1. The Cell Cycle “The Life of a Cell”
DNA Part III:
The Cell Cycle “The Life of a Cell”

2. Cells & Cell Reproduction
Cells must reproduce else they die. The "life of a cell" is termed the cell cycle. The cell cycle has distinct phases, which are called G1, S, G2, and M.
Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase.

3. The G1 Phase of the Cell Cycle
During this time organelles are reproducing, protein synthesis is occurring for growth and differentiation.
Because, transcription is occurring, the DNA is uncoiled.
This phase is the most variable, ranging from almost nothing to years.

4. The G1 Phase of the Cell Cycle
Most cells that differentiate will do so during this phase. Cells arrested in G1 may no longer have the capability of reproducing and are said to be in G0.
Certain cells in G0, however, when given some external or internal cues may revert back to G1 and enter the cell cycle again.
Nerve and muscle cells are usually arrested in G0.

5. S Phase of the Cell Cycle
The S or synthesis phase is the second phase of the cell cycle.
DNA uncoils
DNA replication occurs
Additional organelle replication occurs
This phase ensures that each emerging daughter cell will have the same genetic content as the mother cell.

6. G2 Phase of the Cell Cycle
The G2 or Gap 2 phase occupies the time from the end of S until the onset of mitosis.
During this time, the cell prepares for mitosis by making and organizing necessary proteins such as the tubulin needed to construct microtubules which used to make spindle fibers.
On the average this phase may take four hours.

7. M Phase or Mitosis
During mitosis the nucleus is replicated and the cytoplasm divides to produce two genetically identical daughter cells.
Remember that the DNA is replicated in S prior to mitosis.
The phases are triggered by the accumulation of cell signals.

8. The Amount of DNA Varies During the Cell Cycle
This graph represents the amount of DNA found in the cell during the cell cycle. What caused the changes? What happens at the end of Mitosis?

9. What Controls the Cell Cycle?
Pay attention to the 3 points in the cycle that serve as “checkpoints”

10. Internal Controls of the Cell Cycle
The control of the cell cycle is dependent on an accumulation of “signal molecules”.
Quite often these signal molecules must be phosphorylated in order to be functional. This are simple illustrations.

11. Cyclins vs. Kinases
Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase (Cdk) enzymes. Only with the cyclin is the Cdk active. Cyclins were originally named because their concentration varies in a cyclical fashion during the cell cycle.
A kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. .

12. Cyclins vs. Kinases
Certain cyclins are made at certain times during the cell cycle, and their concentration will rise and fall. Cyclins are also destroyed after they are no longer needed by the cell.
CDKs are not destroyed as they are only activated or deactivated.
Which cyclin affects which phase of the cycle? (you don’t have to memorize it but be able to read it in the graph!)

13. Kinases Phosphorylate Cell Signal Molecules
Certain kinases may have two forms (active and inactive).
Kinases are enzymes (proteins) that phosphorylate certain molecules or other enzymes.
Most cell cycle signals are phosphorylated by kinases.
Note: Kinases are a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. They are not to be confused with phosphorylases, which carry out phosphorolysis, the breaking of a bond using an inorganic phosphate group; or with phosphatases, which remove phosphate groups. (They all start to sound alike, don’t they?)

14. Cyclins Activate Kinases
Most cell cycle kinases are activated by molecules called cyclins. A kinase that requires a cyclin for activation is called a cyclin-dependent kinase or Cdk.

15. Cyclins Activate Kinases
The cyclin attaches to the Cdk. It is now called a cyclin-Cdk complex.
The complex that regulates the M (mitosis) portion of the cell cycle has 3 names (ugh!): the maturation-promoting factor, mitosis-promoting factor or M-Phase promoting factor. Luckily they are all referred to as “MPF”.
MPF is activated at the end of G2 by a phosphatase, which removes an inhibitory phosphate group added earlier.
The MPF is also called the M phase kinase because of its ability to phosphorylate target proteins at a specific point in the cell cycle and thus control their ability to function.

16. An example of how MPF initiates mitosis ….
MPF promotes the entrance into mitosis (the M phase) from the G2 phase by phosphorylating multiple proteins needed during mitosis. The steps follow:
The nuclear lamina depolymerizes causing it to disassemble which in turn causes the nuclear membrane to disassemble
Histone H1 binds to the DNA in chromosomes, causing the chromosomes to condense
Cytoskeletal proteins allow cytoskeletal filaments to assemble which leads to:
Formation of the mitotic spindle which separates the daughter chromosomes
formation of the cleavage furrow by microfilaments which allows cytokinesis (constricting the cell at the center) to occur resulting in the formation of two new cells
No – you don’t need to memorize the details – but a basic understanding about how one thing can lead to another is good!

17. Cyclins Activate Kinases
Once the CDK phosphory-lates certain signals, the cyclin is destroyed.
In the cell, the concentration of cyclins will rise and fall depending on the phase of the cell cycle.
When the cyclin is destroyed the Cdk returns to an inactive form (it is NOT destroyed!).

