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The Cell Cycle

Define the cell cycle, describe its various stages and say how it is regulated

What is the cell cycle? The interval between 2 successive mitotic divisions resulting in the production of 2 daughter cells
What must a cell do to divide? GROW, copy its genetic material (DNA) and physically SPLIT into 2 daughter cells
Why is the cell cycle a cycle, rather than a linear pathway? Because at the end of each cycle the two daughter cells can start the exact same process again from the beginning
In eukaryotic cells/cells with a nucleus, how many major phases of the cell cycle is there? 2
Name the two phases of the cell cycle Interphase and the Mitotic Phase
What happens during interphase? The cell GROWS and makes a COPY of its DNA
What happens during the mitotic phase? The cell SEPARATES its DNA into 2 sets and DIVIDES its cytoplasm, forming two new cells
What 3 phases make up interphase? The G1, S, and G2 phases together
What does the prefix 'inter' mean and what does this reflect? Between, reflecting that interphase takes place between one mitotic (M) phase and the next
What happens during the G1 phase (aka the first gap phase)? The cell grows physically LARGER, COPIES ORGANELLES, and makes the molecular building blocks it will need in later steps
What happens in the S phase? The cell synthesizes a complete COPY OF DNA in its nucleus. It also duplicates a microtubule-organizing structure called the centrosome. The centrosomes help SEPARATE DNA during M phase
What do the centrosomes help do during mitosis? The centrosomes help separate DNA during the M phase
What happens during the second gap phase, or G2 phase and when does it end? The cell grows more, makes proteins and organelles, and begins to reorganize its contents in preparation for mitosis. G2 phase ENDS when MITOSIS BEGINS
What happens during the mitotic (M) phase? The cell DIVIDES its copied DNA and CYTOPLASM to make 2 NEW CELLS
What 2 processes does the M phase involve? 1. Mitosis 2. Cytokinesis
What happens in mitosis? The nuclear DNA of the cell CONDENSES into VISIBLE CHROMOSOMES and is PULLED APART by the MITOTIC SPINDLE, a specialised structure made out of microtubules
What 4 stages does mitosis take place in? 1. Prophase (sometimes divided into EARLY PROPHASE and PROMETAPHASE) 2. Metaphase 3. Anaphase 4. Telophase
What happens in cytokinesis? The cytoplasm of the cell is split in 2, making 2 new cells
When does cytokinesis usually begin? Just as mitosis is ending, with a LITTLE OVERLAP
How does cell division occur in animals? Cell division occurs when a band of CYTOSKELETAL FIBRES called the CONTRACTILE RING contracts inward and pinches the cell in two, a process called CONTRACTILE CYTOKINESIS. The indentation produced as the ring contracts inwards is the CLEAVAGE FURROW
What do some types of cells do? E.g.? Some types of cells divide rapidly, and in these cases the daughter cells may IMMEDIATELY UNDERGO ANOTHER ROUND OF CELL DIVISION E.g. many cell types in an early embryo divide rapidly, and so do cells in a tumour
How long does each cell take to go through the cell cycle? Human cells? Different cells take DIFFERENT LENGTHS OF TIME to complete the cell cycle. A typical human cell might take about 24hrs to divide
How long do certain mammalian cells take to divide? Fast-cycling mammalian cells, like the ones that LINE THE INTESTINE, can complete a cycle every 9-10hours when they're grown in culture
What sort of cells enter the GO phase and what do they do? Some types of cell DIVIDE SLOWLY or NOT AT ALL These cells may exit the G1 phase and enter a RESTING STATE called G0 PHASE
What is a cell doing in GO? A cell is NOT ACTIVELY PREPARING TO DIVIDE, it's just doing its job E.g. it might conduct signals as a neuron or store carbohydrates as a liver cell
Are all cells in GO for eternity or what? Give examples. G0 is a permanent state for some cells, while others may RE-START DIVISION if they get the right signals • Erythrocytes PERMANENTLY IN G0 • Fibroblasts in dermis in G0 but re-enter the cell cycle during wound healing
What is cancer? a neoplastic disease the natural course of which is often fatal
What does neoplasm mean? tumour = new and abnormal growth, specifically one in which cell multiplication is uncontrolled and progressive
