9.2 Cell cycle, disrupted

Learning Outcomes:2. Describe the events that occur during the cell cycle including DNA replication and mitosis.3. Explain how mutations contribute to errors in cell cycle regulation and cancerReminders: Do the “middle-of-the-term” survey in the assessment folder of VISTAResearch one disease for the criteria listed in the Midterm II Information page on VISTA

Cell division is regulated

Why could cell division be stimulated? –to form a certain structure while an organism is developing eg dividing root cells in a young dandelion seedling–to replace injured cells eg after a sunburn fried cells are replaced-to replace cells which die after a certain time period eg skin cells (shed continuously), red blood cells (live 120 days)Why could cell division be inhibited?–to prevent cells from becoming too crowded-once a cell is specialized into a very elaborate shape it no longer divides eg nerve cells

Cells are regulated at checkpoints during their cycleWhy? All the events in cell cycle must occur in a certain ordereg. Cells can’t do mitosis until all their DNA is replicated. This is checked. QUESTION: What else would a cell want to check?

- Is it big enough with enough energy and raw materials to carry out cell division?

QUESTION: If you want to make sure mitosis happens correctly, when would be a beneficial point to check that mitosis is proceeding correctly? (Hint: what is the purpose of mitosis?)Recall what happens: (Arrows = a,b,c,d,e) (c = d = anaphase, e = tilaphase)

D is correct answer. Want to make sure microtubules are attached to both sides of a chromosome’s centromere.

The phases of the cell cycle during which a cell is growing (G1, S, G2) are collectively called interphase. Cells spend 90% of their time in interphase versus 10% of their time in mitosis.

G0 usually happens to nerve cells. They stop dividing because they are so complicated

One more major checkpoint (in G1):Why would it exist? 1.-Cells must be a certain size before daughter cells would be large enough to function normally2.-Must have enough nutrientsQUESTION: What else should be checked?3.-DNA should be checked for damage before replication begins. p53 protein checks for DNA damage. If there is too much damage the cell arrests in G and then goes through programmed cell death

In multicellular organisms certain signals must be present to allow a cell to divide at all. Cell lacking these signals go into G0.Eg. Nerve cells (never divide) go into G0

Genes on chromosomesGenes carry the information to make all proteins in the cell. This includes all the enzymes which perform most chemical reactions in the cell. Proteins can also be structural like the protein tubulin – many subunits of tubulin make the microtubules.

One gene consists of a long sequence (~1000 to 10 000 nucleotides) on the DNA molecule. The sequence of nucleotides is read and translated into an amino acid sequence (protein). Each chromosome contains hundreds of genes, but at any one time a cell is only making proteins from some of the genes (not all). Which genes are actively making proteins depends on signals the cell is receiving.

For example, when a cell receives a signal that it is close contact with other cells (contact inhibition), genes will be stimulated that make proteins that prevent the cell from passing the G1 checkpoint so it will not divide.

Specific genes function to regulate or control the cell cycle by coding for growth factors or inhibitory factors.

Each sequence of three nucleotides codes for one amino acid that will link up to form a protein. For example, the nucleotide sequence ATG codes for the amino acid methionine. QUESTION: If you have 369 nucleotides…how many amino acids would be in the protein coded by this sequence? 123 Animo Acids (just divide by 3)

What happens if there is a mistake in the matching of bases during replication? Although cells have machinery to check for mistakes in DNA replication occasionally mistakes occur which are not fixed..they become mutations. One type of mutation occurs when one nucleotide could be substituted for another possibly changing one amino acid. Deletion of one or more nucleotides, or an insertion of one or more extra nucleotides could result in a shift in the reading of the three base code.

Challenge question: Why it is it a worse mutation to delete one nucleotide as opposed to three nucleotides? -> all the amino acids are different past the point of the deletion (Because the sequence then becomes corrupted). If 3 nucleotides are deleted, then the sequence is the same as before minus the 1 acid generated by those nucleotides (assuming they are in sequence)

Cancer cells are dividing out of control. They don’t respond to the normal signals regulating cell division (ignore checkpoints) and instead divide continuously.

Mutations in genes which regulate the cell cycle could lead to cancer.Proto-oncogenes: genes which stimulate cells to divide under certain circumstances in normal cells eg. genes which allow cells to pass through the G1 checkpoint

Mutations in these genes could cause cells to divide all the time…if this happens then the mutant genes are called oncogenes (from Greek ogkos = tumour, mass) See Fig. 5.12 (left and below)

FYI: p53 is a gene of particular interest for cancer researchers because it is found mutant in half of all human cancers. There are rare inherited mutations in p53 (Li-Frameni syndrome). Non-genetic problems can occur with the p53 protein as well. For example, the p53 protein can be inactivated by HPV, a DNA tumour virus. Also, some sarcomas (type of tumours) produce another protein mdm-2 which binds to and inactivates p53 protein allowing sarcoma cells to continue dividing while ignoring cell cycle controls.

Other causes of cancer:Viruses eg. HPV (human papilloma virus...can bind to an inactivate p53)Carcinogens: molecules which can promote rapid unregulated cell division or cause DNA damage leading to mutations egs.: compounds in grilled food like barbequed steaks, compounds such as acrylamide in deep-fried food like potato chips and french fries, compounds in tobacco smoke, formaldehyde (a preservative used in embalming), vinyl chloride (use to make PVC), asbestos, dioxins etc. Note: cells of the gastrointestinal tract are shed regularly which may prevent mutations from building up in those cells. Also those same cells contain many enzymes which can detoxify some carcinogens.

tumour-supressor genes: genes which inhibit cells from dividing and/or cause cells to dieeg1. gene which could normally keep cells in G0 eg2. gene which causes cells with badly damaged DNA to die, such as p53Mutations in tumour-suppressor genes could also cause cells to divide all the time.

The main idea of this lecture is that overriding cell cycle checkpoints can lead to cancerQUESTION: What if a cell ignores the M phase checkpoint? What mistakes can occur?

What is the consequence of missing an entire chromosome or having an extra chromosome if there is a problem in mitosis?One chromosome carries hundreds of genes. Genes containing the instructions to make proteins which perform many functions in cells and organisms. The loss or gain of a chromosome could cause a cell to make too many or too few of some kind of proteins so that the cell doesn’t function normally. If this is only one cell in a tissue there may be no consequence to the large multicellular organism. The cell may die on its own or be killed by the immune system. QUESTION: What cells of the human immune system target and destroy abnormal human cells?

It is interesting to note that many cancer cells have significant changes in their genome…did a change in the number of chromosomes cause them to become cancerous or did they become cancerous due to some smaller problem and then later