18. Cyclins Activate Kinases
Below is an example of how the M cyclin concentration affects MPF or M/CDK activity.

19. Cyclic Nature of Cyclins in the Cell Cycle
Revisit this graph.
The term cyclin was coined by R. Tim Hunt who discovered them while studying the cell cycle of sea urchins cells. He said he named after his hobby of cycling and at the time he did not realize the role of these molecules in the cell cycle. However due the cyclic nature of the concentration of these compounds and their role in the cell cycle, the name stuck. Cyclins (D, E, A, B) are named based on the their protein structure and conserved parts. Older classification of cyclins is based on their role in the cell cycle. Most introductory books use the terms like S cyclin and M cyclin.
R. Tim Hunt along with Leland Hartwell and Sir Paul Nurse received the Nobel Prize in Medicine in 2001 for their discovery and research in the role of cyclins and CDKs in the cell cycle.
This graph displays the cyclic nature of various cyclins in a given cell cycle. Notice again that a number of cyclins are involved in the cell cycle and that they activate a number of different kinases.

20. Random info ….
The term cyclin was coined by R. Tim Hunt who discovered them while studying the cell cycle of sea urchins cells. He said he named it after his hobby of cycling and at the time he did not realize the role of these molecules in the cell cycle. However due the cyclic nature of the concentration of these compounds and their role in the cell cycle, the name stuck. Cyclins (D, E, A, B) are named based on the their protein structure and conserved parts. Older classification of cyclins is based on their role in the cell cycle. Most introductory books use the terms like S cyclin and M cyclin.
R. Tim Hunt along with Leland Hartwell and Sir Paul Nurse received the Nobel Prize in Medicine in 2001 for their discovery and research in the role of cyclins and CDKs in the cell cycle.
Revisit this graph. 20 20

21. Different Types of Cyclins Function of Cyclin/CDK Complex
G1-CDK
Cyclin D
Drives the transition G1  S transition
G1/S-CDK
Cyclin E
Cyclins bind to CDK at the end of G1 and commits the cell to DNA replication.
S-CDK
Cyclin A
Cyclins bind the CDK during S and are necessary for the initiation of DNA replication
M-CDK
Cyclin B
Cyclins promote the events of Mitosis
These are some known cyclin/CDK complexes and their role in the cell cycle. (Don’t memorize – just understand the general functions)

22. Cyclins/CDKs Control the Cell Cycle
The cell cycle has a number of several external and internal checkpoints much like a timer or clock. Often, moving past these check points involves chemical signals that have been phosphorylated by cyclin-CDK complexes.
G1/S (R point) checkpoint is the primary determining factor for cell division to take place. Growth factors are affecting the cell cycle, and cells are growing. Once the R point is passed the DNA is going to be replicated. If a cell receives a go-ahead signal at this check-point, it will complete the cell cycle and divide. However, if the cell does not receive the go-ahead signal in G1, the switches to a nondividing state called G0. If the cell passes the G1 checkpoint, it is usually committed to cell reproduction.

23. Cyclins/CDKs Control the Cell Cycle
The G2 checkpoint represents the commitment for starting the process of mitosis. This checkpoint also ensures that the DNA has been replicated correctly. If the DNA has been damaged, then the cell does not continue to mitosis. Once the CDK and cyclin combine, it is called “maturation promoting factor" or “mitosis promoting factor” or MPF.
The M/spindle checkpoint ensures that all the chromosomes are attached to the spindle in preparation of mitosis. The separation of the chromatids is irreversible.
Once chromatids are replicated they are held together by a protein substance called cohesin protein. Another protein called seperase can destroy this protein but has two forms active and inactive. 23 23

24. Cell Cycle Recap .

25. External Signals also affect cell division
External Signals also affect cell division. Mammalian cells need certain nutrients and regulatory proteins. In addition external growth factors are can determine cell division in mammals. For example, when the skin has been damage (wound), platelets release a substance called platelet-derived growth factor (PDGF). This growth factor stimulate fibroblasts cells to start to reproduce and make scar tissue. 25 25

26. External Factors Also Influence the Cell Cycle
Cell reproduction and the healing of a wound.
Hemostasis - Bleeding is contained via blood clotting.
Inflammation - Bacteria and debris removed. Damaged platelets release platelet derived growth factors. These external growth factors signal fibroblast to start to reproduce and make new cells.
Proliferation - Fibroblast reproduce forming an extra cellular matrix
Remodeling - Extra collagen and cells that are not needed are removed.

27. Insert Animation from link on previous slide. Record only G1
Scroll over the bottom of the image in presentation mode and press play (the “Play” button on the screen is simply an image, thus inactive). 27 27

28. S of the Cell Cycle
Scroll over the bottom of the image in presentation mode and press play (the “Play” button on the screen is simply an image, thus inactive).
This phase ensures that each emerging daughter cell will have the same genetic content as the mother cell.
The average time for S is around 9 hours, if the cell cycle lasts 24 hours.
Be sure to connect this information to the previous PowerPoint on DNA replication. 28 28

29. G2 Phase of the Cell Cycle
Scroll over the bottom of the image in presentation mode and press play (the “Play” button on the screen is simply an image, thus inactive). 29 29

30. M Phase or Mitosis
Scroll over the bottom of the image in presentation mode and press play (the “Play” button on the screen is simply an image, thus inactive).
This animation ends with a summary of the entire process. 30

31. What Controls the Cell Cycle?
This serves as an introduction to the controls of the cell cycle. Emphasize the 3 points in the cycle that serve as “checkpoints”. 31 31