List the tumour progression stages Normal - Dysplastic - Benign - Pre-malignant - Malignant (cancer)
What does dysplastic mean? an abnormal growth but not a tumour
What does pre-malignant mean? histologically malignant but not spread around the body
How long is the G1 phase? 10 hours
How long is the S phase? 7.5 hours
How long is the G2 phase? 3.5 hours
How long is the M phase? 1 hour
How long is the generation time of the cell cycle? 22 hours
What is the restriction point? (R)? a point in G1 of the animal cell cycle at which the cell becomes “committed” to the cell cycle and after which extracellular proliferation stimulants are no longer required
What does the checkpoint between G1 and S check for? check for CELL SIZE and FAVOURABLE ENVIRONMENTAL CONDITIONS
What is the checkpoint between G2 and M to check for? damaged or unduplicated DNA and unduplicated centrosomes
What is a checkpoint with regards to the cell cycle? point in the eukaryotic cell division cycle where progress through the cycle can be halted until conditions are suitable for the cell to proceed
What is the cell monitored for? The cell is monitored for favourable external environment (presence of growth factors). Favourable internal environment (sufficient growth)
What internal things are checked for? DNA damage, Replication errors, Spindle formation, Chromosome integrity
What is the restriction point and when is it? the point at G1 at which commitment occurs and the cell no longer requires growth factors to complete the cell cycle. This point has been mapped at 2-3 hours prior to the onset of DNA synthesis.
What is the restriction point dependent on and what acts as the gatekeeper at the restriction point? Dependent on the accumulation of cyclin D. Retinoblastoma (RB) protein acts as a gatekeeper at the restriction point.
What is the G0 phase? quiescence - when the cell is not actively proliferating and needs an external stimulus to re-enter the cell cycle Note: it may still be active in terms of carrying out its differentiated function!!
What are cdks? kinases = enzymes that add a phosphate group to substrate (target)
What does phosphorylation of cdk substrates lead to? regulation of the cell cycle, e.g. phosphorylation of nuclear lamins leads to disintegration of nuclear membrane which facilitates mitosis
How does a normal cell know how to divide? Firstly external signals for growth (e.g. hormones, peptide growth factors) need to bind to cell surface (plasma membrane) receptors - e.g. epidermal growth factor receptor (helps control division of keratinocytes) e.g. HER2 (human EGF R2)
What happens after external signals bind to cells? After external signal internal molecules activated in turn, e.g. ones coding for cyclins, which switch on cdks, allowing cell to go through cell cycle, and DNA polymerase - need that for the S phase
What are proto-oncogenes and what do they code for? normal cellular genes, They code for proteins needed for normal cell division/proliferation
What can specific mutations in proto-oncogenes cause? uncontrolled cell division/proliferation
What are specific mutated proto-oncogenes called? oncogenes
What does activation of proto-oncogenes allow? allows cells to bypass the need for extracellular growth signals
How many alleles need to acquire an activating mutation in order for a proto-oncogene to become an oncogene? Only one allele (copy) of a proto-oncogene needs to acquire an activating mutation for it to become oncogenic; the resulting oncogene is 'dominant-acting'
What do oncogenes code for? 1. A hyperactive version of the protein product OR 2. The normal protein product, but: -in abnormal quantities -at the wrong time -in the wrong cell type
What is a point mutation? a type of mutation that causes a single nucleotide base substitution, insertion or deletion of the genetic material, DNA or RNA - e.g patients with colon cancer have a mutation in a variation of ras called ki-ras
Deletion? e.g. if you deleted the regulatory site of a protein it could grow out of control
What could chromosomal rearrangement in oncogenes give rise to? a HYBRID PROTEIN - e.g. the bcr-abl protein that's associated with Chronic Myelogenous Leukaemia (CML)
