internal:
Internal Clock: fluctuations in cyclin proteins
Kinases (CDK’s
This complex initiates passage through a checkpoint

40. External Controls-able to override other
Growth Factors-may come from near-by or be secreted by distant glands; may be internally secreted and act on the cell
Anchorage dependence—need a substrate upon which to grow (platform)
Density Dependence (gap-stimulates production and release of growth factors from neighboring cells)

41. M = mitosis is when chromosomes become
The cell cycle is tightly controlled, both in terms of initiation and progression. The key features are that the cycle is ordered and unidirectional and there are checkpoints to make sure that each step is completed before the next one begins.
M = mitosis is when chromosomes become
condensed and separate and the cell divides:
visible changes. ~ 1 hr
G = Gap
G0 or resting state (can be forever) enters and
exits via G1
S = DNA Synthesis, ~10 hrs in 24 hr cell cycle
G2 is short gap before mitosis
The timing of gene expression of different cyclins results in phosphorylation of different target proteins at
different times.
Phosphorylation of the target initiates a chain of events leading to the activation of transcription factors
that promote transcription of genes required for the next stage of the cell cycle.
Sequential activation of different CDK-cyclins leads to sequential activation of transcription factors and,
in turn, progression of the cell cycle.
Various checkpoints serve as monitors of the

43. In a malignant tumor, the cells leave the original site to impair the functions of one or more organs.
This typically fits the “colloquial definition” of cancer as something that is not simple but possibly deadly.
Cancer cells often lose attachment to nearby cells, are carried by the blood and lymph system to other tissues, and start more tumors in a event called metastasis.
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44. Fig
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45. What are some the the side effects of treatment?
Treatments for metastasizing cancers include high-energy radiation and chemotherapy with toxic drugs.
These treatments target actively dividing cells.
What are some the the side effects of treatment?
Researchers are beginning to understand how a normal cell is transformed into a cancer cell.
The causes are diverse.
However, cellular transformation always involves the alteration of genes that influence the cell cycle control system.
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46. Cancer
Transformation
Tumor: benign or malignant
Metastasis

47. Extrinsic Controls
In addition to intrinsic controls exerted by CDKs and checkpoints, many external controls affect cell division. Both normal and abnormal cell cycles can be triggered by such extrinsic controls. For example, the hormone estrogen affects the development of a wide variety of cell types in women. Estrogen exerts its effects on a receptive cell by binding to a specific receptor protein on the cell's nuclear membrane. By binding to an estrogen receptor, estrogen initiates a cascade of biochemical reactions that lead to changes in the cell-cycle program. Normally, estrogen moves cells out of a resting stage into an active cell cycle.
In a different context, however, even normal levels of estrogen encourage the growth of some forms of breast cancer. In these cases, estrogen increases the speed with which the cancerous cells complete their cell cycles, leading to more rapid growth of the tumor. The most effective current drug therapies for such breast cancers block the estrogen receptor's estrogenbinding ability, making cells unresponsive to estrogen's proliferation signal. Thus, while estrogen itself does not cause breast cancer, it plays an important role in stimulating the growth of some cancers once they initiate by other mechanisms, such as by an unregulated CDK or a defect in a cell-cycle checkpoint.