Control of Cell Cycle Unit 2 Part f III
How often do cells divide and why? The timing and rate of cell division in different parts of the plant or animals are crucial to normal growth, development and maintenance. Frequency depends on the type of cell human skin cells frequently throughout life Liver maintains ability to divide but only do it when required Nerve/Muscle do not divide
Why the Differences? Regulation occurs at the molecular level. 100 µm.1 Figure 12.2 A (a) Reproduction. An amoeba, a single-celled eukaryote, is dividing into two cells. Each new cell will be an individual organism (LM).
Control System The cell cycle control system is a cyclically operating set of molecules in the cell that both triggers and co-ordinates key events in the cell cycle. Internal controls which are built in but there are external adjustments that take place.
Cell Cycle Checkpoints A checkpoint in the cell is a critical point where stop and go-ahead signals can regulate the cycle. The signals report whether crucial cellular processes up to that point have been completed correctly, and so whether or not the cell cycle should proceed Checkpoint also register signals from outside the cell.
http://outreach.mcb.harvard.edu/animations/ checkpoints.swf Normal Cell Division Animation
G 1 Checkpoint Occurs towards end of G1 phase If go ahead is received at G1 checkpoint then the cell cycle will most likely proceed and division will take place Enough cell growth needs to have occurred before the cell can enter the S phase of interphase. If NOT, it will exit switching into a non dividing state call the G0 phase. Most cells in the human body are actually in G0 phase e.g. Nerve and Muscle cells
G2 Checkpoint Occurs at the end of G2. Where DNA replication is assessed in order for the cell cycle to continue. Controls entry into mitosis. Ensures new daughter cell receives all the genetic information needed.
M Checkpoint Occurs during metaphase and before anaphase of mitosis Checks if the chromosomes have aligned to the spindle
G 1 checkpoint Control system S G 1 M G 2 M checkpoint Figure 12.14 G 2 checkpoint
Where cell cycle stops until it receives the go ahead signal G 0 G 1 checkpoint G 1 G 1 Figure 12.15 A, B (a) If a cell receives a go-ahead signal at the G 1 checkpoint, the cell continues on in the cell cycle. (b) If a cell does not receive a go-ahead signal at the G 1 checkpoint, the cell exits the cell cycle and goes into G 0, a nondividing state.
Cell Cycle Regulation Cell cycle needs regulation to ensure events proceed in the correct order and that each event is completed before the next event starts. To understand this we need to examine the types of molecules that make up the cell cycle control system Certain molecules determine the sequence of cell cycle.
EXPERIMENTS In each experiment, cultured mammalian cells at two different phases of the cell cycle were induced to fuse. Experiment 1 Experiment 2 S G 1 M G 1 RESULTS S S M M When a cell in the S phase was fused with a cell in G 1, the G 1 cell immediately entered the S phase DNA was synthesized. When a cell in the M phase was fused with a cell in G 1, the G 1 cell immediately began mitosis a spindle formed and chromatin condensed, even though the chromosome had not been duplicated. Figure 12.13 A, B CONCLUSION The results of fusing cells at two different phases of the cell cycle suggest that molecules present in the cytoplasm of cells in the S or M phase control the progression of phases.
Cell Cycle Clock Cell cycle control molecules pace the sequence of events of the cell cycle. Their abundance and activity can cause rhythmic fluctuations.
Cyclins and Cyclin Dependent Kinases Protein kinase enzymes activate or inactivate other proteins by phosphorylating them. Two groups of proteins, cyclins and cyclindependent kinases (Cdks), are responsible for promoting the cell cycle. Particular protein kinases give the go-ahead signals at G 1 and G 2 checkpoints.
The kinases that drive the cell cycle are actually present at a constant concentration in a growing cell, but most of the time they are in an inactive form. To be active they must be attached to a protein called cyclin. When they are attached they are called cyclin-dependant kinases or Cdks. The activity of Cdk rises and falls with changes in the concentration of its cyclin.
Mitosis Promoting Factor (MPF) Is a Cdk. One of the first to be discovered Promotes entry into mitosis Regulatory protein involved in G2 checkpoint. Cyclins accumulate during G2 and associate Cdk molecules, the resulting MPF complex initiates mitosis by phosphorylating a variety of proteins
1. By the G2 checkpoint (red bar), enough cyclin is available to produce many molecules of MPF. 2. MPF promotes mitosis by phosphorylating various proteins and including other enzymes. 3. One effect of MPF is the initation of a sequence of events leading to the breakdown of its own cyclin. The Cdk component of MPF is recycled. Its kinase activity will be restored by association with new cyclin that cumulates during interphase.
As the cell size increases during G 1 cyclin proteins accumulate and combine with kinases to form Cdk. At the G 1 checkpoint there is another protein involved called retinoblastoma protein (Rb) which is to prevent excessive cell growth by inhibiting cell cycle progress until the cell is ready to divide.
Retinoblastoma Retinoblastoma restricts the cells ability to replicate DNA by preventing progression from the G 1 to the S phase of the cell cycle. When the cell is ready to divide, the retinoblastoma is phosphorylated by Cdk s where it becomes inactive and allows the cell cycle to continue.
When the cyclins that accumulate during G 2 associate with Cdk molecules, the resulting MPF complex initates mitosis, by phosphorylating a variety of proteins.
The retinoblastoma protein undergoes cell cycleregulated phosphorylation. In early G1 the protein is hypophosphorylated and its phosphorylation increases as cells progress through the cell cycle. During mitosis phosphates are removed and the cycle of phosphorylation starts over during the next G1 phase. During mitosis phosphates are removed and the cycle of phosphorylation starts over during the next G1 phase.
Play http://www.nobelprize.org/educational/medic ine/2001/index.html
Negative Regulators Negative regulator molecules (Rb, p53 and p21) act primarily at the G1 checkpoint and prevent the cell moving forward to division until damaged DNA is repaired.
p53 Any damage to DNA by high-energy radiation or toxic chemicals triggers the expression of the p53 gene. Once made, the p53 functions as a transcription factor for several genes. It often activates a gene whose product halts the cell cycle by binding to the Cdks, allowing time for the cell to repair the DNA. P53 halts cell cycle and recruits enzymes to repair damaged DNA. If the DNA cannot be repaired, p53 triggers apoptosis to prevent duplication
The p53 gene therefore prevents a cell from passing on mutations due to DNA damage. If mutations do accumulate and the cell survives through many divisions cancer may occur.
Abnormal Cell Division http://outreach.mcb.harvard.edu/animations/ checkpoints.swf Animation on Abnormal Cell Division
Cancer Cells Cancer cells do not exhibit anchorage dependence or density-dependent inhibition. (b) Cancer cells. Cancer cells usually continue to divide well beyond a single layer, forming a clump of overlapping cells. Figure 12.18 B 25 µm
Malignant tumors invade surrounding tissues and can metastasize Exporting cancer cells to other parts of the body where they may form secondary tumors Tumor Lymph vessel 1 A tumor grows from a single cancer cell. Figure 12.19 Glandular tissue Cancer cell 2 Cancer cells invade 3 Cancer cells spread 4 A small percentage of neighboring tissue. through lymph and blood vessels to other parts of the body. Blood vessel Metastatic Tumor cancer cells may survive and establish a new tumor in another part of the body.
Research Types of mutations asosociated with cancer. For example the influence of environmental factors and viruses, the conversion of protooncogenes into oncogenes and mutation in tumour suppressing genes.