What can happen to the regulatory region of a gene? can mutate • Gene amplification can happen, where you end up getting multiple copies of the protein being made, e.g. HER2 oncogene in breast carcinoma • Herceptin is a monoclonal antibody and it blocks the HER2 receptor so stops cells growing too much
What is chromosomal rearrangement? where the control region of one gene connects to the protein coding region of another gene • E.g. Ig-myc • Myc is a proto-oncogene - the proto-oncogene is put besides a very strong promoter which is switched on all the time
Who does retinoblastoma occur in? occurs in children - develop the tumour around 4, Scientists noticed that in some kids it developed around 2 years old, Knudson's 'Two-hit' hypothesis - some children already have a hereditary fault in the causative gene, so only need one more mutation
What won't you have in a normal cell with no growth factors? you won't have cdks activated, you won't have retinoblastoma phosphorylated, it will stop transcription of genes you need for progression around the cell cycle, and the cell cycle will be arrested so the cell will not divide
What happens if you add external growth factors to a cell? you end up with phosphorylated retinoblastoma, which allows DNA polymerase etc to be switched on and you get normal cell growth - the cell can pass the restriction point
What might happen to a molecule in the signal transduction pathway? A molecule in the signal transduction pathway may be mutated which could also lead to phosphorylated retinoblastoma, so cell with activated proto-oncogene passes restriction point
What happens if part of the retinoblastoma is missing? If part of the retinoblastoma is missing - the part that would bind to the transcription factors, needed to switch on the genes for cell growth, the cell with mutated Rb still passes the restriction point
What is a telomere? a region of repetitive nucleotide sequences at each end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighbouring chromosomes
Can normal cells divide indefinitely? There is a limit to the number of times normal cells can divide
What are structures that can stop cells dividing called? TELOMERES Telomeres prevent end-to-end fusion of chromosomes
What happens if the telomeres are rubbed away? What happens to them every time a cell divides? If they are rubbed away the chromosomes could stick together and then the cell dies • Telomeres are a particular sequence of DNA - TTAGGG • They are gradually eroded every time a cell divides - eventually cells die, so they have a limited lifespan
What is telomerase? enzyme that repairs the telomeres of the chromosomes so that they do not become progressively shorter during successive rounds of chromosome replication
What happens if the telomerase enzyme is switched on all the time? In tumour cells if the telomerase enzyme is switched on all the time it's going to keep adding more telomeres onto the cell, which makes the cell immortal - it can keep growing forever
What might constant telomerase expression lead to? Constitutive telomerase - expression may lead to immortalisation of cells
What way involving a proto-oncogene can lead to uncontrolled cell proliferation? 1. Activation of a proto-oncogene whose normal role is to stimulate cell proliferation
What to do with tumour suppressor genes can lead to uncontrolled cell proliferation? 2. Loss of both copies of a tumour suppressor gene whose normal function is to act as a brake on cell proliferation
What to do with telomerase leads to uncontrolled cell proliferation? 3. Constitutive expression of telomerase, leading to immortalisation of the cell
Name a DNA repair enzyme BRCA1 tsg
If there's a mutation in the repair enzyme...? If there's a mutation in that repair enzyme more likely to have a mutation that develops cancer
What are DNA repair enzymes and what can they do? Proteins needed for 'quality control' of cell, can induce apoptosis of damaged cells
What is P53? a tumour suppressor gene - 'guardian of the genome'
What else is P53? a tetrameric transcription factor - it has 4 subunits
How does P53 work? a 'dominant negative' manner - you only need 1 of the allele being mutated to make abnormal protein units, changes gene function
What will low levels of P53 switch on and what is it? switch on p21 cyclin-dependent kinases (cdk inhibitor). • Low levels of P53 result in p21 expression and inhibits cell cycle progression, which allows for DNA repair
