Transcript Cell Death
AH Biology: Unit 1 Control of the Cell Cycle The cell cycle: summary G1 Interphase Cytokinesis M Mitosis S G2 The cell cycle: summary G1 Cytokinesis Telophase Anaphase Metaphase Prophase Mitosis Interphase M S G2 - Why does the progress of a cell through the cell cycle need to be monitored and regulated? - What features should an effective cell cycle control system possess? The cell cycle control system can be studied using model organisms • Yeast: Identification of mutations that arrest the cell cycle at specific points. Affected genes are known as cell-division-cycle (cdc) genes. The cell cycle contains control points G1 G1 checkpoint I M checkpoint (exit from M phase) M G2 checkpoint (entry to M phase) S G2 (entry to S phase) The cell cycle contains control points G1 G1 checkpoint I M checkpoint (initiation of anaphase) G2 checkpoint (assembly of spindle fibres) M S G2 (initiation of DNA replication) The control points are checkpoints for the cell cycle control system G1 M checkpoint: Are all chromsomes attached to spindle fibres? G2 checkpoint: Has all nuclear DNA been replicated? I M S G2 G1 checkpoint: Has the cell reached a sufficient size? Are environmental conditions favourable? If events have not been completed the control system receives signals and arrests the cell cycle. The G1 checkpoint • Timing: Towards the end of G1 phase. • Controls: Entry to S phase (triggers the initiation of DNA replication). • Assesses: Cell size and environmental conditions. • Purpose: Ensures that sufficient cell growth has occurred and environmental conditions are favourable for proliferation. What could happen to a yeast cell whose G1 checkpoint mechanism has been inactivated? With nutritional cell cycle control Cell size Without nutritional cell cycle control Nutrient supply reduced Time In multicellular organisms the G1 checkpoint operates through intracellular and extracellular signals Fibroblast grown in culture with adequate nutrient supply and serum Cell progresses through cycle and proliferates Fibroblast grown in culture with adequate nutrient supply and plasma Cell cycle is arrested Serum contains a protein that can bind to cells and stimulate them to progress through the cell cycle. Extracellular signal molecules with this function are called mitogens. The most important decision • Cells may either proliferate or leave the cell cycle. • In the absence of mitogens cells enter a nondividing state called the G0 phase. • Cells can become terminally differentiated and remain in G0 permanently or re-enter the cell cycle when they receive appropriate signals. G0 G1 Reversibility depends on cell type Interphase Cytokinesis M Mitosis S G2 Some types of cell can proliferate continuously • Stem cells • Tumour cells Most liver cells exist in a reversible G0 phase G0 Normal hepatocyte: mitogenic signal absent G0 G1 G1 I I M Cell proliferation is stimulated by damage to liver M S G2 S G2 Red blood cells, neurons and skeletal muscle cells exist in a terminally differentiated G0 state The G2 checkpoint • Timing: End of G2 phase. • Controls: Entry to M phase (triggers assembly of mitotic structures). • Assesses: Completion of DNA replication. • Purpose: Ensures that all DNA is replicated so that daughter cells can each receive a complete copy of the genome and function correctly. The M checkpoint • Timing: During metaphase. • Controls: Exit from M phase (triggers anaphase and cytokinesis). • Assesses: Attachment of all chromosomes to spindle fibres. • Purpose: Ensures that each daughter cell receives the same chromosome complement as its parent when anaphase occurs. The M checkpoint All chromosomes attached to spindle fibres One chromosome is not attached to spindle fibres Cell cycle progresses: cell enters anaphase Cell cycle arrested until all chromosomes are properly attached Checkpoints operate through negative intracellular signals • The presence of unattached chromosomes generates signals that stop the cell from progressing to anaphase. The molecular mechanisms of cell cycle control The cell cycle is controlled by the activity of cyclin-dependent kinases (Cdks) Cdk inactive G1 Cdk active M S G2 Cdk active Cdk inactive The cell cycle control system can be studied using model organisms • Spisula: a mollusc used in the study of protein synthesis (eg of cyclins) in embryonic cells. A time course of intracellular cyclin protein Relative level of cyclin protein Mitosis Mitosis Time Mitosis The activity of Cdks is regulated by cyclins Cyclin binding Inactive Cdk Cdk with protein kinase activity (cyclin–cdk complex) Different cyclins bind to Cdks at different phases of the cell cycle - The binding of G1-cyclins allows a cell to pass through the G1 checkpoint. - The binding of S-cyclins allows a cell to initiate DNA replication in the S phase. - The binding of M-cyclins promotes the events of mitosis. The activation of cyclin-Cdk complexes triggers cell cycle events G1-Cdk G1 M M-Cdk Mitosis triggered S G2 S-Cdk DNA replication triggered A certain level of phosphorylation of target proteins results in the cell progressing to the next stage of the cycle. Active retinoblastoma protein (Rb) inhibits cell cycle progression G1 S Retinoblastoma is targeted by G1-Cdk Synthesis of S-cyclins Active G1-Cdk P Active Rb P Inactive Rb Active S-Cdk DNA replication What would be the consequence of a mutation to the gene that codes for the Rb protein? The cell cycle has checkpoints for DNA damage Mutagen In which part(s) of the cell cycle would you expect these checkpoints to occur? What should a cell with damaged DNA do? DNA damage prior results in the activation of the protein p53 1. Damaged DNA 2. Protein kinase activity triggered P Unstable p53 Stable p53 Active p53 can promote the transcription of genes that induce cell cycle arrest P Regulatory DNA Expression of p21 gene p21 protein Cyclin–Cdk complex inactivated Cell arrested in G1 Active p53 can affect a cell in different ways Stimulates DNA repair P Promotes transcription of genes that induce cell cycle arrest Promotes transcription of genes that induce apoptosis What would be the functional consequences of an inability to activate p53? Ataxia telangiectasia: a genetic disease associated with an inability to activate p53 What could cause the development of telangiectases (small clusters of enlarged blood vessels)? Cell cycle review Interactive cell cycle animation. Control of cell cycle game on the Nobel Prize website (simulation). Animation of the action of the Rb and p53 proteins.