What does high levels of P53 do? promotes apoptosis, and results in apoptosis
What is true in about 50% of human cancers? P53 is inactivated in about 50% of all human cancers
What does P53 do inside the cell and what does this stimulate? In the cell, P53 protein binds DNA, which stimulates another gene to produce a protein called p21 that interacts with a cell-division stimulating protein (cdk2). When p21 is complexed with cdk2 the cell can't pass through to the next stage of division
What can mutant P53 no longer do? no longer bind DNA in an effective way and, as a consequence the p21 protein is not made available to act as the 'stop signal' for cell division. Thus, uncontrolled cell division takes place, which leads to tumours being formed
How does a tumour initially get nutrients and what is angiogenesis? Tumour initially gets nutrients via diffusion. Angiogenesis = the development of new blood vessels
What can't tumours do without a blood supply and what happens to them? What does this stimulate the tumour to do? • Tumours can't grow beyond 1-2mm diameter without blood supply • Tumour becomes hypoxic (low oxygen) • Stimulates tumour cells to produce vascular endothelial growth factor, which encourages endothelial cells to multiply and grow towards tumour
What are 80% of human cancer cells? How are epithelial cells held together and what do cancer cells show? epithelial origin (carcinomas). Epithelial cells are held together by a cell adhesion molecule called E-cadherin .Often, cancer cells show deceased/dysfunctional E-cadherin - epithelial cells become more like mesenchymal cells - transition
When is the synthesis of cyclin D initiated and what does it drive? during G1 and drives the G1/S phase transition • In proliferating cells, the cyclin D-cdk4/6 complex accumulation is very important for cell cycle progression
What does the cyclin D-cdk4/6 complex do?
What does cyclin E do? binds to G1 phase cdk2, which is required for the transition from G1 to S phase of the cell cycle Cyclin E/cdk2 phosphorylates retinoblastoma protein (Rb) to promote G1 progression
What will hyper-phosphorylated Rb do? Hyper-phosphorylated Rb will no longer interact with E2F transcriptional factor, thus release it to promote expression of genes that drive cells to S phase through G1 phase
What happens as the cell passes from G1 into S phase? cyclin A associates with cdk2, replacing cyclin E This complex makes chromatin capable of replication. As the amount of cyclin A/cdk2 complex increases, the complex initiates DNA replication Cyclin A/cdk2 complex involved in S phase progression
What is cyclin B necessary for and what is it? a MITOTIC CYCLIN - cyclin B levels start to rise in G2 in preparation • Cyclin B is necessary for the progression of the cells into and out of M phase of the cell cycle
What is cyclin B also known as? Maturation Promoting Factor (MPF)
What does ativation of the cdk1-cyclin B complex do? brings the onset of mitosis. Binding of cdk1 to cyclin B is essential for activation of the kinase. The degradation of the cyclin B subunit of cdk1/cyclin B is required for inactivation of the kinase and exit from mitosis
What are Cyclin-dependent kinase inhibitors (CKIs)? small proteins that block cyclin/CDK activity either by forming an inactive complex or by acting as a competitive CDK ligand
Give examples of Cyclin-dependent kinase inhibitors (CKIs) P21 CIP, p27 KIP, p16 INK
Give some effects of Cdk1/cyclin B complex (Maturation Promoting Factor) • Nuclear envelope destroyed - lamins line the inside of the nuclear membrane, Chromosome condensation - histones help - large protein complexes called condensins play a large role, Spindle formation - microtubule-associated proteins (MAPS) did this
What do mutations in tumour suppressor genes result in? Mutations in tumour suppressor genes result in loss of function, allowing cell cycle to proceed
What does RB do? inhibits cell cycle progression until appropriate conditions are met - it regulates the E2F transcription factor, puts 'brakes' on E2F activity (S phase gene expression)
What does P53 do? inhibits the cell cycle to allow for DNA repair (p21 transcription) or induces apoptosis
What are RB and P53? Tumour suppressor genes
Created by: Aimee76